Presence of gout is associated with increased prevalence and severity of knee osteoarthritis among older men: results of a pilot study.

BACKGROUND: Gout and osteoarthritis (OA) are the most prevalent arthritides, but their relationship is neither well established nor well understood. OBJECTIVES: We assessed whether a diagnosis of gout or asymptomatic hyperuricemia (AH) is associated with increased prevalence/severity of knee OA. METHODS: One hundred nineteen male patients aged 55 to 85 years were sequentially enrolled from the primary care clinics of an urban Veterans Affairs hospital, assessed and categorized into 3 groups: gout (American College of Rheumatology Classification Criteria), AH (serum urate ≥6.8 mg/dL, no gout), and control (serum urate <6.8 mg/dL, no gout). Twenty-five patients from each group subsequently underwent formal assessment of knee OA presence and severity (American College of Rheumatology Clinical/Radiographic Criteria, Kellgren-Lawrence grade). Musculoskeletal ultrasound was used to detect monosodium urate deposition at the knees and first metatarsophalangeal joints. RESULTS: The study showed 68.0% of gout, 52.0% of AH, and 28.0% of age-matched control subjects had knee OA (gout vs control, P = 0.017). Odds ratio for knee OA in gout versus control subjects was 5.46 prior to and 3.80 after adjusting for body mass index. Gout subjects also had higher Kellgren-Lawrence grades than did the control subjects (P = 0.001). Subjects with sonographically detected monosodium urate crystal deposition on cartilage were more likely to have OA than those without (60.0 vs 27.5%, P = 0.037), with crystal deposition at the first metatarsophalangeal joints correlating most closely with OA knee involvement. CONCLUSIONS: Knee OA was more prevalent in gout patients versus control subjects and intermediate in AH. Knee OA was more severe in gout patients versus control subjects.

Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: concordance between readers.

OBJECTIVE: Criteria for sonographic diagnosis of monosodium urate (MSU) crystal deposition have been developed, but the interreader reproducibility of this modality is not well established. We therefore assessed agreement using a systematic approach. METHODS: Fifty male subjects ages 55-85 years were recruited during primary care visits to an urban Veterans Affairs hospital, and were assessed by musculoskeletal ultrasound (US) of the knees and first metatarsophalangeal (MTP) joints to evaluate for the double contour sign and tophi as evidence of MSU crystal deposition. Images were read by 2 blinded rheumatologists trained in musculoskeletal US, and the degree of concordance was determined for individual subjects, total joints, femoral articular cartilage (FAC), and first MTP joints. Subjects were further categorized into 3 diagnostic groups: gout, asymptomatic hyperuricemia (no gout, serum uric acid [UA] ≥6.9 mg/dl), and controls (no gout, serum UA ≤6.8 mg/dl), and reader concordance within these 3 groups was assessed. RESULTS: We observed almost perfect agreement between readers for 1) individual subjects (yes/no; n = 50, 100% agreement, κ = 1.000), 2) total joints (n = 200, 99% agreement, κ = 0.942), 3) FAC (n = 100, 99% agreement, κ = 0.942), and 4) first MTP joints (n = 100, 99% agreement, κ = 0.942). Furthermore, findings by side (right/left) and diagnostic group (gout, asymptomatic hyperuricemia, control) showed substantial to almost perfect concordance for all measures. MSU deposition was seen most commonly in gout patients, and deposition was also seen in some subjects with asymptomatic hyperuricemia, but in only 1 control. CONCLUSION: Musculoskeletal US is reliable for detecting MSU deposition in FAC and first MTP joints in gout and asymptomatic hyperuricemia.

Molecular cloning and functional characterization of MCH2, a novel human MCH receptor.

Melanin-concentrating hormone (MCH) is involved in the regulation of feeding and energy homeostasis. Recently, a 353-amino acid splice variant form of the human orphan receptor SLC-1 () (hereafter referred to as MCH(1)) was identified as an MCH receptor. This report describes the cloning and functional characterization of a novel second human MCH receptor, which we designate MCH(2), initially identified in a genomic survey sequence as being homologous to MCH(1) receptors. Using this sequence, a full-length cDNA was generated with an open reading frame of 1023 base pairs, encoding a polypeptide of 340 amino acids, with 38% identity to MCH(1) and with many of the structural features conserved in G protein-coupled receptors. This newly discovered receptor belongs to class 1 (rhodopsin-like) of the G protein-coupled receptor superfamily. HEK293 cells transfected with MCH(2) receptors responded to nanomolar concentrations of MCH with an increase in intracellular Ca(2+) levels and increased cellular extrusion of protons. In addition, fluorescently labeled MCH bound with nanomolar affinity to these cells. The tissue localization of MCH(2) receptor mRNA, as determined by quantitative reverse transcription-polymerase chain reaction, was similar to that of MCH(1) in that both receptors are expressed predominantly in the brain. The discovery of a novel MCH receptor represents a new potential drug target and will allow the further elucidation of MCH-mediated responses.

