Search

Most previous transient receptor potential vanilloid subtype 1 (TRPV1) antagonist programs have been put on hold, mainly because of on-target adverse events: hyperthermia and impaired noxious heat sensation. NEO6860 is a TRPV1 antagonist, blocking capsaicin activation of the target, with little or no effect against pH or heat activation. The hypothesis is that this pharmacological profile will translate into analgesia without undesired effects on the body temperature or heat-pain threshold. This phase I, double blind, placebo controlled, ascending dose study, included 64 subjects. Pharmacodynamics (intradermal capsaicin test) was explored. The study was comprised of 6 dose levels (50, 100, 200, 400, 800, and 1,200 mg) and 2 doses of 500 mg, 12 hours apart. NEO6860 was rapidly absorbed and systemic exposure increases were less than dose proportional. Median time of maximum observed plasma concentration values ranged from 2 to 3 hours. The mean apparent plasma terminal elimination half-life was between 4 and 8 hours. No significant food-effect or gender-effect was observed. The most frequently reported events were feeling hot, headache, paresthesia, nausea, and dizziness. Single oral doses of up to 800 mg and two 500-mg doses administered 12 hours apart of NEO6860 were well tolerated in this study. Unlike other TRPV1 antagonists, no clinically significant increase in temperature or heat pain threshold/tolerance was noted despite thorough and specific monitoring of these parameters. At all doses, most subjects reported a sensation of “feeling hot,” with a rapid onset and transient. NEO6860 showed an improvement in the pharmacodynamics parameters (evoked pain and secondary hyperalgesia) at 3 and 8 hours post NEO6860 dosing. Perspective This first in human study on NEO6860, showed that an antagonist of TRPV1, blocking only the activation by capsaicin has been identified. This finding paves the way for the development of a new powerful analgesic for many pain conditions, without the fear of the side effects observed with previous TRPV1 antagonists.

Purpose: Unintentional injuries are the primary cause of morbidity and mortality among young children in the US. Ten percent of these injuries occur while in early childcare settings. Because of these statistics the AAP Healthy Futures project developed curriculum on injury prevention for early childcare providers. The goal of our project was to use the curriculum to educate early childcare providers about safety, to involve pediatric trainees in the process thereby educating them, and to promote partnerships between our AAP chapter …

Introduction:. NEO6860 is a TRPV1 antagonist when activated by capsaicin but not by heat or pH, developed to relieve pain without the adverse events reported with non–modality-selective TRPV1 antagonists. Objective:. The primary Objective of this study was to evaluate the analgesic efficacy and safety of NEO6860 after 1 day oral dosing in patients with Kellgren-Lawrence stage I, II or III osteoarthritis of the knee. Method:. This randomized, double-blinded, 3-period crossover, phase II study compared 1 day (2 doses) of NEO6860 (500 mg twice a day), placebo, and naproxen in 54 patients with osteoarthritis knee pain. Primary endpoint was reduction in pain intensity (PI) on Numerical Rating Scale after exercise, using the staircase test, 8 hours after dose. Results:. Level of PI, compared with baseline, was numerically lower during NEO6860 and naproxen periods vs placebo at 3 and 24 hours, but not at 8 hours after first dose. A statistically significant effect for naproxen and a trend for NEO6860 were observed at 3 and 24 hours. Least square means' (95% confidence interval) change in PI at 24 hours was −0.67 (−1.09 to −0.26), −0.97 (−1.39 to −0.55), −0.29 (−0.71 to 0.13) for NEO6860, naproxen, and placebo, respectively. NEO6860 exposure was ∼1.6 times higher compared with previous phase I. In this study, NEO6860 safety profile was less favorable than naproxen or placebo. Possibly NEO6860-related adverse events included: feel hot, headache, nausea, dizziness, fatigue, hypoaesthesia, and increased blood pressure. Conclusion:. In this exploratory study, NEO6860 did not statistically significantly outperform placebo but showed an analgesic trend, without impacting body temperature and heat pain perception. Further studies are warranted to explore the potential of NEO6860 in other pain indications. We intent to optimize the dose and evaluate analgesic synergism with other mechanism.

