The combination of calcipotriol and methotrexate compared with methotrexate and vehicle in psoriasis: results of a multicentre placebo-controlled randomized trial.

BACKGROUND: A multicentre, randomized, double-blind, vehicle-controlled, parallel-group study was carried out to study the effect of the addition of calcipotriol ointment to methotrexate (MTX) therapy in patients with psoriasis vulgaris. OBJECTIVES: To investigate whether the addition of calcipotriol to treatment with MTX has an MTX-sparing effect, and whether the combination of treatments is safe. Additionally, to compare the effect of calcipotriol or vehicle on the duration of the relapse-free interval after cessation of MTX. METHODS: Patients on maintenance therapy with MTX with controlled psoriasis were selected. The study was divided into three phases: (i) an MTX-free phase with double-blind treatment with either calcipotriol ointment or vehicle; (ii) an MTX titration phase with open MTX treatment and additional double-blind treatment with either calcipotriol or vehicle until target response; and (iii) follow-up phase: in a group of 97 patients, psoriasis was assessed using the modified psoriasis severity score, patients' assessment and safety parameters were monitored as well. RESULTS: The combined use of calcipotriol with MTX resulted in an MTX-sparing effect of 3.4 mg week-1 (phase (II) and 2.6 mg week-1 (phase I and II taken together), while still maintaining efficacy. Calcipotriol treatment increased the time to relapse of psoriasis following discontinuation of MTX: 113 days vs. 35 days. A decrease in aspartate aminotransferase and alanine aminotransferase was seen during the study of 8% (calcipotriol) and 12% (vehicle). CONCLUSIONS: The combination of calcipotriol and MTX was safe and well tolerated. The combination resulted in lower cumulative dosages of MTX compared with MTX and vehicle. Therefore the risk of side-effects is substantially decreased.

Evaluation of the relationship between preoperative risk scores, postoperative and total length of stays and hospital costs in coronary bypass surgery.

OBJECTIVES: Several risk indices have been developed for the prediction of postoperative mortality and morbidity in coronary artery bypass operations, in which the risk scores are currently recorded as routine praxis. The aim of the present study was to determine whether the risk scores can be used to predict the hospital (LOS) and postoperative (POS) lengths of stay and total costs among coronary artery bypass graft (CABG) patients. METHODS: All first-time CABG patients (n=2104) treated at Helsinki University Central Hospital during 1997-1998 were preoperatively scored using the Cleveland Clinic preoperative model. A multivariate analysis was used to evaluate the effects of the risk scores on the LOS and POS and total costs. RESULTS: The mean preoperative risk score for the patients was 1.69. The increase in preoperative risk score was associated with an increase in the LOS (0.8 days by point), and POS (with 0.55 days by point). An age over 74 years increased the LOS by an extra day. The mean total cost for the CABG procedure was 8750 euros (SD 4430 euros). The costs increased as the risk score increased. Compared with the zero risk score, a score value of 2 was associated with a 1300 euros increase in total cost and a score value of over 6 was associated with an over 7000 euros cost increase. On average, the costs increased by 6980 euros (80%) for one major complication and by 935 euros (10%) in the elderly (>74 years of age). CONCLUSIONS: The results show that increasing risk scores were associated with longer postoperative hospital lengths of stay (POS and LOS) and with increased total costs. An age over 74 years appears to be an independent risk factor in increased POS, LOS and total cost. These results may help to estimate the impact of the preoperative risk profile on the resource requirement in CABG surgery.

Transfusion practice in Helsinki University Central Hospital: an analysis of diagnosis-related groups (DRG).

