Predictors for the 5-year risk of serious infections in patients with rheumatoid arthritis treated with anti-tumour necrosis factor therapy: a cohort study in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry.

OBJECTIVE: The use of TNF inhibitors leads to an increased risk of serious infections in RA. Predicting this risk would facilitate the prevention of serious infections. The objective of this study was to identify which factors are predictive of the increased risk of serious infections in RA patients treated with TNF inhibiting therapy. METHODS: Data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry of 2044 patients with RA were used for the analyses. Data were censored at stopping TNF inhibitors or end of observation time up to 5 years. Univariate and multivariate analysis of baseline variables was performed using Cox regression with time to the first serious infection as dependent variable. RESULTS: During a follow-up time of 5 years, 128 of 2044 (6.3%) patients developed a first serious infection with a total of 141 serious infections. The incidence rate in the first year after start of TNF inhibiting therapy was 4.57 first serious infections per 100 patient-years and 2.91 per 100 patient-years over 5 years. Age, corticosteroid use, visual analogue scale (VAS) pain, HAQ, tender joint count 28 joints (TJC28) and the presence of comorbidities were significant predictors for developing a serious infection during TNF inhibiting therapy in the multivariate model. CONCLUSION: Age, corticosteroid use, VAS pain, HAQ, TJC28 and the presence of comorbidities all at baseline were significant predictors for developing a serious infection during TNF inhibiting therapy in RA patients.

The provisional ACR/EULAR definition of remission in RA: a comment on the patient global assessment criterion.

OBJECTIVES: The provisional ACR/European League Against Rheumatism (EULAR) definition of remission in RA requires a score of ≤1 on the patient global assessment (PGA, 0-10 scale). We explored the relation between the PGA criterion and the patient's clinical disease state in an observational dataset. METHODS: Data of 512 newly diagnosed RA patients of the Dutch Rheumatoid Arthritis Monitoring (DREAM) remission induction cohort were analysed. Both 28-joint counts and more comprehensive joint counts (tender joint count-53, swollen joint count-44) were used. RESULTS: ACR/EULAR remission was present in 20.1% of the patients when using 28-joint counts and in 17.4% of the patients when applying more comprehensive joint counts. In 108 patients, the PGA score was >1 despite fulfilment of the remaining criteria (TJC28, SJC28 and CRP in mg/dl ≤1). Residual disease activity was observed in 31.5% (34/108) and median (interquartile range) scores on PGA, pain and fatigue were 2.4 (1.8-4.0), 2.0 (1.1-3.0) and 2.7 (1.3-5.0), respectively. Applying more comprehensive joint counts showed comparable results. In 19.5% (100/512) of patients, disease activity was absent (TJC53 = 0, SJC44 = 0, and CRP ≤1). In 41% (n = 41) of these patients, the PGA score was >1. Receiver operating characteristic analysis showed moderate accuracy of the PGA to discriminate between fulfilment and no fulfilment of all remaining criteria. CONCLUSION: Frequently, patients did not meet the PGA criterion despite a good clinical disease state. Apparently the PGA is not solely influenced by RA disease activity. In patients with marked divergence between the PGA and objective clinical measurements, caution should be taken when applying the provisional ACR/EULAR definition of remission.

Implementation of a treat-to-target strategy in very early rheumatoid arthritis: results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study.