Introduction: Few studies of the demographics, natural history, and clinical management of inclusion body myo- sitis (IBM) have been performed in a large patient population. To more accurately define these characteristics, we developed and distributed a questionnaire to patients with IBM. Methods: A cross-sectional, self-reporting survey was conducted. Results: The mean age of the 916 participants was 70.4 years, the male-to-female ratio was 2:1, and the majority reported difficulty with ambulation and activities of daily living. The earliest symp- toms included impaired use and weakness of arms and legs. The mean time from first symptoms to diagnosis was 4.7 years. Half reported that IBM was their initial diagnosis. A composite functional index negatively associated with age and disease duration, and positively associated with participation in exercise. Conclusions: These data are valuable for informing patients how IBM manifestations are expected to impair daily living and indicate that self-reporting could be used to establish outcome measures in clinical trials. Muscle Nerve 52: 527-533, 2015

Systematic review and effectiveness analysis.Assess the effectiveness of anticonvulsants for the management of post spinal cord injury (SCI) neuropathic pain.Studies from multiple countries were included.CINAHL, Cochrane, EMBASE and MEDLINE were searched up to April 2013. Quality assessment was conducted using the Jadad and the Downs and Black tools. Effect sizes and odds ratios were calculated for primary and secondary outcome in the included studies.Gabapentinoids, valproate, lamotrigine, levetiracetam and carbamazepine were examined in the 13 included studies, ten of which are randomized controlled trials. Large effect size (0.873-3.362) for improvement of pain relief was found in 4 of the 6 studies examining the effectiveness of gabapentin. Pregabalin was shown to have a moderate to large effect (0.695-3.805) on improving neuropathic pain post SCI in 3 studies. Valproate and levetiracetam were not effective in improving neuropathic pain post SCI, while lamotrigine was effective in reducing neuropathic pain amongst persons with incomplete lesions and carbamazepine was found effective for relief of moderate to intense pain.Gabapentin and pregabalin are the two anticonvulsants which have been shown to have some benefit in reducing neuropathic pain.

A MAPLE system compiles definitions of regular grids into a custom FORTRAN program. These regular grids are defined in terms of symbols which represent the geometry of the object being analyzed. The FORTRAN program takes as input, the numeric values for these symbols. It generates the global stiffness matrix, K. This is solved for the displacement vectors in the equation Kx = B. This system produces the same displacements as NASTRAN and has been benchmarked favorably against this commercial product.

Objective To assess the clinical usefulness of 2 novel therapies for treatment-resistant myositis. Methods Thirty patients with refractory myositis, of whom 25 had an inadequate or no response to previous cytotoxic therapy, were randomized to begin either a combination of weekly oral methotrexate and daily azathioprine (MTX/AZA) or intravenous methotrexate with leucovorin rescue (IV MTX) every 2 weeks for 6 months. Crossover to the alternate therapy occurred according to defined rules; evaluations of muscle strength and functional abilities were performed at the beginning, and after 3 and 6 months, of each treatment. Results Of the 15 patients initially randomized to oral MTX/AZA, 8 improved with oral therapy and 1 improved with IV MTX during the crossover period. Of the 15 patients initially randomized to IV MTX therapy, 3 improved with the IV therapy and 4 with the oral combination during the crossover period. Although the study lacked the power to directly compare both treatments, intention-to-treat analysis showed a trend in favor of those patients who first received oral combination therapy (P = 0.025). There were 0.09 adverse events per patient-month with oral combination therapy and 0.16 per patient-month with IV therapy (P = 0.09). Conclusion Combination oral MTX/AZA may benefit patients with treatment-resistant myositis, including those who previously had inadequate responses to either MTX or AZA alone. IV MTX with leucovorin rescue may also benefit some patients with refractory myositis.

Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic–pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.

Techniques are developed for dealing with parametric constructive solid geometry. They include methods of generating the side constraints to ensure that the object is still the same conceptually as that originally entered by the engineer. These are generated at the same time the constructive solid geometry (CSG) model is converted to a B-REP representation. In addition, a speedup technique for finite element analysis is developed. Empirical work shows that it is 20 times faster than running the equivalent NASTRAN deck.

