Objective. Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis (SSc; scleroderma) and lead to pain, impaired function, and tissue loss. We investigated whether treatment with the endothelin receptor antagonist, bosentan, decreased the development of new digital ulcers in patients with SSc.Methods. This was a randomized, prospective, placebo-controlled, double-blind study of 122 patients at 17 centers in Europe and North America, evaluating the effect of treatment on prevention of digital ulcers. The primary outcome variable was the number of new digital ulcers developing during the 16-week study period. Secondary assessments included healing of existing digital ulcers and evaluation of hand function using the Scleroderma Health Assessment Questionnaire.Results. Patients receiving bosentan had a 48% reduction in the mean number of new ulcers during the treatment period (1.4 versus 2.7 new ulcers; P ‫؍‬ 0.0083). Patients who had digital ulcers at the time of entry in the study were at higher risk for the development of new ulcers; in this subgroup the mean number of new ulcers was reduced from 3.6 to 1.8 (P ‫؍‬ 0.0075). In patients receiving bosentan, a statistically significant improvement in hand function was observed. There was no difference between treatment groups in the healing of existing ulcers. Serum transaminase levels were elevated to >3-fold the upper limit of normal in bosentantreated patients; this elevation is comparable with that observed in previous studies of this agent. Other side effects were similar in the 2 treatment groups.Conclusion. Endothelins may play an important role in the pathogenesis of vascular disease in patients with SSc. Treatment with the endothelin receptor antagonist bosentan may be effective in preventing new digital ulcers and improving hand function in patients with SSc.

Results. Forty-five patients were enrolled. There was significant morbidity and mortality, including 1 death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r ‫؍‬ ؊0.54, P ‫؍‬ 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r ‫؍‬ 0.37, P ‫؍‬ 0.027).Conclusion. We report the first evaluation of a systemically administered and repeatedly dosed anti-TGF␤1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of

Objective. To determine the validity, reliability, and feasibility of durometer measurements of skin hardness as an outcome measure in clinical trials of scleroderma. Methods. Skin hardness was measured during a multicenter treatment trial for scleroderma using handheld digital durometers with a continuous scale. Skin thickness was measured by modified Rodnan skin score (MRSS). Other outcome data collected included the Scleroderma Health Assessment Questionnaire. In a reliability exercise in advance of the trial, 9 investigators examined the same 5 scleroderma patients by MRSS and durometry. Results. Forty-three patients with early diffuse cutaneous systemic sclerosis were studied at 11 international centers

30 patients with supraspinatus or bicipital tendonitis were randomly allocated to active infrared laser therapy at 904 nm three times weekly for 2 weeks, dummy laser or drug treatment for 2 weeks. Objectively maximum active extension, flexion and abduction of the shoulder, and subjectively pain stiffness movement and function were measured at 0 and 2 weeks. Significant improvement of active over dummy laser was noted for all seven assessments. Active laser therapy produced significant improvement over drug therapy for all three objective measures and pain. Naproxen sodium significantly improved only movement and function compared to dummy laser. These results demonstrate the effectiveness of laser therapy in tendonitis of the shoulder.

Two methods have been proposed to quantify the extent of skin involvement in scleroderma. These are (1) a scoring system which quantifies and summates this severity rating in 17 areas of skin surface and (2) a method estimating the percentage of skin involvement using a shaded manikin. We report on a study comparing the inter-observer reliability of these two approaches using the ratings of six clinicians on 12 patients. Systematic bias between observers was noted with both methods, but inter-observer agreement, as-assessed by the intraclass correlation coefficient (ICC), was higher with the score method. The manikin method resulted in a greater degree of disagreement between the observers, as well as a higher amount of random error, reflecting the difficulty of defining the bounds of abnormal skin. Despite the presence of bias, the score method is the preferred method for assessing the level of skin involvement.

NSAIDs significantly reduce overall pain over 4 weeks. This short-term responsiveness is retained, and even after several years of therapy with tiaprofenic acid pain scores increased over 2 weeks when it was changed to placebo. Our results do not show long-term benefits from the use of NSAIDs in OA and the majority of patients had persisting pain and disability despite therapy.

Three different assessment methods for the classification of Raynaud's phenomenon (RP) were compared. These were (i) a previously validated method using colour charts supplemented with a short questionnaire, (ii) answers to a questionnaire based on criteria derived from the consensus opinion of a group of clinicians, and (iii) individual clinician's assessment using standard descriptions based upon the same consensus view. We report the results of a study involving six clinicians and 30 subjects investigating the level of repeatability between the three methods and also the reliability between the six clinicians. There did not exist any overall systematic bias between the six clinicians. Further, agreement between them, as assessed by the kappa statistic, ranged from moderate to good. However, there did exist systematic bias between the results from all three of the classification approaches with agreement between them ranging from only poor to moderate. We conclude that the previously validated colour chart assessment is too insensitive to detect RP. Further, a structured questionnaire based on perceived clinician's opinion could not reproduce clinicians' classification in practice. By contrast, supplying clinicians with standard descriptions did yield a reliable classification system for RP.

The survival of Bacillus subtilis spores at temperatures near 100' was determined in buffered suspensions. Known numbers (about 105/g.) of these spores were mixed into dough which was baked normally into bread. Temperatures taken near the centre of the loaf, near the crust, and midway between the two showed that the temperature within the loaf was 100-IOIO and this was only just attained a t the centre. These temperatures were comparable with similar measurements in various baked products. . Viable counts were made on the dough just before entering the oven and on baked samples taken a t the thermocouple positions.The thermal death/time curves for spores were not exponential, a small proportion of the spores surviving for relatively long periods. In dough, about half the spores germinated between mixing the dough and putting it into the oven. Comparison of the survival of spores in the bread with that expected from the temperature treatment and from the experiments in buffer solutions suggested that the heat resistance in bread is roughly the same as, certainly no less than, that in phosphate buffer of pH 6.5. Only a small proportion of the surviving spores generated ropy patches within a week, owing perhaps to peculiarities in water distribution within the loaf.Corresponding loaves were incubated a t 37".In btlffer solutions vegetative cells were killed in about z min. a t 75". ( I ) IntroductionThat certain bacteria can survive baking in bread is plain, for the well-known defect, ' rope ', is caused by their development from spores usually present in the original flour1 or in the yeast.= Most workers agree that some spores can resist baking. Thus, Aubertin et al.3 confirmed that sporing bacteGa (Bacillus mesentericus, Clostridium -+erfringens) survive, and although Edmonson, Thorn & Giltner4 failed to recover Clostridium botulinzlm that had been included in doughs and baked at 220" for 35 min., more recent workers have succeeded. For example, Ingram & Robinson5 record the isolation of C1. botulinum type A from experimental canned bread ; Soloski & Cryns,6 Kadavy & Dack7 and Bever & Halvorsons also showed that canned bread from doughs inoculated with Cl. botulinum sometimes developed toxin on storage, unless the bread had a pH below 5.0 and a moisture content below 3474, and viable spores but no toxin were found in bread even with these properties.I t seemed to us from a review of the literature that further study of the temperature distribution in a loaf was needed, as apparently there must be occasions when, in parts a t least, lethal temperatures are not attained.Thus we have found : (i) that when cloth contaminated with Staphylococcus aureus and Salmonella paratyphi was inserted in doughs, although the salmonellas were all killed the staphylococci sometimes were not, and other non-sporing bacteria survived too, though they were not identified ; (ii) that living baking-yeast can occasionally be recovered from the crumb, suggesting (cf. Lundg) that the localized temperature cannot have exceeded about 65" ; and...