The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K(+) channels TREK-1 and TRAAK.

We have cloned and functionally expressed the human orthologue of the mouse TRAAK gene. When cDNA for hTRAAK is expressed in either Xenopus oocytes or HEK293 cells it forms a K(+)-selective conductance and hyperpolarises the resting membrane potential. Quantitative mRNA expression analysis using Taqman revealed that hTRAAK mRNA is predominantly present in the central nervous system where it exhibits a regionally diverse pattern of expression. Like the related channel TREK-1, the activity of TRAAK was potentiated by arachidonic acid. The neuroprotective agent sipatrigine (10 microM) inhibited both hTREK-1 (73.3+/-4.4%) and hTRAAK (45.1+/-11.2%) in a reversible, voltage-independent manner. Inhibition of both channels was dose-dependent and for TREK-1 occurred with an IC(50) of 4 microM. The related compound lamotrigine, which is a better anticonvulsant but weaker neuroprotective agent than sipatrigine, was a far less effective antagonist of both channels, producing <10% inhibition at a concentration of 10 microM.

Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery.

Potassium channels are amongst the most heterogeneous class of ion channels known and are responsible for mediating a diverse range of biological functions. The most recently described family of K+ channels, the 'two pore-domain family', contain four membrane spanning domains and two pore-forming domains, suggesting that two channel subunits associate to form a functional K+ pore. Several sub-families of the two pore domain potassium channel family have been described, including the weakly inward rectifying K+ channel (TWIK), the acid-sensitive K+ channel (TASK), the TWIK-related K+ channel (TREK) and the TWIK-related arachidonic acid stimulated K+ channel (TRAAK). However, comparison of the mRNA expression of these channels has been difficult due to the differences in methods used and the species studied. In the present study, we used a single technique, TaqMan semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), to investigate the mRNA distribution of all currently known two pore potassium channels in human central nervous system (CNS) and peripheral tissues. TWIK-1 and the TWIK-1-like channel KCNK7 were predominantly expressed in the CNS, in contrast to TWIK-2 which was preferentially expressed in peripheral tissues such as pancreas, stomach, spleen and uterus. TASK-1 was expressed in the CNS and some peripheral tissues, whereas TASK-2 was exclusively expressed in the periphery except for mRNA expression observed in dorsal root ganglion and spinal cord. In addition, mRNA expression of the recently identified TASK-3, was almost completely exclusive to cerebellum with little or no mRNA detected in any other tissues. TREK-1 and TRAAK mRNA expression was predominantly CNS specific in contrast to the closely related TREK-2, which was expressed in both CNS and peripheral tissues. Studying the mRNA expression profiles of known two pore domain K+ channels will aid in the understanding of the biological roles of these channels. Furthermore, identification of common areas of expression may help identify which channels, if any, associate to form heteromeric K+ channel complexes.

Cloning, localisation and functional expression of a novel human, cerebellum specific, two pore domain potassium channel.

We have isolated, by degenerate PCR, a complementary DNA encoding a novel two pore domain potassium channel. This is the 7th functional member of the human tandem pore domain potassium channel family to be reported. It has an open reading frame of 1.125 kb and encodes a 374 amino acid protein which shows 62% identity to the human TASK-1 gene: identity to other human members of the family is 31-35% at the amino acid level. We believe this gene to be human TASK-3, the ortholog of the recently reported rat TASK-3 gene: amino acid identity between the two is 74%. 'Taqman' mRNA analysis demonstrated a very specific tissue distribution pattern, showing human TASK-3 mRNA to be localised largely in the cerebellum, in contrast rat TASK-3 was reported to be widely distributed. We have shown by radiation hybrid mapping that human TASK-3 can be assigned to chromosome 8q24.3. Human TASK-3 was demonstrated to endow Xenopus oocytes with a negative resting membrane potential through the presence of a large K(+) selective conductance. TASK-3 is inhibited by extracellular acidosis with a mid-point of inhibition around pH 6. 5, supporting the predictions from the sequence data that this is a third human TASK (TWIK-related acid sensitive K(+) channel) gene.

Neuromedin U is a potent agonist at the orphan G protein-coupled receptor FM3.