Transfusion data combined with data automatically recorded in hospital databases provides an outstanding tool for blood utilization reporting. When the reporting is performed with an online analytical processing (OLAP) tool, real time reporting can be provided to blood subscribers. When this data is combined with a common patient classification system, Diagnosis-Related Groups (DRG), it is possible to produce statistical results, that are similar in different institutions and may provide a means for international transfusion bench-marking and cost comparison. We use a DRG classification to describe the transfusion practice in Helsinki University Central Hospital. The key indicators include the percentage of transfused patients, the number of transfused units and costs in different DRG groups, as well as transfusion rates per DRG weighted treatment episodes. Ninety-three per cent of all transfusions could be classified into different DRGs. The largest blood-using DRG group was acute adult leukaemia (DRG 473), which accounted for 10.4% of all transfusion costs. The 13 largest blood consuming DRGs accounted for half the total costs in 1998. Currently, there is a lack of an internationally accepted standardized way to report institutional or national transfusion practices. DRG-based transfusion reporting might serve as a means for transfusion benchmarking and thus aid studies of variations in transfusion practice.

Isotretinoin improves the appearance of photodamaged skin: results of a 36-week, multicenter, double-blind, placebo-controlled trial.

Photodamaged skin occurs as a result of long-term exposure to ultraviolet radiation. The incidence of photodamage in European and North American populations with Fitzpatrick skin types I, II, and III is estimated at 80% to 90%. We conducted a double-blind clinical trial to test the efficacy and safety of 0.1% isotretinoin versus vehicle cream in 800 patients with moderate to severe photodamaged skin. Patients applied either 0.1% isotretinoin or matching vehicle cream to the face, forearms, and hands once nightly for 36 weeks. Local irritation and adverse events were assessed, and plasma retinoid levels were measured before and during treatment. Treatment response increased throughout the 36-week treatment period and the overall appearance of photodamaged skin was significantly better than with the vehicle alone. Topical application of 0.1% isotretinoin is an effective and well-tolerated treatment leading to clinically apparent improvement in the appearance of photodamaged skin of the face, forearms, and hands.

Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds.

The present study was carried out to characterize the patterns of expression of matrix metalloproteinases or their tissue inhibitor (TIMP-1) in normally healing, acute vs. chronic, skin wounds. In situ hybridization was performed to localize collagenase, stromelysin-1, stromelysin-2, matrilysin, urokinase plasminogen activator (uPA) and TIMP-1 mRNAs in 14 chronic venous ulcers and 10 normally healing wounds, representing different time points after wounding. Surgical wounds, made in piglets harvested at several time points, were studied as controls. Collagenase, stromelysin-1 and -2, as well as uPa, were expressed in keratinocytes in both acute and chronic wounds, while epithelial TIMP-1 mRNA was not detected in any chronic wound biopsies studied. However, TIMP-1 was expressed at the epithelial edges of both acute human and pig wounds. Our results suggest that the balance between metalloenzymes and their inhibitor TIMP-1, is disturbed, in poorly healing wounds.

Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers.

Although extracellular proteolysis is a prerequisite for normal wound healing, uncontrolled proteolytic tissue destruction appears to be a pathogenic factor in non-healing wounds. The aim of our study was to compare the activities of the serine proteinases of polymorphonuclear origin, elastase and cathepsin G, and the metalloproteinases, gelatinase and collagenase, in chronic leg ulcer exudate (10 patients) and acute wound fluid (6 patients). Serine proteinase activities were low in leg ulcer exudates but very high in some but not all acute wound fluids. Total collagenase activity, measured as activity against type I collagen monitored by SDS-PAGE and densitometry, was higher in chronic leg ulcer exudate than in acute wound fluid and its degree of autoactivation was relatively high. Doxycycline inhibition studies suggested that the collagenase activity in chronic leg ulcer exudate was MMP-1 ("fibroblast-type") and not MMP-8 ("neutrophil-type"). Zymographic analysis of the gelatinolytic enzymes in acute wound fluid showed a progressive increase from the day of operation to postoperative day 5, but the degree of activity was lower than in chronic leg ulcer exudate and the low molecular mass activation products were faint. The leg ulcer gelatinase profiles were characterized by high expression of 92/82- and 72/62-kDa duplex bands and by the presence of low molecular mass activation products. Leg ulcer collagenase seems to be derived from mononuclear rather than polymorphonuclear cells, which are known to be involved in acute wound healing. In conclusion, the present study shows that gelatinase and collagenase, but not elastase and cathepsin G are found in chronic leg ulcer exudate.