BACKGROUND Raynaud9s phenomenon, an episodic vascular disorder induced by cold temperatures or stress and characterized by white, blue, and red discoloration of the fingers and toes, may affect up to 20% of the general population. KEY POINTS Raynaud9s phenomenon may exist independently (primary) or in association with an underlying disease (secondary), most commonly systemic sclerosis. The pathophysiologic features include vasospasm, endothelial cell changes, vessel obstructive features, and hemorrheologic factors. Raynaud9s phenomenon is the initial manifestation of disease in 70% of patients with systemic sclerosis, in whom it may be present for many years before the development of the connective tissue disease. Patients with primary Raynaud9s phenomenon need only conservative management and should be reassured that digital ischemia and loss of tissue occur extremely rarely. Pharmacologic agents that have been studied include vasodilators, platelet inhibitors, serotonin antagonists, and fibrinolytics. CONCLUSIONS For prognostic and therapeutic reasons, it is important to determine if Raynaud9s phenomenon is associated with an underlying condition and if the patient may develop a connective tissue disease.

In myositis, disease-specific autoantibodies may be directed against an aminoacyl-tRNA synthetase, usually histidyl-tRNA synthetase. To explore the basis for this phenomenon, we have made recombinant histidyl-tRNA synthetase in the baculovirus system. It was enzymatically active and recognized by human autoantibodies. A truncated protein lacking the first 60 amino acids was inactive as an antigen and as an enzyme. This region is within the first two exons, is predicted to have a coiled-coil configuration, and is found in some other synthetases but not in Escherichia coli or yeast histidyl-tRNA synthetase. Circular dichroism showed that the peptides from this region (amino acids 1-60 and 1-47) have the predicted high alpha-helical content, but smaller fragments (1-30, 14-45, and 31-60) do not. The peptides with a high alpha-helical content could inhibit autoantibodies almost completely, whereas the smaller peptides were unable to do so. The amino acid sequence of this coiled-coil domain in human histidyl-tRNA synthetase resembles the sequence of the extended this coiled-coil arm near the NH2 terminus of bacterial seryl-tRNA synthetase as well as similar regions in some eukaryotic aminoacyl-tRNA synthetases, raising the possibility that this domain serves a similar tRNA-stabilizing role and has been preserved from a common ancestor.

Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, polymyositis, myasthenia gravis, and Hashimoto's thyroiditis result from abnormalities in immune regulation culminating in the stimulation of autoreactive lymphocytes. The pathogenicity of the autoantibodies in these diseases is a function of Ig specificity, isotype, p l , and affinity. Some autoantibodies directly damage host tissue by binding to determinants expressed on host cells. Others recognize intracellular or intranuclear antigens (such as Sm, Ro/SSA, and Jo-1). In the latter case, target molecules are not readily accessible to the autoantibodies. However, when released into immunologically accessible locations, the autoantigens complex with circulating Ig to form pathogenic immune complexes capable of inducing inflammatory reactions in the kidneys, vascular epithelium, and other organs. The function and character of autoantibodies have been studied extensively in animal models of autoimmune disease. In humans, such studies have primarily involved the analysis of long-lived monoclonal autoantibody-producing cells, generated by EBV transformation. Yet the production of EBV-transformed clones may be subject to a selection bias, such that lines cloned in vitro may be unrepresentative of the repertoire expressed in vivo . Studies of autoantibody-secreting human cells have also been limited due to the relatively small number of clones that can be derived and maintained from individual donors. The development of a rapid and unbiased technique for identifying autoantibody-secreting human B cells would facilitate analysis of the origin and character of such lymphocytes. Identifying the genes responsible for the production of specific autoantibodies would also improve our understanding of the etiology and pathogenesis of human disease. In the present work, we describe a technique for (i) identifying individual autoantibody-secreting cells and then (ii) PCR-amplifying their variable heavy (and light) chain genes. Individual clones of autoantibody-secreting lymphocytes were identified using an antigen-specific ELIspot assay. These clones were generated during short-term in vitro culture, thereby reducing the potential for repertoire bias compared to EBV-transformation and hybridoma formation. This method permitted relatively large numbers of Ag-specific B cells from individual patients to be identified. Messenger RNA from those clones was reverse-transcribed and amplified to identify and analyze the Ig genes responsible for encoding specific autoantibodies.

