Improvement of agreement in TCM diagnosis among TCM practitioners for persons with the conventional diagnosis of rheumatoid arthritis: effect of training.

OBJECTIVE: To investigate whether a training process that focused on consensus on Traditional Chinese Medicine (TCM) diagnostic criteria will improve the agreement of TCM diagnosis on patients with rheumatoid arthritis (RA). DESIGN: The design was a prospective survey. SETTING: The study was conducted at the General Clinical Research Center, University of Maryland Hospital System, Baltimore, MD. SUBJECTS: The participants were 42 patients with RA. PRACTITIONERS: The practitioners included 3 licensed acupuncturists with a minimum of 5 years' licensure and education in Chinese herbs. METHODS: A training session of TCM diagnostic procedures was conducted with an open case discussion and "real time" practice. After the training, 3 TCM practitioners examined the same 42 patients with RA separately. Patients filled out a questionnaire to serve as the data for the "Inquiry" component while physical examinations, including observations of tongue and palpation of radial pulse, were conducted by the 3 practitioners. Each practitioner provided a TCM diagnosis based upon the examination results. These diagnoses were then examined with respect to the rate of agreement among the 3 practitioners. RESULTS: The average agreement with respect to the TCM diagnoses among the 3 pairs of TCM practitioners was 73% (64.3%-85.7%). Statistically significant differences were found between this study and the two previous studies (p < 0.001). CONCLUSIONS: After training focused on consensus on TCM diagnostic criteria, we found that these 3 same TCM practitioners who were used in phase II of the study produced a significantly higher agreement when compared to study phase I or phase II. Our study suggests that improved consensus on TCM diagnostic criteria results in increased agreement of diagnosis.

Development of new pyrrolopyrimidine-based inhibitors of Janus kinase 3 (JAK3).

A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.

Synthesis and evaluation of (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones as Kv1.5 channel blockers for the treatment of atrial fibrillation.

A series of novel (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones were prepared and examined for utility as Kv1.5 channel blockers for the treatment of atrial fibrillation.

Variability in the traditional Chinese medicine (TCM) diagnoses and herbal prescriptions provided by three TCM practitioners for 40 patients with rheumatoid arthritis.

OBJECTIVE: To ascertain if previous findings of low levels of agreement of Traditional Chinese Medicine (TCM) pattern diagnoses made by TCM practitioners in patients with rheumatoid arthritis (RA) were a function of practitioner differences or would be replicated with a different sample of clinicians, and to examine the relationship between TCM diagnosis and herbal treatment plans. DESIGN: A prospective survey. SETTING: General clinical research center, University of Maryland Hospital System, Baltimore, MD. SUBJECTS: Forty (40) patients with RA. PRACTITIONERS: Licensed acupuncturists with at least 5 years' experience and education in Chinese herbs. METHODS: Three (3) TCM practitioners examined the same 40 RA patients separately, following the traditional Four Diagnostic Methods. Patients filled out questionnaires and physical examinations, including observations of the tongue and palpation of radial pulse, were conducted by the 3 practitioners. Each practitioner then provided both a TCM diagnosis and an herbal prescription. These diagnoses/prescriptions were examined with respect to the rate of agreement among the 3 practitioners. RESULTS: The average agreement with respect to the TCM diagnoses among the 3 TCM practitioners was 31.7 % (range, 27.5-35%). The degree to which the herbal prescriptions agreed with textbook recommended practice for each TCM diagnosis was 91.7% (range, 85-100%). The most commonly used TCM assessments in arriving at these diagnoses were inquiry about factors affecting pain and pulse diagnosis. No statistically significant differences were found between this study and our previous study regarding the level of agreement on TCM diagnosis. CONCLUSION: The average agreement of the diagnoses provided by 3 TCM practitioners was at the same low level as previously reported. No association was found between the diagnostic methods used and the consistency of diagnosis. Both studies, however, found a high degree of consistency between the TCM pattern diagnoses provided and the herbal treatment plans made as a result of those diagnoses.

Is acupuncture analgesia an expectancy effect? Preliminary evidence based on participants' perceived assignments in two placebo-controlled trials.

This purpose of this article is to contrast the analgesic efficacy of acupuncture following dental surgery with the analgesic effects based on the expectation of benefit in two independently conducted placebo-controlled trials evaluating acupuncture as an adjunctive therapy for dental surgery. Both trials used pain following dental surgery as the outcome variable, and both included a blinding check to ascertain patients' beliefs regarding which treatment they were receiving. Although no statistically significant analgesic effect was observed between the acupuncture and placebo groups, participants in both experiments who believed they received real acupuncture reported significantly less pain than patients who believed that they received a placebo. Patients' beliefs regarding the receipt of acupuncture bore a stronger relationship to pain than any specific action possessed by acupuncture. These results also support the importance of both employing credible controls for the placebo effect in clinical trials and evaluating the credibility of those controls.