Collagen VII in severe recessive dystrophic epidermolysis bullosa: expression of mRNA but lack of intact protein product in skin and cutaneous cells in vitro.

The collagen VII gene, COL7A1, is the candidate gene for both the recessive and dominant forms of dystrophic epidermolysis bullosa (EBD). Collagen VII is a structural protein of the anchoring fibrils, which are rudimentary or altered in several subtypes of EBD. In severe recessive mutilating EBD, anchoring fibrils and collagen VII are not detectable in skin of most patients. To elucidate the underlying pathogenetic mechanisms, we analyzed collagen VII expression in cutaneous cells of six patients with this severe EBD subtype. Neither keratinocytes nor fibroblasts synthesized detectable amounts of collagen VII protein; however, Northern blot analysis revealed small amounts of normal-size collagen VII mRNA in both EBD and control fibroblasts. When the mRNA was amplified using reverse transcription-polymerase chain reaction, correct amplimers were present in all specimens. The results demonstrate that transcription of the COL7A1 gene occurs in these patients with severe mutilating EBD and suggest that post-transcriptional or post-translational events lead to absence of collagen VII protein from skin.

Supervised four-week heliotherapy alleviates the long-term course of psoriasis.

The long-term effects of psoriasis heliotherapy were studied in a randomized cross-over trial with a 2-year follow-up. We allocated 95 patients randomly to receive a 4-week heliotherapy course, either at the onset or in the middle of the follow-up period. After a highly significant immediate alleviation of psoriasis about 50% of the patients still had a reduction of psoriasis 6 months later and about 25% one year later. A favourable carry-over treatment effect was still observed during the second follow-up year. Taking advantage of the cross-over design, the effect of heliotherapy was calculated to be statistically significant during the first follow-up year, and the apparent long-term alleviation of psoriasis after the heliotherapy was reflected in a significant period effect. The alleviation of psoriasis was accompanied by a significant decrease in the use of antipsoriatic treatments.

Single-dose oral azithromycin versus seven-day doxycycline in the treatment of non-gonococcal urethritis in males.

One hundred and twenty male patients with signs and symptoms compatible with non-gonococcal urethritis were enrolled in a prospective-randomized study to compare the efficacy and safety of a single oral-dose of 1 g azithromycin and a seven-day course of 100 mg doxycycline twice-daily. Clinical examination and culture samples for Chlamydia trachomatis were performed before and approximately 8, 15 and 35 days after starting treatment. Both treatment groups were comprised of 30 chlamydia-positive patients evaluable for efficacy. The eradication rate of C. trachomatis in baseline-positive patients at the first follow-up visit in the azithromycin group was 96% with one persistent case, and 100% in the doxycycline group. After about two weeks, there were two re-occurrences in the azithromycin group, resulting in a cumulative eradication rate of 90% with three culture-positive cases. The corresponding figure in the doxycycline group was still 100%, but there were leucocytes present in the urethral smear of two patients who later proved to be true culture-positive re-occurrences. After about five weeks, there was an additional re-occurrence in the azithromycin group leading to a cumulative eradication rate of 87%, while two re-occurrences in the doxycycline group gave a cumulative eradication rate of 93%. There was no statistically significant difference in efficacy between the single-dose azithromycin and seven-day course of doxycycline in the treatment of patients with chlamydial urethritis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of heliotherapy on skin and joint symptoms in psoriasis: a 6-month follow-up study.