OBJECTIVE: Clinical remission is the ultimate therapeutic goal in rheumatoid arthritis (RA). Although clinical trials have proven this to be a realistic goal, the concept of targeting at remission has not yet been implemented. The objective of this study was to develop, implement, and evaluate a treat-to-target strategy aimed at achieving remission in very early RA in daily clinical practice. METHODS: Five hundred thirty-four patients with a clinical diagnosis of very early RA were included in the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study. Treatment adjustments were based on the Disease Activity Score in 28 joints (DAS28), aiming at a DAS28 of <2.6 (methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with biologic agents in case of persistent disease activity). The primary outcome was disease activity after 6 months and 12 months of followup, according to the DAS28, the European League Against Rheumatism (EULAR) response criteria, and the modified American College of Rheumatology (ACR) remission criteria. Secondary outcomes were time to first DAS28 remission and outcome of radiography. RESULTS: Six-month and 12-month followup data were available for 491 and 389 patients, respectively. At 6 months, 47.0% of patients achieved DAS28 remission, 57.6% had a good EULAR response, and 32.0% satisfied the ACR remission criteria. At 12 months, 58.1% of patients achieved DAS28 remission, 67.9% had a good EULAR response, and 46.4% achieved ACR remission. The median time to first remission was 25.3 weeks (interquartile range 13.0-52.0). The majority of patients did not have clinically relevant radiographic progression after 1 year. CONCLUSION: The successful implementation of this treat-to-target strategy aiming at remission demonstrated that achieving remission in daily clinical practice is a realistic goal.

Deep origin and hot melting of an Archaean orogenic peridotite massif in Norway.

The buoyancy and strength of sub-continental lithospheric mantle is thought to protect the oldest continental crust (cratons) from destruction by plate tectonic processes. The exact origin of the lithosphere below cratons is controversial, but seems clearly to be a residue remaining after the extraction of large amounts of melt. Models to explain highly melt-depleted but garnet-bearing rock compositions require multi-stage processes with garnet and clinopyroxene possibly of secondary origin. Here we report on orogenic peridotites (fragments of cratonic mantle incorporated into the crust during continent-continent plate collision) from Otrøy, western Norway. We show that the peridotites underwent extensive melting during upwelling from depths of 350 kilometres or more, forming a garnet-bearing cratonic root in a single melting event. These peridotites appear to be the residue after Archaean aluminium depleted komatiite magmatism.

Memory for lists of sounds by the bottle-nosed dolphin: convergence of memory processes with humans?

After listening to a list of as many as six discriminably different 2-second sounds, a bottle-nosed dolphin classified a subsequent probe sound as either "old" (from the list) or "new." The probability of recognizing an old probe was close to 1.0 if it matched the most recent sound in the list and decreased sigmoidally for successively earlier list sounds. Memory span was estimated to be at least four sounds. Overall probabilities of correctly classifying old and new probes corresponded closely, as if recognition decisions were made according to an optimum maximum likelihood criterion. The data bore many similarities to data obtained from humans tested on probe recognition tasks.

Bottle-nosed dolphin: double-slit pupil yields equivalent aerial and underwater diurnal acuity.

In bright daylight, and at best viewing distances, the bottlenosed dolphin resolves visual gratings approximately equally well in air and in water. Aerial resolution improves with increased viewing distance, while underwater resolution improves with decreased viewing distance. The double-slit pipil overcomes the gross myopia in air measured by ophthalmoscope and produces the indicated effects of viewing distance.

Isolation of tobacco DNA segments with plant promoter activity.

We constructed a promoter probe vector, pGVL120, to isolate plant DNA segments with promoter activity in tobacco. Plant nuclear DNA Sau3A fragments were inserted in front of the npt-II sequence, and a mixture of recombinant plasmids was mobilized to Agrobacterium sp. and used to transform tobacco protoplasts. By kanamycin selection, transformed plant cell lines containing NPT-II T-DNAs were isolated. Eight of these cell lines were regenerated and analyzed for the levels of NPT-II activity in stem, root, midrib, and leaf. These levels demonstrated novel regulation patterns in each isolate. One cell line, T20, was analyzed in detail and found to contain four different T-DNAs. One of the recloned T-DNAs, T20-2, contains an insert of 401 base pairs in front of the NPT-II sequence, and by reintroducing this T-DNA into plant cells we could demonstrate that this insert provides a promoter sequence. The NPT-II enzyme activity under the control of the P20 promoter is especially high in stem and root, but low in leaf and callus, both in the originally isolated T20 plant and in independently isolated transformants with the T20-2 T-DNA.

Reporting presence or absence of named objects by a language-trained dolphin.