Involvement of peripheral opioid mechanisms in electroacupuncture analgesia.

The involvement of the peripheral opioid system in modulating inflammatory pain has been well documented. This study aimed to investigate the possibility of electroacupuncture (EA)-mediated peripheral opioid release. Rats were injected with complete Freund's adjuvant in one of the hind paws to induce localized inflammatory pain. The pain behavioral changes were measured by paw withdrawal latency (PWL) to a noxious thermal stimulus. At day 5 of inflammation, rats received a second injection of saline or opioid antagonists into the inflamed paw, followed by EA at 30 Hz, 2 mA, and 0.1 ms for 30 minutes. The EA was conducted at acupuncture point GB30. A control was used in which needles were inserted at GB30 but no electrical stimulation was applied. Rats receiving EA showed a significantly longer PWL as compared with the control from 30 minutes to three hours after EA treatment. Intraplantar but not intraperitoneal injection of naloxone methiodide, a peripherally acting opioid receptor antagonist, eliminated the analgesic effect at 30 minutes after EA treatment. Intraplantar injection of an antibody against beta-endorphin and a corticotropin-releasing factor antagonist also produced a reduction in PWL in rats receiving EA. These data strongly suggest that peripheral opioids are released by EA at the inflammatory site.

concise synthesis of 4-acylamino analogues of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acids (LY354740) from an acylnitroso Diels-Alder cycloadduct.

Concise total syntheses of 4-acylamino analogues of LY354740 were accomplished employing an N-Boc acylnitroso Diels-Alder cycloadduct as the starting material. The syntheses involved N-O bond cleavage, oxidation, intermolecular cyclopropanation, Bucherer-Bergs reaction, hydrolysis, and regioselective acylation with a temporary copper chelate. The synthesis of an optically active compound was also achieved.

Larger effect sizes were associated with higher quality ratings in complementary and alternative medicine randomized controlled trials.

OBJECTIVE: To determine if the quality of complementary and alternative medicine (CAM) placebo controlled randomized controlled trials (RCTs) is related to the effect sizes they produce when the type of interventions and outcome variables are controlled. STUDY DESIGN AND SETTING: A sample of 25 CAM meta-analyses was identified from MEDLINE and hand searches containing published effect sizes for at least three efficacy trials employing placebo control groups. From these 25 reviews, 26 pairs of trials were selected: the one reporting the largest effect size and the matching trial reporting the smallest effect size. Quality and publication characteristics were then abstracted from each trial. RESULTS: Unlike the preponderance of past evidence examining the relationship between quality and effect size, the present study found that trials possessing the largest effect sizes within a meta-analysis were also associated with higher quality ratings than their counterparts possessing the lowest effect sizes (P=.019). CONCLUSIONS: Possible theoretical reasons for this unexpected positive relationship include (a) sampling error, (b) reduced within group variation, (c) fraudulent reporting, and (d) the restriction of the analyses to placebo controlled trial.

The variability of TCM pattern diagnosis and herbal prescription on rheumatoid arthritis patients.

CONTEXT: The consistency of diagnosis made among Traditional Chinese Medicine (TCM) practitioners and the relationship between TCM diagnosis and Chinese herbal prescription have not been adequately examined. OBJECTIVE: To investigate the degree of consistency with which TCM diagnoses and herbal prescriptions can be made by practitioners examining rheumatoid arthritis (RA) patients. To survey TCM diagnostic patterns and to examine the correlation between herbal prescriptions and these diagnoses for a sample of RA patients. DESIGN: A prospective survey. SETTING: General Clinical Research Center, University of Maryland Hospital System, Baltimore, MD. PATIENTS: Rheumatoid arthritis patients. PRACTITIONERS: Licensed acupuncturists with a minimum of 5 years licensure and education in Chinese herbs. METHODS: Three TCM practitioners examined the same 39 RA patients separately, following the traditional "Four Diagnostic Methods." Patients filled out a questionnaire to serve as the data for the "Inquiry" component. They then underwent a physical examination, including the tongue and pulse, conducted by each of the practitioners. Based upon the examination results, each practitioner provided both a TCM diagnosis and a herbal prescription. These diagnoses/prescriptions were then examined with respect to the rate of agreement among the 3 practitioners. RESULTS: The average agreement with respect to the TCM diagnoses among the 3 pairs of TCM practitioners was 28.2% (25.6 to 33.3% with kappas ranging from 0.23 to 0.30). The degree to which the herbal prescriptions agreed with textbook recommended practice of each TCM diagnosis was 93.2% (range = 87.2 to 100%). CONCLUSION: The total agreement on TCM diagnosis on RA patients among 3 TCM practitioners was low. When less stringent, but theoretically justifiable, criteria were employed, greater consensus was obtained among the 3 practitioners. The correspondence between the TCM diagnosis and the herbal formula prescribed for that diagnosis was high, although there was little agreement among the 3 practitioners with respect to the herbal formulas prescribed for individual patients.