The effect of heliotherapy on psoriasis skin lesions and arthritis was studied in a trial comprising 4 weeks of therapy in the Canary Islands and a 6-month follow-up period. A total of 373 patients participated in the heliotherapy and 361 patients completed the follow-up period. The severity of skin lesions was evaluated using a psoriasis severity index (PSI), and that of the arthropathy by using an arthritis index (AI). During heliotherapy, the PSI decreased significantly from the initial median value of 4.5 to the final value of 0.2. A reduction in the PSI of at least 75% was achieved in 84% of the patients. Guttate psoriasis improved significantly better than plaque-type or erythrodermic psoriasis. There was no correlation between skin type and improvement. Initially, 129 patients had symptoms of arthritis. During heliotherapy, the AI decreased significantly from the initial median value of 6 to the final value of 2. The median time until starting another treatment after heliotherapy was 80 days, and the PSI had returned to its original value in 49% of the patients in 6 months. In patients with joint symptoms the AI returned to the pretreatment level within 6 months. A 4-week heliotherapy period effectively cleared psoriasis, alleviated joint symptoms, and reduced both morbidity and treatment requirement to a considerable extent in the ensuing 6-month period.

Proteolytic activity in leg ulcer exudate.

Twenty-five leg ulcer exudate samples from 17 patients with chronic non-healing venous leg ulcer were analyzed for proteolytic activity using radial caseinolysis procedures and zymographic analysis, and for fibronectin fragmentation using immunoblotting technology. Caseinolytic activity was detected in 21 of the 25 samples. A minority of them were inhibited (3 were totally, 6 partially inhibited) by aprotinin, a serine proteinase inhibitor, suggesting that proteinase(s) other than plasmin were also responsible for the caseinolysis. In zymographic analysis, 23 of the 25 samples showed positive reactions for enzyme activities comigrating with plasmin and urokinase-type plasminogen activator. Fibronectin fragmentation, another sign of proteolytic activity, was seen in all but 2 ulcers. No correlation was seen between bacterial infection or inflammatory cells and the above parameters in the wound fluid. Acute wound fluid collected from the donor sites of patients undergoing split skin grafting was used as a control. In the control specimens no proteolytic activity was found during the days following operation. These results show that there is proteolytic activity in the chronic ulcer exudate and support the possibility that the proteolytic activity and consequent fibronectin fragmentation may be related to the retarded epithelization and ulcer healing.

Keratinocytes and fibroblasts from a patient with mutilating dystrophic epidermolysis bullosa synthesize drastically reduced amounts of collagen VII: lack of effect of transforming growth factor-beta.

Keratinocytes and fibroblasts derived from skin of a patient with recessive dystrophic mutilating epidermolysis bullosa (EB) did not synthesize collagen VII as assessed by indirect immunofluorescence staining or immunoblotting, but expressed another basement membrane protein, laminin, in a normal manner. In contrast to control cells, no stimulation of collagen VII production was achieved in co-cultures of EB keratinocytes and fibroblasts. Further, treatment of normal keratinocytes or co-cultures with TGF-beta 2 significantly increased their expression of collagen VII, whereas the cytokine failed to induce its synthesis in the EB cells. Mixed co-cultures were constructed with normal fibroblasts and EB keratinocytes and vice versa. Both combinations showed strong expression of collagen VII in the normal cells but no synthesis in the EB counterparts. These results suggest that in this patient with severe mutilating dystrophic EB, inability of cutaneous cells to synthesize sufficient amounts of collagen VII underlies the lack of anchoring fibrils and skin fragility.

Comparative efficacy and safety of amorolfine nail lacquer 2% versus 5% once weekly.

Altogether 157 patients with onychomycosis affecting not more than 80% of the surface area of nail with intact lunula and matrix were treated once weekly for up to 6 months with amorolfine nail lacquer (2 or 5%) in a double-blind randomized design. Clinical examinations were carried out before, monthly during, and 1 and 3 months after therapy. Mycological examinations were performed before, 1 and 3 months after therapy. One hundred patients were evaluated. According to the overall assessment by the investigators, which was based on the clinical response and mycological findings, there was cure in 12%, improvement in 55% and failure in 33+ of the 2% group. The corresponding figures in the 5% group were: cure in 38%, improvement in 32% and failure in 30%. The difference in the number of cures was statistically significant in favour of the 5% nail lacquer. The most common pathogens isolated were Trichophyton rubrum in 59% of cases and Trichophyton mentagrophytes in 22%. Three months after the end of the treatment the mycological culture was negative in 55% of the 2% group and in 60% of the 5% group. Both concentrations were well tolerated. Only three patients (2%) experienced mild local adverse events. No systemic side-effects occurred and no patient discontinued treatment due to an adverse event. In conclusion, the 5% nail lacquer was more effective than the 2% nail lacquer when used once weekly for up to 6 months for the treatment of mild to moderate onychomycosis, and both concentrations were well tolerated.