Background The therapeutic options for patients with polymyositis or dermatomyositis that is resistant to corticosteroids are limited, unproved, and often toxic. Uncontrolled trials concluded that both plasma exchange and leukapheresis are beneficial, but despite the considerable use of these approaches, proof of their efficacy is lacking. Methods Thirty-nine patients with definite polymyositis or dermatomyositis were randomly assigned to receive plasma exchange (replacement of one volume of plasma with 5 percent albumin in saline), leukapheresis (removal of 5×109 to 10×109 lymphocytes), or sham apheresis in a double-blind manner, with 12 treatments given over a one-month period. Muscle strength, functional capacity, and serum levels of muscle-associated enzymes were measured before and after the 12 procedures. Results In each group 3 of 13 patients had improvements in strength and functional capacity. The condition of 3 patients treated with leukapheresis and 1 treated with plasma exchange deter...

To determine if intravenous cyclophosphamide (IV-C) causes an excess of cervical dysplasia and/or cancer in systemic lupus erythematosus (SLE) patients, a retrospective review was conducted. Patients with SLE who received IV-C between 1988–98 (study group) were compared with a group of SLE patients who had not received IV-C (control group). Of the 79 IV-C-treated SLE patients identified, we excluded 18 because of absence of pertinent data. We found 10 cases of cervical dysplasia in the remaining 61 patients, compared to 2 in 49 non-exposed patients (P < 0.04). Comparison of the two groups revealed no difference in: mean years of disease duration, months of follow-up and age. The non-exposed patients were more likely to be on estrogen and hydroxychloroquine but less often on steroids and azathioprine. The study group with and without dysplasia were assessed; we found no difference in the mean, or total IV-C dose, smoking and estrogen use. There was a significant decrease in time to dysplasia in those, given IV-C, with previous dysplasia compared to those without. These preliminary data suggests that IV-C causes an increased number of abnormal Papanicolaou (Pap) smears in SLE patients, particularly those with previous dysplasia.

This paper describes a working system for the generation of global stiffness matrices whose elements are functions of shape parameters. The Symbolic Finite Element Analysis System (SFEAS) takes a STRUDL-like [R. D. Logcher, J. J. Connor, Jr and M. F. Nelson, ICES STRUDL-II The Structural, Design Language Engineering User's Manual, Volume 2 Additional Design and Analysis Features , ICES Users Group, Cranston, RI (1983)] syntax. The important difference between this and STRUDL is that the joint coordinates, material properties, and forces are entered as expressions of various parameters. The result is a K matrix, each element being a function of those same parameters.

Barriers to teaching and learning creative thinking and meta-thinking seem to be related to teaching and learning any new concept. Paradoxically, the very thinking processes inhibited by these barriers offer promising pathways to dissolving the barriers themselves. This article outlines both the specific barriers and some directions for solutions .

To determine the baseline and longitudinal consistency in reproducibility of the semiflexed metatarsophalangeal (MTP) position in repeat examinations of patients with knee osteoarthritis (OA) recruited for a multicenter clinical trial that terminated within one year (mean duration 0.81 yr), based on precise measurements both of minimum medial tibiofemoral compartment joint space width (JSW) and of tibial inter-rim distance.Two technologists from 8 and one technologist from 14 clinical radiology units had received previous training in performing nonfluoroscopic semiflexed MTP knee examinations and in quality control criteria for film acceptance. Patients (N = 402; F = 269) were recruited from 58 rheumatology sites and referred to 22 centers, or "x-ray hubs," across North America. At baseline and at study exit, both knees were x-rayed twice on the same day. All films had quality control, and accepted films were digitized at the Central Radiographic Facility and transmitted to the Central Analysis Facility for computerized measurement of minimum medial compartment JSW and tibial inter-rim distance. JSW loss was calculated in the placebo group for the study period.The median SD of the difference in JSW between same-day test/retest film pairs was 0.9 mm for 767 baseline film pairs (knees with JSW0 mm), and 0.08 mm for 631 exit film pairs. JSW reproducibility was unaffected by subject's sex, age, and degree of JSW loss. Among all x-ray hubs, JSW reproducibility was excellent in 14 (SD0.1 mm), good in 6 (0.1SD0.2 mm), and moderate in 2 hubs (0.2SD0.3 mm). No statistical difference was found in technologists' ability either in positioning OA knees or in their test/retest reproducibility in repositioning joints at baseline and at study exit. JSW did not alter significantly during the study period.The protocol for the semiflexed MTP knee position provides a highly reproducible method for anatomically repositioning the knee and for measuring JSW, necessary for OA clinical trials. It is a simple method that can be employed readily at clinical radiology units, as shown by the similarity in JSW precision between x-ray hubs. The results from this large dataset show that throughout the study precise measurements of JSW were obtained from same-day repeat radiographs, findings that together with previous single-center studies confirm the reliability of this method for clinical trial use.