Referential "reporting" was defined as the transmission of information about the presence or absence of symbolically-referenced real-world objects. In Experiment 1 two bottlenosed dolphins (Tursiops truncatus), trained in earlier studies to carry out instructions conveyed by imperative sentences expressed in artificial gestural or acoustic languages, each gave spontaneous indications that an object referenced in an imperative was absent from their tank. In Experiment 2 the dolphin tutored in the gestural language was taught to make explicit reports of object absence by pressing a "No" paddle in response to imperatives referencing an absent object. Absence was reported correctly on 84% of 97 missing-object probes inserted at random intervals among 598 sentences referring to objects that were present. Reports were typically made after active search of the tank for an average of 15.0 sec. False reports, that objects present were absent, were few (7.5%). In Experiment 3, the dolphin was taught an interrogative sentence form that enabled us to ask direct questions about the presence or absence of specific objects. Responses by the dolphin on the No paddle indicated absence, while responses on a "Yes" paddle indicated presence. From one to three objects were shown the dolphin and then placed in the tank in a discrete-trial procedure. In response to the interrogative, reports or object presence or absence were better than 91% correct with a single object in the tank and either that object or some other object referenced; accuracy declined to 72-78% correct with three objects present, but was still well above chance. Several lines of evidence suggested that the dolphin was attempting to remember which objects it had been shown, rather than conducting an active environmental search as in Experiment 2. The memory strategy became less efficient as the number of objects to be remembered increased. Overall, the results evidenced the language-trained dolphin's understanding of references to present or absent objects, its ability to inventory its environment to seek information about those objects, and its ability to report its obtained knowledge to others.

Immunohistochemical localization of substance P and enkephalin in the nucleus tractus solitarii of the rhesus monkey, Macaca mulatta.

The nucleus tractus solitarii in the monkey Macaca mulatta was found to have several subdivisions based upon cytoarchitectonics and immunohistochemistry. Subdivisions that could be identified included commissural, medial, parvicellular, dorsolateral, ventrolateral, intermediate, and interstitial. Substance P and enkephalin immunoreactivity was localized within discrete regions of the nucleus tractus solitarii, by means of the peroxidase-antiperoxidase technique. Substance P immunoreactivity occurred most frequently in the interstitial subdivision of the nucleus tractus solitarii. Moderate accumulations of substance P immunoreactivity were present in the commissural, medial, parvicellular, dorsolateral, and intermediate subdivisions, but very little was present in the ventrolateral subdivision. Enkephalin immunoreactivity followed the staining patterns of substance P; however, the amounts of enkephalin immunoreactivity were less than amounts for substance P. Following colchicine treatment, large numbers of enkephalin-immunoreactive neurons were distributed throughout all subdivisions, many being located in the parvicellular and medial subdivisions. The few substance P-immunoreactive neurons found were restricted to the parvicellular subdivision. The distribution of substance P and enkephalin immunoreactivity in M. mulatta is very similar to that described in the cat and rat. In addition, the extensive overlap of the distribution of these two putative neurotransmitters provides morphological evidence for their possible participation in the autonomic regulation within the nucleus tractus solitarii.

Responses to anomalous gestural sequences by a language-trained dolphin: evidence for processing of semantic relations and syntactic information.

This study examined the responses of a bottlenosed dolphin (Tursiops truncatus) to "normal" (semantically and syntactically correct) sequences of gestures and to anomalous sequences given within an artificial gestural language highly familiar to the animal. Anomalous sequences violated the semantic rules or syntactic constraints of the language. The dolphin discriminated anomalous from normal sequences in that rejections (refusals to respond) occurred to some anomalous sequences but never to normal sequences. Rejections rarely occurred, however, if the anomalous sequence contained a subset of gestures that would comprise a normal unit if joined together. Such units were typically perceived by the dolphin and responded to even if they consisted of gestures that were not sequentially adjacent. All semantic elements of a sequence were processed by the dolphin in relation to other elements before the dolphin organized its final response. The results show the importance of both semantic properties and semantic relations of the referents of the gestures and of syntactic (ordering) constraints in the dolphin's interpretations of the anomalies.

Bottlenosed dolphin and human recognition of veridical and degraded video displays of an artificial gestural language.