Neuromedins are a family of peptides best known for their contractile activity on smooth muscle preparations. The biological mechanism of action of neuromedin U remains unknown, despite the fact that the peptide was first isolated in 1985. Here we show that neuromedin U potently activates the orphan G protein-coupled receptor FM3, with subnanomolar potency, when FM3 is transiently expressed in human HEK-293 cells. Neuromedins B, C, K, and N are all inactive at this receptor. Quantitative reverse transcriptase-polymerase chain reaction analysis of neuromedin U expression in a range of human tissues showed that the peptide is highly expressed in the intestine, pituitary, and bone marrow, with lower levels of expression seen in stomach, adipose tissue, lymphocytes, spleen, and the cortex. Similar analysis of FM3 expression showed that the receptor is widely expressed in human tissue with highest levels seen in adipose tissue, intestine, spleen, and lymphocytes, suggesting that neuromedin U may have a wide range of presently undetermined physiological effects. The discovery that neuromedin U is an endogenous agonist for FM3 will significantly aid the study of the full physiological role of this peptide.

Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus.

The t(X;18)(p11.2;q11.2) chromosomal translocation commonly found in synovial sarcomas fuses the SYT gene on chromosome 18 to either of two similar genes, SSX1 or SSX2, on the X chromosome. The SYT protein appears to act as a transcriptional co-activator and the SSX proteins as co-repressors. Here we have investigated the functional domains of the proteins. The SYT protein has a novel conserved 54 amino acid domain at the N-terminus of the protein (the SNH domain) which is found in proteins from a wide variety of species, and a C-terminal domain, rich in glutamine, proline, glycine and tyrosine (the QPGY domain), which contains the transcriptional activator sequences. Deletion of the SNH domain results in a more active transcriptional activator, suggesting that this domain acts as an inhibitor of the activation domain. The C-terminal SSX domain present in SYT-SSX translocation protein contributes a transcriptional repressor domain to the protein. Thus, the fusion protein has transcriptional activating and repressing domains. We demonstrate that the human homologue of the SNF2/Brahama protein BRM co-localizes with SYT and SYT-SSX in nuclear speckles, and also interacts with SYT and SYT-SSX proteins in vitro. This interaction may provide an explanation of how the SYT protein activates gene transcription.

Skin irritation potential of mixed surfactant systems.

Virtually all current detergent formulations contain mixtures of surfactants. Our experience and test data on these formulations, which is in agreement with that of many others, has shown that in use the formulations exhibit lower acute irritation potential than predicted by simple summation of the irritation potential of the individual actives. Using the criteria of the Dangerous Preparations Directive (EC Directive 88/379/EEC), many of these formulations classify as irritant in the neat state, with consequent labelling requirements. Such classification is based on addition of irritant components giving a total concentration which exceeds a nominal threshold. In this study, mixtures of surfactants were tested by application to a panel of 31 human volunteers for up to 4 hr, using the technique established for the assessment of acute skin irritation potential. The positive control, sodium dodecyl sulfate (SDS) at 20% concentration, gave an 84% positive response. Dimethyl dodecyl amido betaine (DDAB) at the same concentration gave a 94% response. However, a combination of 20% of each of these surfactants in the same panellists gave a response of only 44%--a significant reduction in the irritation potential. A further test conducted with a mixture of 10% SDS and 10% DDAB in a second panel gave a 31% positive response compared with a 94% positive response to the 20% SDS control in that panel. These results clearly demonstrate that the acute irritation potential of mixed surfactants cannot be predicted by simple summation of the irritation potential of the component substances. Initial results of the mechanistic investigation indicate that the reduced irritation induced by the mixed surfactant systems correlates with a reduced critical micelle concentration (CMC). However, the reduced CMC itself seems not to be responsible for the lowered irritation, since these experiments were conducted at concentrations well above the CMC. It is proposed that the critical event leading to skin irritation is binding to skin protein and that in mixed surfactant systems, the individual surfactants exhibit less affinity for this protein.

Effects of antihypertensive drugs on coronary artery disease risk: a meta-analysis.