To determine the effect of BAY 12-9566, a matrix metalloproteinase inhibitor, on articular cartilage metabolism in patients with osteoarthritis (OA).Thirty-five patients with OA were randomized to receive oral daily dosing of BAY 12-9566 (25, 100, or 400 mg) or placebo for 3 weeks prior to knee surgery. Cartilage samples were obtained at surgery and examined for markers of proteoglycan aggrecan turnover (846 epitope, a putative synthesis marker, and keratan sulfate epitope content) and type II collagen synthesis (C-propeptide content), cleavage by collagenase (COL 2-3/4C short), denaturation, and content (COL2-3/4m epitope). BAY 12-9566 concentrations were measured by HPLC in serum, synovial fluid, and cartilage.Comparisons between study drug and placebo treatments revealed that at the 100 mg dose there was a significant increase in the 846 epitope (p = 0.012). Total type II collagen content was also higher at this dosage (p = 0.012). Alterations in collagen degradation and synthesis were not detected.BAY 12-9566 at daily doses of 100 mg significantly altered proteoglycan turnover, resulting in a cartilage composition reflected by the content of the 846 epitope that is more characteristic of a young growing individual. The increase in this epitope may signify increased matrix synthesis. The increase in type II collagen content was unexpected, since there was no other evidence for altered collagen turnover. However, increased matrix assembly would also be indicated by this increased content.

Background Infliximab is a chimeric, monoclonal antibody against tumour necrosis factor (TNF) alpha, recently developed to complement methotrexate therapy in RA patients with a less than optimal response to treatment. To date it has only been studied in clinical trials. Objectives To describe referral patterns, patient response to treatment, and adverse events in a cohort of RA patients treated with infliximab in a real world setting. Methods Patients who had received their first dose of infliximab between 1/00 and 6/00 were included to ensure the possibility of at least 6 months of drug exposure. We evaluated patients at baseline, and followed them prospectively every 2 months for a total of 6 months. Patients completed several questionnaires regarding RA history, treatment, and disease activity (HAQ, pain, fatigue, tender and swollen joint counts) at each infusion. All subjects were contacted between infusions for reporting of side effects. Results 36 patients were treated with infliximab between January 1 – June 30, 2000 (female n = 33, mean age = 63 ± 12.9 y, disease duration = 15.3 ± 10.2 y). They had previously failed an average of 3 DMARDs. 24 patients were on oral steroids at baseline. 16 patients received infliximab without concurrent MTX. 12 of 36 patients discontinued treatment before 6 months. Discontinuation reasons were inadequate response (n = 5), repeated episodes of dyspnea (n = 3), asthma (n = 1), chest tightness (n = 1), phlebitis (n = 1), and patient noncompliance (n = 1). Table 1 shows individual measures of disease activity in 24 patients who completed 6 months of infliximab. We detected a significant improvement in HAQ scores, and trends toward improvement in pain scores and tender joint counts. HAQ scores improved in 19/24, stiffness in 14/24, pain in 13/24, fatigue in 13/24, tender joint counts in 13/24 and swollen joints in 15/24 of patients. Since initiating infliximab therapy, of the 36 patients receiving 198 infusions, 18 patients reported a total of 33 adverse events (headaches n = 8, nausea n = 2, abdominal pain n = 2, chest pain n = 1, chills n = 2, dyspnea n = 3, myalgias n = 3, pruritis n = 4, fatigue n = 3, and rash n = 5). Conclusion Infliximab is often used in more difficult RA patients (older, long-standing RA, multiple DMARD failures). This referral pattern may explain the increased incidence of adverse events and suboptimal clinical response noted in our cohort. However, our results suggest a trend towards rapid, clinically important improvement in measures of disease activity. Ongoing follow-up of this growing group of patients will provide necessary information regarding the appropriate role of infliximab in the treatment of RA.