2 bottlenosed dolphins proficient in interpreting gesture language signs viewed veridical and degraded gestures via TV without explicit training. In Exp. 1, dolphins immediately understood most gestures: Performance was high throughout degradations successively obscuring the head, torso, arms, and fingers, though deficits occurred for gestures degraded to a point-light display (PLD) of the signer's hands. In Exp. 2, humans of varying gestural fluency saw the PLD and veridical gestures from Exp. 1. Again, performance declined in the PLD condition. Though the dolphin recognized gestures as accurately as fluent humans, effects of the gesture's formational properties were not identical for humans and dolphin. Results suggest that the dolphin uses a network of semantic and gestural representations, that bottom-up processing predominates when the dolphin's short-term memory is taxed, and that recognition is affected by variables germane to grammatical category, short-term memory, and visual perception.

Effect of amphetamine-induced dopamine release on radiotracer binding to D1 and D2 receptors in rat brain striatal slices.

The in vivo binding of positron emission tomography (PET) and single photon emission computer tomography (SPECT) radiotracers to dopamine D2 receptors in the striatum can be influenced by competition with endogenous dopamine. The present study was undertaken to determine if a similar inhibition of radiotracer binding to dopamine receptors could be observed following pharmacologically-evoked dopamine release in rat brain striatal slices. Striatal slices were incubated in a large volume of oxygenated Krebs saline and exposed to amphetamine or methamphetamine to evoke dopamine release within the slice. Amphetamine and methamphetamine, at concentrations up to 30 microM, reduced [3H]raclopride binding in the slices by 77% and 86%, respectively, with 50% inhibition at 1.6 microM amphetamine or 3.0 microM methamphetamine. Neither drug produced a significant effect on binding of [3H]SCH 23390 in the slices. This suggests that dopamine was able to interfere with radiotracer binding to D2 but not D1 receptors. The dopamine uptake blockers, cocaine and methylphenidate, had relatively little effect by themselves on [3H]raclopride binding but, by inhibiting amphetamine-induced dopamine release, significantly reduced inhibition of [3H]raclopride binding by a low (3 microM) amphetamine concentration. At a higher (30 microM) amphetamine concentration the inhibition of [3H]raclopride binding was not antagonized by uptake blockers and data obtained from homogenate binding experiments indicated a direct displacement of [3H]raclopride binding by amphetamine at this concentration. In conclusion the data obtained in the present study demonstrate that the effects of amphetamine on striatal radiotracer accumulation observed in PET and SPECT can also be observed in brain slices in vitro and, at least at low amphetamine concentrations, are mediated by competition with released dopamine.

Seeing through sound: dolphins (Tursiops truncatus) perceive the spatial structure of objects through echolocation.

Experiment 1 tested a dolphin (Tursiops truncatus) for cross-modal recognition of 25 unique pairings of 8 familiar, complexly shaped objects, using the senses of echolocation and vision. Cross-modal recognition was errorless or nearly so for 24 of the 25 pairings under both visual to echoic matching (V-E) and echoic to visual matching (E-V). First-trial recognition occurred for 20 pairings under V-E and for 24 under E-V. Echoic decision time under V-E averaged only 1.88 s. Experiment 2 tested 4 new pairs of objects for 24 trials of V-E and 24 trials of E-V without any prior exposure of these objects. Two pairs yielded performance significantly above chance in both V-E and E-V. Also, the dolphin matched correctly on 7 of 8 1st trials with these pairs. The results support a capacity for direct echoic perception of object shape by this species and demonstrate that prior object exposure is not required for spontaneous cross-modal recognition.

Vocal mimicry of computer-generated sounds and vocal labeling of objects by a bottlenosed dolphin, Tursiops truncatus.