A mechanism-based inhibitor targeting the DD-transpeptidase activity of bacterial penicillin-binding proteins.

Penicillin-binding proteins (PBPs) are responsible for the final stages of bacterial cell wall assembly. These enzymes are targets of beta-lactam antibiotics. Two of the PBP activities include dd-transpeptidase and DD-carboxypeptidase activities, which carry out the cross-linking of the cell wall and trimming of the peptidoglycan, the major constituent of the cell wall, by an amino acid, respectively. The activity of the latter enzyme moderates the degree of cross-linking of the cell wall, which is carried out by the former. Both these enzymes go through an acyl-enzyme species in the course of their catalytic events. Compound 6, a cephalosporin derivative incorporated with structural features of the peptidoglycan was conceived as an inhibitor specific for DD-transpeptidases. On acylation of the active sites of dd-transpeptidases, the molecule would organize itself in the two active site subsites such that it mimics the two sequestered strands of the bacterial peptidoglycan en route to their cross-linking. Hence, compound 6 is the first inhibitor conceived and designed specifically for inhibition of DD-transpeptidases. The compound was synthesized in 13 steps and was tested with recombinant PBP1b and PBP5 of Escherichia coli, a dd-transpeptidase and a dd-carboxypeptidase, respectively. Compound 6 was a time-dependent and irreversible inhibitor of PBP1b. On the other hand, compound 6 did not interact with PBP5, neither as an inhibitor (reversible or irreversible) nor as a substrate.

The efficacy of mindfulness meditation plus Qigong movement therapy in the treatment of fibromyalgia: a randomized controlled trial.

OBJECTIVE: To test the short and longterm benefits of an 8 week mind-body intervention that combined training in mindfulness meditation with Qigong movement therapy for individuals with fibromyalgia syndrome (FM). METHODS: A total of 128 individuals with FM were randomly assigned to the mind-body training program or an education support group that served as the control. Outcome measures were pain, disability (Fibromyalgia Impact Questionnaire), depression, myalgic score (number and severity of tender points), 6 minute walk time, and coping strategies, which were assessed at baseline and at 8, 16, and 24 weeks. RESULTS: Both groups registered statistically significant improvements across time for the Fibromyalgia Impact Questionnaire, Total Myalgic Score, Pain, and Depression, and no improvement in the number of feet traversed in the 6 minute walk. However, there was no difference in either the rate or magnitude of these changes between the mind-body training group and the education control group. Salutary changes occurring by the eighth week (which corresponded to the end of the mind-body and education control group sessions) were largely maintained by both groups throughout the 6 month followup period. CONCLUSION: While both groups showed improvement on a number of outcome variables, there was no evidence that the multimodal mind-body intervention for FM was superior to education and support as a treatment option. Additional randomized controlled trials are needed before interventions of this kind can be recommended for treatment of FM.

Structural aspects for evolution of beta-lactamases from penicillin-binding proteins.

Penicillin-binding proteins (PBPs), biosynthetic enzymes of bacterial cell wall assembly, and beta-lactamases, resistance enzymes to beta-lactam antibiotics, are related to each other from an evolutionary point of view. Massova and Mobashery (Antimicrob. Agents Chemother. 1998, 42, 1-17) have proposed that for beta-lactamases to have become effective at their function as antibiotic resistance enzymes, they would have had to undergo structure alterations such that they would not interact with the peptidoglycan, which is the substrate for PBPs. A cephalosporin analogue, 7beta-[N-Acetyl-L-alanyl-gamma-D-glutamyl-L-lysine]-3-acetoxymethyl-3-cephem-carboxylic acid (compound 6), was conceived and synthesized to test this notion. The X-ray structure of the complex of this cephalosporin bound to the active site of the deacylation-deficient Q120L/Y150E variant of the class C AmpC beta-lactamase from Escherichia coli was solved at 1.71 A resolution. This complex revealed that the surface for interaction with the strand of peptidoglycan that acylates the active site, which is present in PBPs, is absent in the -lactamase active site. Furthermore, insertion of a peptide in the beta-lactamase active site at a location where the second strand of peptidoglycan in some PBPs binds has effectively abolished the possibility for such interaction with the beta-lactamase. A 2.6 ns dynamics simulation was carried out for the complex, which revealed that the peptidoglycan surrogate (i.e., the active-site-bound ligand) undergoes substantial motion and is not stabilized for binding within the active site. These factors taken together disclose the set of structure modifications in the antibiotic resistance enzyme that prevent it from interacting with the peptidoglycan, en route to achieving catalytic proficiency for their intended function.

