Digital vascular response to topical glyceryl trinitrate, as measured by laser Doppler imaging, in primary Raynaud's phenomenon and systemic sclerosis.

OBJECTIVE: To investigate digital microvascular responses to topical glyceryl trinitrate (GTN) in patients with primary Raynaud's phenomenon (PRP), limited cutaneous systemic sclerosis (LCSSc) and healthy control subjects, using laser Doppler imaging. METHODS: Ten patients with PRP, 13 with LCSSc and 10 control subjects were studied. Baseline skin microvascular blood flow of the dorsum of the index, middle and ring fingers of the non-dominant hand was measured using scanning laser Doppler imaging. After the initial image, 2% GTN ointment was rubbed on the dorsum of one finger for 1 min; placebo ointment was rubbed on the dorsum of a second finger for 1 min, and the third finger remained untreated. Further laser Doppler scanning of these three fingers was conducted immediately, 10 and 20 min after ointment application. RESULTS: There was increased blood flow response to placebo compared with no treatment (P<0.001) and to GTN compared with placebo (P=0.004). The change in blood flow over time differed significantly between placebo and GTN (P<0.001), but not between placebo and no ointment application: blood flow increased with GTN and decreased with placebo/no treatment at 10 and 20 min. There were no differences in initial baseline blood flow or response between the subject groups. CONCLUSIONS: An exogenous supply of nitric oxide by topical GTN ointment causes local endothelial-independent vasodilatory responses in PRP, LCSSc patients and control subjects. As well as demonstrating the effectiveness of topical GTN in patients with PRP and LCSSc, this study illustrates the ability of laser Doppler imaging to quantify local vasodilatory effects.

The grading of hallux valgus. The Manchester Scale.

This article describes a new, noninvasive method of assessing the severity of hallux valgus deformity by means of a set of standardized photographs. Six podiatrists were independently asked to grade the level of deformity of 13 subjects (26 feet) on a scale of 1 (no deformity) to 4 (severe deformity). The reliability of the four-point scale for the severity of hallux valgus was investigated by means of kappa-type statistics for more than two raters. The results showed that the grading method had excellent interobserver repeatability with a combined kappa-type statistic of 0.86, making it a suitable instrument for clinical and research purposes.

A double-blind placebo-controlled trial of antioxidant therapy in limited cutaneous systemic sclerosis.

OBJECTIVE: To evaluate the effects of a combination of micronutrient antioxidants (selenium, beta-carotene, vitamin C, vitamin E and methionine) with allopurinol in patients with limited cutaneous systemic sclerosis (SSc). METHODS: The study was designed as a placebo-controlled double-blind crossover study. A carryover effect was detected retrospectively for some of the prescribed antioxidants, and so the data were analysed as: (a) a between group comparison of the first 10 week treatment period; and (b) a within group comparison of the first and second 10-week periods in those who received placebo treatment first. Study end-points were plasma von Willebrand factor (vWF), thermographic response to a standard cold challenge, frequency and duration of Raynaud's attacks, patient opinion, and specialised biochemical parameters (fatty acid profiles, antioxidants and markers of free radical injury). RESULTS: Thirty-three patients were recruited. The median duration of Raynaud's phenomenon was 10 years (range 2 to 50 years) in the active-first group and 10 years (range 4 to 53 years) in the placebo-first group. In the 10-week study, there were no differences between the active and placebo groups in the change from baseline for vWF, for the parameters of the rewarming curve, or for patients' symptoms. Despite a rise in circulating antioxidant levels, there was no fall in markers of free radical mediated injury. In the 20-week cross-over study, patients did not experience any clinical benefit from active treatment compared to placebo. CONCLUSION: No clinical benefit could be demonstrated from active treatment. There are several possible explanations for this negative result, including the short duration of therapy. It is possible that antioxidant therapy, to be effective, needs to be given early in the SSc disease process, before the onset of irreversible tissue damage.

Quantitation of microcirculatory abnormalities in patients with primary Raynaud's phenomenon and systemic sclerosis by video capillaroscopy.