A bottlenosed dolphin (Tursiops truncatus) was trained to mimic computer-generated "model" sounds, using a whistle mode of vocalization. Prior to training, the whistle sounds of this dolphin were limited to a few stereotyped forms, none of which resembled the model sounds. After training, high-fidelity imitations were obtained of model sounds having (a) moderately or widely swept, slow-rate frequency modulation (1-2 Hz), (b) narrowly or moderately swept frequency modulation at moderate to rapid rates (3-11 Hz), (c) square-wave frequency transitions, and (d) unmodulated (pure-tone) waveforms. New models, not heard previously, could be mimicked immediately, often with good fidelity, including mimicry of amplitude variation that had not been explicitly reinforced during training. Subsets of familiar models were mimicked with high reliability in repeated tests. In additional training, control of the mimic response was transferred from the acoustic model to objects shown the dolphin (e.g., a ball or a hoop) so that, in effect, the dolphin gave unique vocal labels to those objects. In a test of accuracy and reliability of labeling, correct vocal labels were given on 91% of 167 trials comprised of five different objects presented in random order. The dolphin's ability for vocal mimicry compared favorably with that of the more versatile mimic birds, and it contrasted sharply with the apparent lack of vocal mimicry ability in terrestrial mammals other than humans. The ability to label objects vocally was similar to abilities shown for some birds and similar, in principle, to abilities of great apes trained in visual languages to label objects through gestures or other visual symbols.

Dolphins (Tursiops truncatus) comprehend the referential character of the human pointing gesture.

The authors tested a dolphin's (Tursiops truncatus) understanding of human manual pointing gestures to 3 distal objects located to the left of, to the right of, or behind the dolphin. The human referred to an object through a direct point (Pd), a cross-body point (Px), or a familiar symbolic gesture (S). In Experiment 1, the dolphin responded correctly to 80% of Pds toward laterally placed objects but to only 40% of Pds to the object behind. Responding to objects behind improved to 88% in Experiment 2 after exaggerated pointing was briefly instituted. Spontaneous comprehension of Pxs also was demonstrated. In Experiment 3, the human produced a sequence of 2 Pds, 2 Pxs, 2 Ss, or all 2-way combinations of these 3 to direct the dolphin to take the object referenced second to the object referenced first. Accuracy ranged from 68% to 77% correct (chance = 17%). These results established that the dolphin understood the referential character of the human manual pointing gesture.

Stimulus control and auditory discrimination learning sets in the bottlenose dolphin.

The learning efficiency of an Atlantic bottlenose dolphin was evaluated using auditory discrimination learning-set tasks. Efficiency, as measured by the probability of a correct response on Trial 2 of a new discrete-trial, two-choice auditory discrimination problem, reached levels comparable to those attained by advanced species of nonhuman primates. Runs of errorless problems in some cases rivaled those reported for individual rhesus monkeys in visual discrimination learning-set tasks. This level of stimulus control of responses to new auditory discriminanda was attained through (a) the development of a sequential within-trial method for presentation of a pair of auditory discriminanda; (b) the extensive use of fading methods to train initial discriminations, followed by the fadeout of the use of fading; (c) the development of listening behavior through control of the animal's responses during projection of the auditory discriminanda; and (d) the use of highly discriminable auditory stimuli, by applying results of a parametric evaluation of discriminability of selected acoustic variables. Learning efficiency was tested using a cueing method on Trial 1 of each new discrimination, to allow the animal to identify the positive stimulus before its response. Efficiency was also tested with the more common blind baiting method, in which the Trial 1 response was reinforced on only a random half of the problems. Efficiency was high for both methods. The overall results were generally in keeping with exceptations of learning capacity based on the large size and high degree of cortical complexity of the brain of the bottlenose dolphin.

Auditory delayed matching in the bottlenose dolphin.

A bottlenose dolphin, already highly proficient in two-choice auditory discriminations, was trained over a nine-day period on auditory delayed matching-to-sample and then tested on 346 unique matching problems, as a function of the delay between the sample and test sounds. Each problem used new sounds and was from five to 10 trials long, with the same sound used as the sample for all trials of a problem. At each trial, the sample was projected underwater for 2.5 sec, followed by a delay and then by a sequence of two 2.5-sec duration test sounds. One of the test sounds matched the sample and was randomly first or second in the sequence, and randomly appeared at either a left or right speaker. Responses to the locus of the matching test sound were reinforced. Over nine, varying-sized blocks of problems, the longest delay of a set of delays in a block was progressively increased from 15 sec initially to a final value of 120 sec. There was a progressive increase across the early blocks in the percentage of correct Trial 1 responses. A ceiling-level of 100% correct responses was then attained over the final six blocks, during which there were 169 successive Trial 1 responses bracketed by two Trial 1 errors (at 24- and 120-sec delays). Performance on trials beyond the first followed a similar trend. Finally, when the sample duration was decreased to 0.2 sec or less, matching performance on Trial 1 of new problems dropped to chance levels.