1. The effects of antihypertensive drugs on lipids may also influence their effect on coronary artery disease (CAD). However, the clinical significance of these effects and the extent to which they persist during long-term therapy is uncertain. 2. We performed a meta-analysis on 23 randomized trials published between 1988 and 1994 that compared the effects of atenolol, celiprolol (a beta-blocker with beta 2-adrenoceptor intrinsic sympathomimetic activity), enalapril, nifedipine and doxazosin on plasma cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides and blood pressure (BP). 3. Predicted changes in CAD risk were calculated by incorporating the results for these parameters into the Framingham equations. 4. While there were no differences in antihypertensive efficacy between the drugs, atenolol significantly (P < 0.05) reduced HDL-C and increased total cholesterol, LDL-C and triglycerides compared with celiprolol, enalapril, doxazosin and nifedipine. 5. The magnitude of the effects on lipids was not significantly influenced by the duration of therapy (up to 3 years for atenolol and doxazosin and up to 2 years for celiprolol). 6. The improvement in Framingham equation point scores (systolic BP formula) was significantly (P < 0.05) less for atenolol (-0.54; confidence intervals (CI) -0.29-(-0.78)) than for celiprolol (-1.69; CI -0.68-2.70), doxazosin (-1.67; CI -1.11-(-2.23)), enalapril (-1.43; CI 0.23-(-3.07)) and nifedipine (-1.91; CI -1.22-(-2.59)). Similar results were obtained for the Framingham diastolic BP formula. 7. These results suggest that the adverse effects of atenolol ]on plasma lipids do not improve with prolonged therapy and are theoretically great enough to reduce its efficacy in reducing CAD by approximately two thirds compared with antihypertensive drugs that do not adversely affect plasma lipids. However it must be emphasized that these are theoretical effects. In order to determine the actual differences between these drugs on CAD end points, studies using these end points are required.

Detection and significance of occult metastases in node-negative breast cancer.

The clinical value of lymph node immunohistochemistry was assessed in 343 consecutive patients with apparently node-negative breast cancer using antimucin monoclonal antibodies BC2, BC3 and 3E1.2. Occult metastases were detected in 41 patients (12 per cent). Although most of these were micrometastatic (< 2 mm in diameter), larger or diffuse deposits were found in ten patients. Blind assessment of repeat haematoxylin and eosin stained sections detected metastases in ten of the 41 patients with occult metastases. After a median follow-up of 79 months, patients with occult metastases had a shorter time to disease recurrence (P < 0.05) but not to death. After adjustment for other prognostic factors, the presence of occult metastases in two or more nodes was the most significant predictor of both disease recurrence (P < 0.01) and death (P < 0.01). When the ten patients with positive haematoxylin and eosin sections were excluded from the analysis, the presence of occult metastases in two or more nodes was still associated with a reduced disease-free interval (P < 0.05) and survival (P < 0.05). Lymph node immunohistochemistry is a simple technique affording more accurate definition of nodal involvement than conventional methods.

A comparison of ketoprofen SR and sulindac in the elderly with rheumatoid arthritis.

The elderly (age > 65 years) are more vulnerable to side-effects induced by non-steroidal anti-inflammatory drugs (NSAIDs). We therefore performed a double-blind comparative study of ketoprofen SR and sulindac in patients with active rheumatoid arthritis, 65 years of age or older. Sulindac was chosen because of its possible renal sparing effects, and ketoprofen SR because of its short half life and sustained release delivery system. Eighty patients were entered. More patients withdrew from the study due to side-effects in the sulindac group; both treatment groups had a high incidence of side-effects during this study and during previous exposure to other NSAIDs, demonstrating that the elderly are susceptible to side-effects from NSAIDs.

Correlation between injury severity scores and subjective ratings of injury severity: a basis for trauma audit.

A retrospective review of 1900 road accident victims attending the emergency departments of two Melbourne hospitals was undertaken to identify Injury Severity Score levels which could distinguish between minor, moderate, severe and critical injury. Injuries scoring ISS 6 or below were designated 'minor' because they were associated with a low risk of requiring admission to hospital. Case notes of patients scoring above ISS 6 were then reviewed by a panel of clinicians, who independently rated each patient's overall injury severity as moderate, severe or critical according to what was recorded in the notes and their 'clinical' judgement. ISS values were compared with clinicians' ratings. Measures of each clinician's individual rating consistency, and correlation between pairs of clinicians with respect to inter-rater consistency, were made. By combining data from both hospitals it emerged that 'moderate' injury corresponded to ISS 8-13, 'severe' to ISS 14-20 and 'critical' to ISS 21 and above. These ISS breakpoints will be useful in selecting groups of injured patients for future trauma audit studies.

The Canadian Physiotherapy Quality of Care Project. Analysis of a derailed project.

The Physiotherapy Quality of Care Project was a project of the Canadian Physiotherapy Association, sponsored by the Canadian government to ensure the quality of physiotherapy. A consensus committee of physiotherapy educators and managers developed and tested an instrument to measure changes in patients' functional status during physiotherapy. Despite scientific development and wide distribution, this technology was not adopted. Alternative methods, which were heavily marketed, gained nationwide use instead.

