Longitudinal determinants of employment status in people with relapsing-remitting multiple sclerosis.

Purpose: To investigate longitudinal relationships between employment status and disease-related, (neuro)psychological, and work-related factors in people with multiple sclerosis (MS). Methods: 170 employed people with MS underwent yearly neurological and neuropsychological examinations to assess MS-related disability and cognitive functioning. Additionally, they completed yearly questionnaires assessing depression, anxiety, fatigue, cognitive complaints, workplace support and coping. Multilevel models for change were fitted to examine progression of these factors over three years, and to assess possible relationships with change in employment status. Results: People with a deteriorated employment status after three years reported more depression (p=0.009), a higher impact of fatigue (p<0.001), more cognitive complaints (p<0.001) and less workplace support (p=0.001) at baseline than people with a stable employment status. There were no differences in progression over time of the examined variables between people with a stable or deteriorated employment status. Conclusion: More depression, a higher impact of fatigue, more cognitive complaints and less workplace support are predictive of a deteriorated employment status after three years in individuals with MS. How these factors progress over time is not different between those with a stable or deteriorated employment. MS-related disability, anxiety, objective cognition and coping were not related to a deterioration in employment status.

The development of postthrombotic syndrome in relationship to venous reflux and calf muscle pump dysfunction at 2 years after the onset of deep venous thrombosis.

OBJECTIVE: Postthrombotic syndrome (PTS) develops in 40% to 60% of patients with deep venous thrombosis. Factors that are important in the development of PTS include venous reflux, deep vein obstruction, and calf muscle pump dysfunction (CMD). METHODS: Reflux and CMD in relationship to the severity of PTS were evaluated in a 2-year follow-up study of patients with acute deep venous thrombosis. Duplex scanning was used to measure reflux. The supine venous pump function test (SVPT) measures CMD with strain-gauge plethysmography. The base-line examination was performed within 1 to 5 days after diagnosis. The next examinations were scheduled at 3, 6, 12, and 24 months. RESULTS: The study included 86 legs, and the 2-year follow-up period was completed for 70 legs. Significantly more reflux was found in previously thrombosed vein segments, with an odds ratio of 1.8 after 3 months, of 2.1 after 6 months, of 2.5 after 12 months, and of 3.2 after 24 months. Multiple regression results showed that the most important risk factor for early clinical signs of PTS was superficial reflux in months 3, 6, and 12 (P < or =.02). Deep reflux did not have a synergistic relationship with superficial reflux in correlation with the clinical signs of PTS. The SVPT was not able to predict the development of PTS. CONCLUSION: More reflux develops in previously thrombosed vein segments. As early as after the third month, patients with superficial reflux have an increased risk of development of the first clinical signs of PTS. Within 2 years, the SVPT shows no relationship with clinical signs of PTS.

Multicentre, randomised controlled trial of four-layer bandaging versus short-stretch bandaging in the treatment of venous leg ulcers.

BACKGROUND: Aim of the study was to compare the healing rates of venous ulcers obtained with four-layer bandages (4LB) versus short stretch bandages (SSB). DESIGN: Multicentre, randomised controlled trial performed in 5 centres of the Netherlands and in 2 centres in Austria ("PADS-study" = Profore Austrian Dutch Study). PATIENTS AND METHODS: 112 patients (53 treated with 4LB and 59 treated with SSB) completed at least one post-treatment follow-up, 90 completed the study. Bandaging and ulcer assessment was performed at weekly intervals. Randomisation was carried out for each centre and was stratified according to the size (more or less than 10 cm2) of the ulcerated area. Local therapy consisted of plain absorbing, non-adherent dressings. Time to complete healing was recorded up to a maximum of 16 weeks. The two treatment-groups were comparable regarding their baseline-characteristics. RESULTS: In total 33/53 (62%) of ulcer-patients were healed in the 4LB group, compared with 43/59 (73%) in the SSB group (difference 11%, 95% CI -28% to 7%). 77% of the ulcers with an initial area less than 5 cm2 healed as compared with 33% of the larger ulcers. The different healing rates in the centres could be explained by the different sizes of the treated ulcers. Based on Kaplan-Meier estimates the median healing time was 57 days for the 4LB (95% CI 47-85 days) and 63 days for the SSB (95% CI 43-70 days). CONCLUSION: The ulcer healing rate and the median healing time did not differ among the two types of bandages. The main discriminant criterion for healing was the initial ulcer size. In centres who are experienced users of short-stretch bandages, no statistically significant different healing rates of venous ulcers could be found after 4LB or SSB.