Utility of gastric brushing in the diagnosis of malignant lymphoma.

The gastric brushings (GBRs) and endoscopic biopsies obtained concurrently from 27 patients in whom malignant lymphoma was diagnosed or suggested by either modality were assessed to evaluate the utility of cytologic examination in the diagnosis of gastric lymphoma. GBRs provided a definitive diagnosis of lymphoma in 2 (28%) of 7 patients with a prior history of lymphoma and 10 (56%) of 18 patients with primary gastric lymphoma, yielding an overall sensitivity of 48%. All the lymphomas diagnosed cytologically were large cell type. GBRs were suspicious for a malignant neoplasm in four lymphoma patients whose concurrent biopsies were negative. GBRs obtained from two patients who had gastritis were reported as suspicious for lymphoma. There were no false-positive diagnoses.

Managing ankle injuries in the emergency department.

We review the anatomy and physiology of the ankle joint with attention to the structures most likely to be injured. We discuss the epidemiology of ankle injuries and their physical and radiographic evaluation, including the Ottawa Ankle Rules. Treatment, consultation, and pitfalls are followed by more specific discussions of tendonitis, Achilles tendon injury, tendonous subluxations, tarsal tunnel syndrome, sonovial impingement, and injury to the os trigonum. The references provide a guide for further reading.

Determinants associated with work participation in patients with established rheumatoid arthritis taking tumor necrosis factor inhibitors.

OBJECTIVE: Reduced work participation (WP) is a common problem for patients with rheumatoid arthritis (RA) and generates high costs for society. Therefore, it is important to explore determinants of WP at the start of tumor necrosis factor inhibitor (TNFi) treatment, and for changes in WP after 2 years of TNFi treatment. METHODS: Within the Dutch Rheumatoid Arthritis Monitoring (DREAM) biologic register, WP data were available from 508 patients with RA younger than 65 years and without an (early) retirement pension. WP was registered at start of TNFi treatment and after 2 years of followup and was measured by single patient-reported binary questions whether they had work, paid or voluntary, or had a disability allowance or a retirement pension. Determinants measured at baseline were age, sex, disease duration, functional status [through Health Assessment Questionnaire-Disability Index (HAQ-DI)], 28-joint Disease Activity Score (DAS28), rheumatoid factor, presence of erosions, number of previous disease-modifying antirheumatic drugs, and number of comorbidities. During the 2 years of followup, HAQ-DI response and European League Against Rheumatism response were measured. Univariate analyses (excluded if p value was > 0.2) and multivariate (excluded if p value was > 0.1) logistic regression analyses were used. RESULTS: Determinants associated with WP at baseline were having a better HAQ-DI (OR 0.32, p = 0.000) and male sex (OR 0.65, p = 0.065). After 2 years of TNFi therapy, 11.8% (n = 60) started to work and 13.6% (n = 69) stopped working. Determinants associated with starting to work were better baseline HAQ-DI (OR 0.58), positive RF (OR 2.73), and young age (OR 0.96); and for stopping work, worse baseline HAQ-DI (OR 2.74), low HAQ-DI response (OR 0.31), and comorbidity (OR 2.67), all with p < 0.1. CONCLUSION: Young patients with RA and a high functional status without any comorbidity will have a better chance of working. This supports the main goal in the management of RA: to suppress disease activity as soon and as completely as possible to prevent irreversible destruction of the joints, and thus maintain a good functional status of the patient. Because of the low proportion of variance explained by the models in this study, other factors besides the ones studied are associated with WP.