Long-term trials with BAY 12-9566, a stromelysin inhibitor, have been initiated in osteoarthritis. Validation of the long-term, clinical relevance of early markers has to be tested in these and other trials. Detection of the slowing of cartilage loss (as gauged by measures of joint space narrowing and by other techniques, such as MRI) remains to be proven, but now may be possible in intervention trials.

To assess the clinical usefulness of 2 novel therapies for treatment-resistant myositis.Thirty patients with refractory myositis, of whom 25 had an inadequate or no response to previous cytotoxic therapy, were randomized to begin either a combination of weekly oral methotrexate and daily azathioprine (MTX/AZA) or intravenous methotrexate with leucovorin rescue (I.V. MTX) every 2 weeks for 6 months. Crossover to the alternate therapy occurred according to defined rules; evaluations of muscle strength and functional abilities were performed at the beginning, and after 3 and 6 months, of each treatment.Of the 15 patients initially randomized to oral MTX/AZA, 8 improved with oral therapy and 1 improved with I.V. MTX during the crossover period. Of the 15 patients initially randomized to I.V. MTX therapy, 3 improved with the I.V. therapy and 4 with the oral combination during the crossover period. Although the study lacked the power to directly compare both treatments, intention-to-treat analysis showed a trend in favor of those patients who first received oral combination therapy (P = 0.025). There were 0.09 adverse events per patient-month with oral combination therapy and 0.16 per patient-month with I.V. therapy (P = 0.09).Combination oral MTX/AZA may benefit patients with treatment-resistant myositis, including those who previously had inadequate responses to either MTX or AZA alone. I.V. MTX with leucovorin rescue may also benefit some patients with refractory myositis.

We have written two pieces of software that are necessary for mechanical engineering design and analysis. These are a CAD-CAM system using Constructive Solid Geometry and a finite element analysis system. Both are unique in that they are written in the symbolic math system MAPLE. All entities in each of these programs are entered symbolically. For example, in the CSG system, we talk about a square whose dimensions are a, b and side1. In the finite element analysis, we talk about a symbolic representation for a regular grid. This scheme has advantages over conventional finite element analysis and Constructive Solid Geometry approaches.

purpose: To identify factors associated with responses to treatment with prednisone, methotrexate, or azathioprine in patients with idiopathic inflammatory myopathy, and to compare the efficacy of these drugs. patients and methods: Data were collected on 113 adult patients meeting criteria for definite idiopathic inflammatory myopathy in this retrospective cohort study. Patients were categorized as responding completely, partially, or not at all to each therapeutic trial based upon clinical and laboratory criteria. results: Clinical group, presence of certain myositis-specific autoantibodies, and time from disease onset to diagnosis influenced rates of complete clinical response to these therapeutic agents. Patients with inclusion body myositis responded comparatively poorly to prednisone and the other drugs: 43% had no clinical response to prednisone and none responded completely to any medication. Patients with autoantibodies to aminoacyl-tRNA synthetases or to signal recognition particle proteins were likely to respond partially, but not completely, to prednisone. No patient with a long delay to diagnosis (greater than 18 months) responded completely, compared with 34% of those with a short delay (less than 3 months). A patient's response to the first course of prednisone predicted subsequent responses to prednisone and to azathioprine better than response to methotrexate. Men responded to methotrexate better than women. Among certain subgroups of patients, responses to methotrexate were better than to either azathioprine or retreatment with prednisone. conclusion: Determining the clinical group, autoantibody status, and time from disease onset to diagnosis of patients with myositis provides useful information in predicting clinical responses to therapy, and these factors should be considered in designing future therapeutic trials. Methotrexate therapy may be superior to either azathioprine or further steroid treatment alone in certain patients who do not respond completely to an initial adequate course of prednisone.