Expression of tenascin-C splice variants by human skin cells.

Tenascin-C is an extracellular matrix glycoprotein that is expressed in a spatially and temporally restricted pattern. Various functionally different tenascin-C isoforms can be expressed as a result of alternative splicing of the pre-mRNA. Previously we identified human epidermal keratinocytes as a source of tenascin-C in healing wounds. In this study, we investigated whether different tenascin-C transcripts are expressed by epidermal keratinocytes and dermal fibroblasts. In addition, we compared expression of tenascin-C splice variants at the mRNA and protein levels in tissue samples of normal and diseased skin. Northern blot analysis revealed two major tenascin-C mRNA transcripts of approximately 7500 and 5800 nucleotides in cultured epidermal keratinocytes and fibroblasts, and in biopsies. Although both dermal fibroblasts and epidermal keratinocytes predominantly expressed the larger tenascin-C mRNA, epidermal keratinocytes expressed smaller transcripts at higher levels than dermal fibroblasts. In keratinocytes the levels of the two mRNAs were differentially affected by inflammatory cytokines that increased tenascin-C expression in these cells. The addition of IFN gamma slightly increased the proportion of large transcripts. In contrast, TNF alpha favoured expression of smaller tenascin-C transcripts, and IL-4 equally affected the expression of large and small tenascin-C mRNAs. To enable detection of tenascin-C transcripts that are expressed at very low levels, we amplified by polymerase chain reaction the fibronectin type III repeats whose expression is regulated by alternative splicing. In cDNA of cultured keratinocytes and fibroblasts, and in skin biopsies, several tenascin-C transcripts could be detected that corresponded to tenascin-C variants including different numbers of fibronectin type III repeats. Distribution of tenascin-C isoforms at the protein level was studied immunohistochemically in healthy skin, wounds, psoriatic lesions and epidermal tumours and hyperplasia. No differences were observed in reactivity between an antibody that binds all tenascin-C isoforms and antibodies that bind fibronectin type III repeats that can be spliced out from smaller tenascin-C isoforms. We conclude that the tenascin-C isoforms that are translated from transcripts that we identified at the mRNA level seem to be distributed similarly in the conditions investigated.

Reproducibility of detection of tyrosinase and MART-1 transcripts in the peripheral blood of melanoma patients: a quality control study using real-time quantitative RT-PCR.

In recent years, large discrepancies were described in the success rate of the tyrosinase reverse transcription polymerase chain reaction (RT-PCR) for detecting melanoma cells in the peripheral blood of melanoma patients. We present a quality control study in which we analysed the reproducibility of detection of tyrosinase and MART-1 transcripts in 106 blood samples from 68 melanoma patients (mainly stages III and IV). With this study, we aimed to improve insight in the reproducibility of a RT-PCR for the detection of (minimal) amounts of circulating melanoma cells. We performed two reverse transcriptions on each mRNA sample and performed tyrosinase and MART-1 nested PCRs in duplicate per cDNA sample. Thus, four tyrosinase and four MART-1 measurements were performed per blood sample. In our study, the majority of blood samples was negative for tyrosinase (80%) or MART-1 (66%). Only four samples were positive in all four determinations for tyrosinase and seven for MART-1. Variable results (1-3 times positive results) were obtained for tyrosinase and MART-1 in 16% and 27% respectively. MART-1 PCR had a better performance than tyrosinase PCR. Sensitivity increased when both markers were used. We reasoned that the low number of melanoma marker PCR-positive blood samples can be explained by differences in mRNA quality. By using real-time quantitative PCR, we found that this was not the case: amplification of porphobilinogen deaminase (PBGD), a low copy household gene, was not different in blood samples in which a melanoma marker was not detected from groups in which this marker was detected more or less consistently (1-4 times). When applying real-time quantitative PCR for tyrosinase and MART-1, we found that a low amount of SK-MEL-28 cell equivalents was present in the blood of melanoma patients, with a higher number of equivalents in the group with a consistently positive result. We conclude that low reproducibility of a repeated assay for the detection of circulating melanoma cells is not caused by differences in mRNA quality between the samples, but due to low numbers of amplifiable target mRNA molecules in the mRNA sample. Use of more than one marker and repetition of the assay will increase the probability of finding positive PCR results.