OBJECTIVE: : To assess nailfold capillary density and dimensions in patients with primary Raynaud's phenomenon (PRP), limited cutaneous systemic sclerosis (LSSc) and diffuse cutaneous SSc (DSSc), and healthy control subjects. METHODS: : Using the technique of nailfold video capillaroscopy, capillary density and dimensions were averaged from all visible capillaries in a 3 mm length of the nailfold from right and left ring fingers of each subject. Twenty healthy control subjects, 15 patients with PRP, 13 patients with DSSc and 21 patients with LSSc were examined. Intra-observer and inter-observer variability were calculated in 18 and 23 patients, respectively. RESULTS: : There were significant trends for capillary density to fall and for all dimensions to rise across the four groups (P < 0. 0001 for density and all dimensions, order healthy controls, PRP, DSSc and LSSc). Intra- and inter-observer reproducibility studies showed that although there was good correlation between and within observers, the limits of agreement were between +/-25-50% indicating lack of reproducibility. CONCLUSIONS: : Microcirculatory abnormalities can be quantified using the technique of video capillaroscopy and were most marked in patients with LSSc.

The influence of age on nailfold capillary dimensions in childhood.

OBJECTIVE: To identify the influence of age on nailfold capillary dimensions in children between 6 and 15 years. METHODS: Capillary density (the number of capillaries in a 3 mm length of the distal row) and capillary dimensions were measured in 110 healthy children using the technique of nailfold video microscopy. The age groups studied were as follows: 6 to 7 years (17 children), 8 to 9 years (15 children), 10 to 11 years (34 children), 12 to 13 years (24 children), and 14 to 15 years (20 children). RESULTS: There was a significant trend for the arterial and venous diameters to rise with age. However, this trend was not present for apical or loop diameters, nor for the capillary density. Results did not differ between males and females. CONCLUSION: In studies incorporating capillary dimensions in children, results should ideally be age adjusted, and dimensions should not be categorized as normal or abnormal without taking the child's age into account.

Hospital referrals for low back pain: more coherence needed.

Low back pain is a common reason for hospital referral but little is known of the resulting workload in different specialties. All new outpatient attendances for conditions with low back pain were recorded over one month in a teaching hospital and a district general hospital. The patients were seen in at least ten specialties and two-fifths of them had been seen previously with the same symptom in another department. In the two hospitals, low back pain accounted for 15% and 12% of all new outpatient attendances. A more coherent referral policy is needed.

Development and validation of a questionnaire to assess disabling foot pain.

This study outlines the design and validation of a new self-administered instrument for assessing foot pain and disability. The 19-item questionnaire was tested on 45 rheumatology patients, 33 patients who had attended their general practitioner with a foot-related problem and 1000 responders to a population survey of foot disorders. Levels of reported disability were found to be greatest for rheumatology patients and least for community subjects. In addition, the instrument was able to detect differences in disability levels reported by community subjects who did and did not consult with a health care professional and those who did and did not have a history of past and current foot pain. A good level of agreement was found when items on the questionnaire were compared with similar items on the ambulation sub-scale of the Functional Limitation Profile questionnaire. A Cronbach's alpha value of 0.99 and item-total correlation values between 0.25 and 0.62 confirmed the internal consistency of the instrument. Finally the results of a principal components analysis identified three constructs that reflected disabilities that are associated with foot pain: functional limitation, pain intensity and personal appearance. The design of the foot disability questionnaire makes it a suitable instrument for assessing the impact of painful foot conditions in both community and clinical populations.

Endothelial expression of nitric oxide synthases and nitrotyrosine in systemic sclerosis skin.

Although a multisystem disease, systemic sclerosis (SSc) most commonly affects the skin. The skin lesion is characterized by progressive changes, chief amongst which are vascular abnormalities, including endothelial cell (EC) injury and death, and dermal fibrosis. The pathogenesis of the vascular changes, and their relationship to dermal fibrosis, is poorly understood. The purpose of this study was to examine the potential role of nitric oxide (NO)-related free radical production, as part of an assessment of mechanisms leading to endothelial damage. Histologically graded skin biopsies from 33 patients with SSc (ten grade 0, ten grade 1, eight grade 2, and five grade 3) and eight healthy controls were reacted with antibodies against constitutive (eNOS) and inducible (iNOS) forms of nitric oxide synthase and nitrotyrosine. The degree of staining was assessed using a semi-quantitative system and a staining score was developed for the ECs of different vessel types in different areas of dermis at all grades. In biopsies from patients with SSc, superficial microvessel ECs showed a peak of eNOS expression in grade 1 skin which fell as the grade increased. By contrast, iNOS staining increased with the grade of skin lesion, a pattern paralleled by endothelial nitrotyrosine expression. From these findings, it is concluded that a metabolic switch occurs in dermal ECs from endothelial to cytokine inducible forms of NOS during the progression of the skin lesion of SSc. iNOS is a potent inducer of NO production which, in turn, can mediate NO free radical production. At a time of development of the SSc skin lesion when previous studies report evidence of EC damage, the cells express immunodetectable nitrotyrosine, a marker of NO-mediated free radical injury. The data suggest a role for iNOS-induced NO production in EC damage in SSc.