We have designed a working 2-D Constructive Solid Geometry (CSG) system in MAPLEV, which is currently comprised of more than 1600 lines of code. Our research in this area is important for several reasons. To begin with, it is the first user expandable CSG system. We designed the system to allow the user to add their own definitions of curves and primitives. It is also the first symbolic CSG system. The advantage of this is that the user can change the initial values of the parameters to obtain different sizes of the same conceptual object. An inequality list, generated by our program, will ensure that the object is conceptually the same. This is important as to enable shape optimization of objects. The generated inequality list will also eliminate needless computations as parameters are varied by simply checking whether or not the new input values satisfy the inequality list. Finally, this method of symbolic evaluation serves as a paradigm for other areas of science and engineering.

There is indirect evidence that various viruses have aetiological roles in the idiopathic inflammatory myopathies. By means of a sensitive and specific method based on the polymerase chain reaction (PCR), we sought direct evidence for the presence in affected muscle of nucleic acid sequences from Coxsackie virus, mumps virus, encephalomyocarditis virus, adenovirus, human T-lymphotropic virus types I and II, and human immunodeficiency virus. RNA was extracted from muscle biopsy samples obtained from 44 patients with idiopathic inflammatory myopathies a mean of 45 (range 0-216) months after disease onset. All the subjects were older than 16 years at disease onset. The integrity of the mRNA extracted was confirmed by the successful PCR amplification of insulin receptor mRNA in all samples. The PCR method was able to detect between 1 and 20 molecules of added viral nucleic acid for the picornaviruses sought. No detectable virus sequences were found, however, in any of the patients' muscle samples or in samples from 13 controls. We tested for retroviral DNA in 22 samples (17 patients, 5 controls) that met our criterion for adequate DNA extraction (detectable β-actin DNA by PCR); again no virus sequences were found. Persistence in muscle of these or closely related viruses is unlikely to be a continuing stimulus for disease in the idiopathic inflammatory myopathies.

In idiopathic inflammatory myopathy (IIM; or, polymyositis/dermatomyositis), the myositis-specific autoantibodies anti-Jo-1 and anti-signal recognition particle (anti-SRP), appear to define clinically and immunogenetically distinct groups of patients. We show here that the month during which the onset of weakness occurs is not random in patients with anti-Jo-1 auto-antibodies (average month April, P less than 0.02) and in those with anti-SRP autoantibodies (average month November, P less than 0.02); both groups of patients also experience rapid onset of disease. By contrast, patients classified into the traditional categories of polymyositis and dermatomyositis do not have recognizable seasonal patterns and do not differ in the rate of onset of disease. These findings suggest that searches for seasonal patterns in the onset of autoimmune disorders characterized by disease-specific autoantibodies may provide useful clues to etiology.

The IIM are a heterogeneous group of systemic rheumatic diseases which share the common features of chronic muscle weakness and mononuclear cell infiltrates in muscle. A number of classification schemes have been proposed for them, but none takes into consideration the marked immunologic, clinical, and genetic heterogeneity of the various clinical groups. We compared the usefulness of myositis-specific autoantibodies (anti-aminoacyl-tRNA synthetases, anti-SRP, anti-Mi-2 and anti-MAS) to the standard clinical categories (polymyositis, dermatomyositis, overlap myositis, cancer-associated myositis, and inclusion body myositis) in predicting clinical signs and symptoms, HLA types, and prognosis in 212 adult IIM patients. Although patients with inclusion body myositis (n = 26) differed in having significantly more asymmetric and distal weakness, falling, and atrophy than other patients, there were few other significant differences among the other clinical groups. In contrast, autoantibody status defined distinct sets of patients and each patient had only 1 myositis-specific autoantibody. Patients with anti-amino-acyl-tRNA synthetase autoantibodies (n = 47), compared to those without these antibodies, had significantly more frequent arthritis, fever, interstitial lung disease, and "mechanic's hands"; HLA-DRw52; higher mean prednisone dose at survey, higher proportion of patients receiving cytotoxic drugs, and higher death rates. Those with anti-signal recognition particle antibodies (n = 7) had increased palpitations; myalgias; DR5, DRw52; severe, refractory disease; and higher death rates. Patients with anti-Mi-2 antibodies (n = 10) had increased "V-sign" and "shawl-sign" rashes, and cuticular overgrowth; DR7 and DRw53; and a good response to therapy. The 2 patients with anti-MAS antibodies were the only ones with alcoholic rhabdomyolysis preceding myositis; both had insulin-dependent diabetes mellitus, and both had HLA-B60, -C3, -DR4, and -DRw53. These findings suggest that myositis-specific autoantibody status is a more useful guide than clinical group in assessing patients with myositis, and that specific associations of immunogenetics, immune responses, and clinical manifestations occur in IIM. Thus the myositis-specific autoantibodies aid in interpreting the diverse symptoms and signs of myositis patients and in predicting their clinical course and prognosis. We propose, therefore, that an adjunct classification of the IIM, based on the myositis-specific autoantibody status, be incorporated into future studies of their epidemiology, etiology, and therapy.