Solar ultraviolet (UV) radiation and UV doses received by patients during four-week climate therapy periods in the Canary Islands.

The ultraviolet (UV) radiation doses received by 270 psoriasis patients were studied during 4-week climate therapy periods in November, March or April in the Canary Islands. The daily total solar UV radiation (ambient radiation load, ARL) was measured using frequent readings with a Robertson-Berger sunburning ultraviolet (SUV) meter. A daily personal radiation load (PRL) was calculated for each patient, using sun exposure diary data. To measure the cumulative UV exposure of particular skin sites (skin site dose, SSD), 10 patients wore polysulphone UV dosimeters. The daily ambient radiation load (ARL) ranged from 2.9 to 8.9 erythemal units (EU); the cumulative ARL for a 4-week treatment period was 182.6 EU. The mean daily personal radiation load (PRL), calculated separately for each week of the treatment period, was from 2.5 to 5.6 EU; the mean total 4-week PRL was 118.0 EU, being about 65% of the ARL. The 4-week cumulative skin site dose (SSD) varied between 22.2 and 63.3% (mean 41.2%) of the corresponding personal radiation load (PRL).

Prevention of dryness and eczema of the hands of hospital staff by emulsion cleansing instead of washing with soap.

The acceptability of two handwashing/cleansing methods, cleansing with emulsion or washing with liquid soap and water, were compared in a randomized, prospective long-term study. Thirty-eight members of hospital staff who had a history of hand skin dryness or eczema and a need for frequent handwashing used either liquid soap or emulsion for handwashing or cleansing. The clinical assessment of skin condition was done blindly by the same dermatologist at the onset of the study, and after 2 and 4 months with a predetermined scoring system. The median skin dryness index of persons in the liquid soap group increased significantly from an initial 1.4 to 3.6 during the 4-month winter study period (P less than 0.001), while the corresponding figure in the emulsion group decreased during the same time from 1.9 to 1.1 (P = 0.053). The difference in dryness between the groups was significant after 2 months (P = 0.04) and after 4 months (P less than 0.001). After 4 months, six people in the emulsion group had no dryness of the hands compared to only one in the liquid soap group. Similar trends were noticed in the occurrence of eczema. The median eczema index decreased significantly in the emulsion group from 0.4 to 0.1 during the study. In the liquid soap group, the increase in the median eczema index was from 0.4 to 0.7 (difference not significant). On an individual level, the eczema became worse in only one subject in the emulsion group, but in seven in the liquid soap group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of haem arginate on variegate porphyria.

Four patients with variegate porphyria (VP) were treated with repeated haem arginate infusions daily for 4 days and then weekly for 4 weeks. After the initial four daily doses of haem arginate (haem 3 mg/kg), the excretion of faecal protoporphyrin (mean 579 nmol/g dry wt) fell to an almost normal level (mean 123 nmol/g dry wt), and that of coproporphyrin (mean 162 nmol/g dry wt) to the normal level (mean 21 nmol/g dry wt) in all patients. However, during the period of the four weekly infusions of haem the excretion of porphyrins increased almost to the pretreatment level. Phototesting showed no changes in the photoreactivity of the skin, and no improvement in skin lesions was seen during the treatment. Except for one case of thrombophlebitis no side-effects occurred. In a child with homozygous VP, four daily infusions of haem arginate (2 mg/kg) normalized the faecal protoporphyrin content, but had no effect on the increased erythrocyte protoporphyrin concentration.