The effects of dothiepin on subjects with rheumatoid arthritis and depression.

BACKGROUND: The relative importance of direct analgesic and antidepressant effects of antidepressant drugs in rheumatoid arthritis (RA) is not clear. METHOD: Forty-eight female out-patients with RA, with depression and/or anxiety, were entered into a double-blind, placebo-controlled study of dothiepin in doses up to 150 mg daily to assess the effects on mood [Hospital Anxiety and Depression (HAD) scale and Hamilton Rating Scale (HRS) for Depression], pain [visual analogue scale (VAS)] and disability [Health Assessment Questionnaire (HAQ)]. RESULTS: Repeated measures multivariate analysis of variance revealed that treatment had a significant effect on pain (F(d.f. 1,39) =5.7, P=0.02). There were further interaction effects between treatment and time on pain (F(d. f. 3,117) =3.3, P=0.03), disability (F(d.f. 3,117)=4.2, P=0.008) and duration of early morning stiffness (F(d.f. 3,117) =3.3, P=0.03). Depression (HRS) was considerably reduced in both the dothiepin and placebo groups, and there was no significant difference between groups. Post hoc analyses using analysis of covariance revealed that, in the dothiepin group, pain was significantly reduced by week 4 and remained so at week 12. Disability scores and duration of early morning stiffness were consistently lower in the dothiepin group, although differences failed to reach statistical significance at any follow-up assessment. In the group as a whole, reductions in pain were highly significantly correlated with reductions in HAD depression (r =0.63, P<0.0005), HAD anxiety (r=0.46, P=0.001) and HRS depression (r=0.37, P=0.01). CONCLUSION: Dothiepin is effective in relieving pain, disability and reducing the duration of early morning stiffness in out-patients with RA. Although there is a general association between pain reduction and improved anxiety and depression, the analgesic effect of dothiepin is independent of its antidepressant effect. Individual variation is considerable and further research should try to identify mechanisms of interaction between the antidepressant and analgesic effects of treatment in different patient groups.

A disease severity scale for systemic sclerosis: development and testing.

OBJECTIVE: To develop and test a severity scale for individual organ involvements in systemic sclerosis (SSc, scleroderma). METHODS: An international study group completed the following tasks: (1) developed a glossary of terms including all pertinent variables for 9 potentially affected organ systems; (2) collected prospective data to determine the feasibility and practicality of each proposed variable; (3) revised the initial list of variables; (4) determined the association of each variable with mortality (a proxy for morbidity) using 579 patients in an existing comprehensive longitudinal scleroderma databank; (5) developed a severity grading scale for each organ system by discussion and consensus; and (6) externally validated the scale using an independent group of 680 patients from the same databank. RESULTS: Nine organ-specific severity scales were developed from 0 (no documented involvement) to 4 (endstage disease). The data required for scale completion are relatively easy and practical for all physicians to obtain. CONCLUSION: This preliminary severity scale will be useful for assessing disease severity status in individual patients both at one point in time and longitudinally. The severity scale will assist in the design and conduct of clinical trials and the comparison of study populations with one another. The scale will serve as a framework for developing a scleroderma disease activity index.

No significant effects of sodium aurothiomalate on haem metabolism and mixed function oxygenase activity in patients with rheumatoid arthritis.

OBJECTIVE: Animal studies suggest that gold compounds impair haem synthesis and increase haem degradation and, as a result, reduce activity of the hepatic haemoproteins cytochromes P-450. The aim of this study was to investigate whether intramuscular gold exerts similar effects in patients with rheumatoid arthritis (RA). METHODS: Urinary porphyrin and precursor excretion, erythrocyte protoporphyrin, and antipyrine clearance, were measured in 6 patients with RA before and 10 weeks after commencement of intramuscular gold. RESULTS: Parameters of haem metabolism were unaffected by gold. While antipyrine clearance was not statistically changed after gold treatment, in 3 of the patients there was an average decrease in antipyrine clearance of 23%. CONCLUSION: Further studies examining RA patients at different time points are required to investigate further the possibility of reduced hepatic drug metabolising activity during prolonged treatment with gold.