Canadian physiotherapists' professional identity: an exploratory survey.

This survey was funded and conducted by the Ontario and Canadian Physiotherapy Association Task Force on Professional Identity. Professional identity influences the image an occupation projects to its clients, the public, other occupations and governments. As an aid to planning strategy for advancing the professional image of physiotherapy, an open-ended questionnaire explored Canadian physiotherapists' professional identity. Professional identity is promoted by Canadian Physiotherapy Association (CPA) branches and districts. Most therapists identified their skills and potential benefit for patients, but only 15% identified themselves as a member of a health profession involved in a rewarding career. Physiotherapists have achieved many characteristics of an independent profession, but expressed frustration reveals that some members lack power on a personal and professional level.

A comparison of the efficacy of captopril and enalapril given once daily for the treatment of hypertension: a study using 24-hour ambulatory blood pressure monitoring.

Sixteen patients who had essential hypertension were stabilized on either captopril or enalapril monotherapy and had 24-hour blood pressure profiles monitored by using one of two automatic, non-invasive ambulatory systems: Spacelabs 5300 (Squibb, Princeton, NJ) or PAR Physioport II (Kardiotec, Mannheim). In four subjects (group 1), ambulatory pressures were repeated 4 to 6 weeks later using the same equipment and the same drug. In four subjects (group 2), the drug was changed (dose ratio: captopril:enalapril, 5:1) after the first measurement, but the monitoring equipment was not changed. In four subjects (group 3), the drug was constant, but the equipment was changed for the second measurement of ambulatory pressure. In four subjects (group 4), both drug and equipment were reversed after the first measurement. The results showed that both drugs (given once daily) controlled blood pressure during the 24-hour period, with no clinically significant difference between them.

Oestrogen receptor assay of breast cancer by immunocytochemistry of fine needle aspirates.

Sixty-five patients with operable breast cancer were studied to assess the reliability of immunocytochemical analysis of oestrogen receptor (ER-ICA) in specimens obtained by percutaneous fine needle aspiration. Results obtained with the commercially available ER-ICA kit were compared with those obtained by the routine biochemical radioligand assay of oestrogen receptor (ER) on excised tumour specimens. Fifty-two of 65 percutaneous aspirates were evaluable. Of these, thirty-five (67%) were ER positive by the radioligand method. ER-ICA was found to be a reliable method for oestrogen receptor assay, with a high concordance (90.4%) between it and the radioligand essay. The ER-ICA assay had a sensitivity of 89%, specificity of 94%, positive predictive value of 97% and negative predictive value of 80%. ER-ICA assay performed on material obtained by fine-needle aspiration is a reliable method of ER assay. It can replace formal biopsy for patients with inoperable primary tumours or accessible metastases.

Effects of combined insulin-sulfonylurea therapy in type II patients.

We conducted a double-blind crossover study to determine which patient characteristics best predict a beneficial response to combined insulin-glyburide therapy. Glyburide (15 mg/day) or placebo was added to the treatment regimen of 31 insulin-treated type II (non-insulin-dependent) diabetic subjects. During glyburide therapy, there was a significant improvement in glycemic control with a reduction in glycosylated hemoglobin from 9.9 +/- 1.3 to 9.1 +/- 1.3% (P less than .001). Patients who responded had higher fasting C-peptide levels (P less than .001) and shorter durations of insulin therapy (P less than .01) than those who did not respond. Glyburide withdrawal was associated with a greater than expected deterioration in glycemic control. Patients on insulin therapy for greater than 8 yr are unlikely to benefit significantly from the addition of glyburide to their treatment regimen.

Is captopril effective in controlling blood pressure when administered once daily? An assessment using 24-h ambulatory blood pressure monitoring.

Twelve patients with essential hypertension receiving captopril monotherapy or captopril in conjunction with a diuretic had their 24-h blood pressure profiles monitored using an automatic, non-invasive ambulatory method. The study examined the efficacy of once a day versus twice a day administration of the ACE inhibitor in controlling blood pressure. Six untreated subjects with borderline hypertension were also studied using the same monitoring equipment and with the same frequency, to act as controls because of the possibility of repeated use of the device causing a 'familiarisation' effect. The results obtained indicated that if anything, the once daily dosing produced marginally better blood pressure values. The amplitude of the diurnal blood pressure variation was reduced on a 'second-wearing' of the monitoring equipment suggesting some degree of familiarisation with the apparatus.