Stereo- and regioselectivity of Pd(0)/InI-mediated allylic additions to aldehydes and ketones. In situ generation of allylindium(III) intermediates from N-acylnitroso Diels-Alder cycloadducts and 1-amino-4-acetoxycyclopentenes.

Acylnitroso Diels-Alder cycloadduct (11, 37, and 45)- and cyclopentenyl acetate (8 and 9)-derived allylindium(III) species were generated in situ from palladium(0) catalysts and indium(I) iodide, and the stereo- and regiochemistry of their additions to aldehydes and ketones were investigated. Solvent, catalyst, and ionic effects were examined for the reaction of N-acetyl cycloadduct (11) and benzyloxyacetaldehyde (10). The solvent mixture of THF/H(2)O with Pd(OAc)(2).PPh(3) catalysis was found to be optimal. The addition of N-acetyl cycloadduct to aliphatic aldehydes afforded products in good yields and high regio- and stereoselectivity, with the cis-1,4-isomers constituting 90-95% of the products. The reactions with N-Boc (37a) and N-methylcarbamate (37b) cycloadducts also gave the cis-1,4-products predominantly. The same regio- and stereoselectivity applied to the reactions of 4-acetoxy-1-(N-hydroxyphenyacetamido)cyclopentene (8). 4-Acetoxy-1-phenylacetamidocyclopentene (9), however, afforded trans-1,4-products exclusively. Mechanistic speculations involving chelated transition states are described.

Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis.

OBJECTIVE: We assessed the efficacy of S-adenosylmethionine (SAMe), a dietary supplement now available in the Unites States, compared with that of placebo or nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis (OA). STUDY DESIGN: This was a meta-analysis of randomized controlled trials. DATA SOURCES: We identified randomized controlled trials of SAMe versus placebo or NSAIDS for the treatment of OA through computerized database searches and reference lists. OUTCOMES MEASURED: The outcomes considered were pain, functional limitation, and adverse effects. RESULTS: Eleven studies that met the inclusion criteria were weighted on the basis of precision and were combined for each outcome variable. When compared with placebo, SAMe is more effective in reducing functional limitation in patients with OA (effect size [ES] =.31; 95% confidence interval [CI],.099-.520), but not in reducing pain (ES =.22; 95% CI, -.247 to.693). This result, however, is based on only 2 studies. SAMe seems to be comparable with NSAIDs (pain: ES =.12; 95% CI, -.029 to.273; functional limitation: ES =.025; 95% CI, -.127 to.176). However, those treated with SAMe were less likely to report adverse effects than those receiving NSAIDs. CONCLUSIONS: SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with OA without the adverse effects often associated with NSAID therapies.

Use and referral patterns for 22 complementary and alternative medical therapies by members of the American College of Rheumatology: results of a national survey.

BACKGROUND: This study was designed to determine rheumatologists' self-reported knowledge, perceptions of legitimacy, referral patterns, and use in practice of 22 complementary and alternative medicine (CAM) therapies. METHODS: A survey was mailed to a random sample of 2000 physician members of the American College of Rheumatology asking respondents which (if any) CAM therapies they (1) knew enough about to discuss with patients, (2) considered part of "legitimate medical practice," and (3) "personally administered" to patients, or "referred patients to someone else" to administer. The response rate was 47%. RESULTS: On average, the respondents reported knowing enough to discuss 10 of the therapies with patients, considered 9 to be part of legitimate medical practice, and had referred patients to someone else for 8 of the 22 therapies. Correlates of use and/or referral included sex, age, belief in the legitimacy of the therapies, and self-reported knowledge. CONCLUSIONS: These results provide potentially important preliminary data regarding rheumatologists' responses to dramatic increases in the use of CAM therapies among their patients.