Predicting who develops chronic low back pain in primary care: a prospective study.

OBJECTIVES: To quantify the relative contribution of premorbid and episode specific factors in determining the long term persistence of disabling symptoms of low back pain. DESIGN: Prospective cohort study. SETTING: Two general practices in the south Manchester area. PARTICIPANTS: 180 patients, who previously participated in a cross sectional population survey, who consulted because of low back pain during the study period. They were followed at 1 week and 3 and 12 months after consultation. MAIN OUTCOME MEASURE: Persistent disabling low back pain in the 12 months after the consultation. RESULTS: Disabling low back pain persisted in one third of participants after consultation and was more common with increasing age, among those with a history of low back pain, and in women. Persistence of symptoms was associated with "premorbid" factors (high levels of psychological distress (odds ratio 3.3; 95% confidence interval 1.5 to 7.2), poor self rated health (3.6; 1.9 to 6.8), low levels of physical activity (2.8; 1.4 to 5.6), smoking (2. 1; 1.0 to 4.3), dissatisfaction with employment (2.4; 1.3 to 4.5)) and factors related to the episode of low back pain (duration of symptoms, pain radiating to the leg (2.6; 1.3 to 5.1), widespread pain (6.4; 2.7 to 15), and restriction in spinal mobility). A multivariate model based on six factors identified groups whose likelihood of persistent symptoms ranged from 6% to 70%. CONCLUSIONS: The presence of persistent low back pain is determined not only by clinical factors associated with pain but also by the premorbid state.

Laser doppler imaging--a new technique for quantifying microcirculatory flow in patients with primary Raynaud's phenomenon and systemic sclerosis.

This was a pilot study to investigate the new technique of laser Doppler imaging (scanning laser Doppler) as a tool to quantify microvascular blood flow in the digits of patients with primary Raynaud's phenomenon (PRP) and systemic sclerosis (SSc), and to determine in the first instance whether the flux patterns obtained differ between patients with SSc, patients with PRP, and healthy control subjects. Laser Doppler images of the dorsum of the hand and fingers were acquired at 23 and 30 degrees C in 17 healthy control subjects, 7 patients with PRP, 9 patients with the diffuse cutaneous variant of SSc, and 24 patients with the limited cutaneous variant of SSc. Different flux parameters were compared between groups. Analysis of variance found significant differences between groups in two tests: maximum difference in flux between fingertips of the same hand at 23 degrees C (P = 0.001) and maximum gradient in flux along a finger ("distal-dorsal" flux difference) at 30 degrees C (P = 0. 019). Post hoc tests highlighted the differences between controls and patients with limited cutaneous SSc. This pilot study suggests that laser Doppler imaging may allow objective measurement of microvascular flow in patients with PRP and SSc. This new technique may overcome many of the problems inherent in single-channel laser Doppler equipment.

Predictors of early improvement in low back pain amongst consulters to general practice: the influence of pre-morbid and episode-related factors.

Low back pain symptoms are extremely common. affecting as many as 80% of the population at some time in their lives. However, the majority of the medical costs arise from the minority of patients whose symptoms become chronic. The authors propose a model in which chronicity is determined not only by factors related to the episode of low back pain, but also factors prior to the onset of symptoms (pre-morbid factors). No previous study has collected information on predictors of low back pain chronicity prior to the onset of symptoms. Participants in the South Manchester Low Back Pain Study, recruited by means of a cross-sectional population survey were followed prospectively over 18 months to identify those who consulted their general practitioner with a new episode of low back pain. At interview, 1-2 weeks post-consultation, it was determined whether or not subjects' symptoms had improved. In males, low levels of psychological distress, a higher than average reported level of physical activity, being in employment, and being satisfied with current work status were associated with a quick improvement in symptoms. In addition factors related to the episode, namely a short duration before consultation and symptoms with a sudden onset and confined to the lower back area, also strongly predicted a good early outcome. Using information on both pre-morbid and episode related factors, groups of male patients were identified whose probability of an early resolution of symptoms ranged between 0.25 and 1. Few factors, either pre-morbid or episode-related, were strongly associated with outcome amongst females. This large population-based study has shown, despite the known heterogeneity in the origin of low back pain and the pathologies associated with symptoms, an early improvement in symptoms amongst male attenders at general practice can be predicted on the basis of a small number of variables.

Non-invasive assessment of digital vascular reactivity in patients with primary Raynaud's phenonenon and systemic sclerosis.