Excerpt To the Editor:Low-dose methotrexate therapy has a 1% to 5% incidence of pneumonitis (1). However, Pneumocystis carinii pneumonia resembling methotrexate-induced pneumonitis has been reporte...

This article reports the results of a longitudinal experiment exploring environmental cognitive sets (ways of perceiving or thinking about one's surroundings) that were designed especially to promote awareness of environmental problems and possibilities but also to induce aesthetic experience, environmental understanding, and a playful and creative orientation toward environmental experience. The results of our project indicate that (1) imagining improvements in an environment (the "IMG" set) led subjects to notice and remember more human-induced environmental problems than did normal viewing; (2) although IMG tended to be rated as more interesting and enjoyable than normal viewing for filmed scenes, subjects who were instructed repeatedly to use IMG seemed to tire of its imposed use over an extended period of time; (3) nevertheless, a much higher proportion of these subjects than of subjects with less experimental exposure to IMG reported using this set on their own after the conclusion of the experiment; (4) our specially devised instructions "for being more creative" in imagining environmental changes were very effective in helping college students imagine changes of higher (blind-rated) quality; (5) our research procedures at this stage of development had no discernible systematic effects on overall environmental concern, ability to devise new cognitive sets, or feelings of perceptual control; (6) subjects who freely chose several cognitive sets to use at visited locations showed a highly significant tendency to find at least one experimental set for each location that was more interesting and enjoyable than normal viewing (even though normal viewing at these locations was itself rated as both interesting and enjoyable and as significantly easier than the experimental cognitive sets).

Trabecular carcinoma of the skin (Merkel cell tumor), a neoplasm of putative neural origin, must be differentiated from other small cell tumors primary or metastatic to skin. In order to provide more objective diagnostic criteria, four were examined using monoclonal antibodies against neurofilament proteins (NF) and antiserum specific for neuron-specific enolase (NSE). Immunohistochemistry demonstrated immunoreactive NF in three and NSE in four cases. NF immunoreactivity was arranged in paranuclear balls, consistent with ultrastructural observations of aggregated intermediate filaments. A case of pulmonary oat cell carcinoma metastatic to the skin also contained immunoreactive NF and NSE. Although NF and NSE do not discriminate metastatic oat cell carcinoma from trabecular carcinoma of skin, they are useful antigens that provide objective criteria for recognizing tumors of neural histogenesis or neural differentiation. They should make it possible to exclude non-neural lesions from the differential diagnosis of small cell tumors of the skin.

Human and other mammalian forms of ATase, including the Chinese hamster enzyme, are oxygen-sensitive enzymes and human ATase, like the enzyme from B. subtilis, is an iron-sulfur protein. When protein synthesis is inhibited in cultured Chinese hamster cells, ATase activity is lost in an oxygen-dependent reaction. The hypothesis is developed that the sensitivity of ATase to oxygen inactivation controls the rate of degradation of this enzyme in mammalian cells, similar to the mechanism which has been demonstrated for regulation of ATase degradation in B. subtilis.