OBJECTIVE: To examine digital microvascular responses in patients with primary Raynaud's phenomenon (PRP) and systemic sclerosis (SSc), and compare these to the responses in healthy control subjects. METHODS: Digital microvascular responses to repeated episodes of iontophoresis of acetylcholine chloride (endothelial-dependent), sodium nitroprusside (endothelial-independant) and adrenaline were measured using dual-channel laser Doppler in 8 healthy control subjects, 8 patients with PRP and 8 patients with SSc. RESULTS: There were no significant differences in responses between groups. For each chemical the greatest response was generally seen in period 7 of the protocol (after the third episode of iontophoresis). For acetylcholine chloride in period 7, the age and baseline adjusted ratio of the maximum response of PRP to control was 0.93, 95% CI (0.26, 3.38) and for SSc to control it was 0.60, 95% CI (0.13, 2.81). For sodium nitroprusside in period 7, this age and baseline adjusted ratio of the maximum response of PRP to control was 1.31, 95% CI (0.74, 2.32) and for SSc to control it was 1.35, 95% CI (0.68, 2.67). For adrenaline in period 7, the age and baseline adjusted ratio of PRP to control was 1.51, 95% CI (0.79, 2.89) and for SSc to control it was 2.18, 95% CI (1.01, 4.69). CONCLUSION: This study demonstrates the usefulness of iontophoresis of vasoactive chemicals, combined with laser Doppler blood flowmetry, in the non-invasive assessment of dermal microvascular responses. One possible explanation for the lack of difference in responses between groups is that vasoactive chemicals other than those discussed are important in the pathophysiology of primary and secondary Raynaud's phenomenon.

The role of inflammation in disk herniation-associated radiculopathy.

OBJECTIVE: The causes and physiopathology of low-back pain and acute lumbar radiculopathy remain unclear. A compression of the nerve root by protruded disk has been suggested but explains only partially the physiopathology of radicular pain. This article provides an overview of the role of inflammation in disk herniation-associated radiculopathy. METHODS: A review of the relevant literature in American and European medical journals was performed. RESULTS: Several studies have identified inflammatory mediators (phospholipase A2, prostaglandin E2, leukotrienes, nitric oxide, immunoglobulins, pro-inflammatory cytokines such as interleukin [IL]-1alpha, IL-1beta, IL-6, and tumor necrosis factor alpha [TNFalpha]) and autoimmune reaction (macrophages expressing IL-1beta, intercellular adhesion molecules) in disk herniation. An appealing hypothesis is that the leakage of these agents may produce an excitation of the nociceptors, a direct neural injury, a nerve inflammation, or an enhancement of sensitization to other pain-producing substances (such as bradykinin), leading to the nerve root pain. However, the role of these inflammatory mediators in the pathophysiology of lumbar radiculopathy has not been proven. Several findings suggest that this inflammatory response, which occurs in the early stage of disk herniation, is transient. Indeed, most studies of chronic disk herniation samples failed to demonstrate inflammation. CONCLUSION: Although inflammation may partially explain lumbar radiculopathy, involvement of inflammatory mediators in the physiopathology of disk herniation-associated radiculopathy has not been proven.

Matrix metalloproteinases: the clue to intervertebral disc degeneration?

STUDY DESIGN: A review of the current literature on the role of matrix metalloproteinases in intervertebral disc degeneration. OBJECTIVE: To detail the characteristics of matrix metalloproteinases (classification, structure, substrate specificity and regulation) and to report previous studies of intervertebral discs. SUMMARY OF BACKGROUND DATA: Degeneration of the intervertebral disc, a probable prerequisite to disc herniation, is a complex phenomenon, and its physiopathologic course remains unclear. Matrix metalloproteinases probably play an important role but have received sparse attention in the literature. METHODS: A systematic review of studies reporting a role of matrix metalloproteinases in intervertebral disc degeneration. RESULTS: In several studies, investigators have reported the presence of proteolytic enzymes from disc culture systems and disc tissue extracts in degenerated human intervertebral discs, especially collagenase-1 (MMP-1) and stromelysin-1 (MMP-3). The matrix metalloproteinases are regulated by specific inhibitors (tissue inhibitors of metalloproteinases, or TIMPS), cytokines (interleukin-1), and growth factors. CONCLUSIONS: This field of application is of particular interest because conventional treatments are disappointing in chronic low back pain. Clinical trials with specific inhibitors of metalloproteinases are beginning in osteoarthritis.