Factors influencing participation among melanoma screening attenders.

We surveyed the demographic profile and motives prompting to participate among people attending voluntary melanoma screening clinics in Southern Limburg, the Netherlands, in June 1993. Precampaign public announcements addressed only melanoma and its precursor lesions. All attendees completed a detailed questionnaire addressing demographic particulars and specific fixed choice questions on their motivation to attend. There were 4,146 persons attending the screening clinics. Most attendees opted for examination of a specific lesion (71%). More females than males participated. Fear of having skin cancer was an important reason to participate (27%). Of all attenders, 16% had to be convinced by relatives or friends to attend the screens, and 33% would not have visited a physician on their own initiative when there had not been a free screening. Females were more concerned about skin cancer than males. The local and regional newspapers formed the most important precampaign publicity channel. Free melanoma screenings attract large numbers of people. Males are underrepresented. They are less aware of the risk profile of melanoma. Future screenings should target the male population.

Clinical and haemodynamic sequelae of deep venous thrombosis: retrospective evaluation after 7-13 years.

1. In contrast to the extensive documentation on diagnosis and treatment of deep venous thrombosis (DVT), information about long-term complications, like the post-thrombotic syndrome (PTS), is scarce. Most studies report on clinical examination only, whereas adequate haemodynamic investigation is lacking. Therefore 81 patients with venographically confirmed lower extremity DVT were clinically and haemodynamically reexamined 7-13 years after DVT (mean 10 years) to assess PTS. Interest was focused on the relation between clinical and haemodynamic PTS and the relation between location of the initial DVT and incidence of PTS. 2. Clinical signs and symptoms of PTS were classified according to the latest consensus of the international consensus committee on chronic venous disease. Non-invasive venous vascular laboratory tests were performed to assess the venous outflow resistance and calf muscle pump function (CMP). CMP was determined by the supine venous pump function test (SVPT). 3. Clinically only 20 of 81 patients (25%) were asymptomatic, 34 (42%) had mild PTS (class 1-3), 25 (31%) moderate PTS (class 4) and 2 (2%) severe PTS (class 5-6); 57% had an abnormal CMP. Both the severity of clinical symptoms and the haemodynamic abnormalities were related to the location of the initial thrombus. Of the patients with distal DVT 11% developed moderate clinical PTS and 39% developed an abnormal CMP. CMP and difference in CMP between post-thrombotic and non-thrombotic leg were significantly related to the different classes of PTS. 4. This study indicates that 7-13 years after DVT 31% of the patients had moderate and 2% had severe clinical PTS, while 57% of the patients had abnormal haemodynamic findings (both related to the initial site of the thrombosis). Secondly, it reveals that the risk of PTS after distal DVT is not negligible, which causes concern about not diagnosing and treating patients with distal DVT. Thirdly, we have demonstrated that a functional test, such as the SVPT, is a sensitive test to assess post-thrombotic damage. Therefore its use as a screening tool after a period of DVT should be investigated to select patients at risk of PTS.

Volunteer melanoma screenings. Follow-up, compliance, and outcome.

BACKGROUND: Follow-up information on free melanoma screening clinics is not readily available. OBJECTIVE AND METHODS: We studied the follow-up, compliance, and outcome of positive screenees after a screening campaign for melanoma in the Netherlands. RESULTS: Of the 4146 participants, 486 (11.7%) had a suspicious premalignant or malignant lesion warranting referral to his or her general physician indicating the proposed line of management. Participants with borderline lesions were not referred. Referral of borderline cases should have resulted in a considerable increase of the number of positive screenees (18.1%). All positive screenees but two gave permission for follow-up. Only 18 screenees (3.7%) were lost during follow-up. Moreover, one screenee with a presumed basal cell carcinoma and six screenees suspicious of having a premalignant lesion decided not to seek medical attention despite several reminders. The positive predictive value for melanoma was 17.2%, and for nonmelanoma skin cancers was 42.9%. CONCLUSION: A selective referral policy may reduce the generated costs of melanoma screenings substantially. Adequate follow-up of positive screenees is mandatory in order to determine the ultimate yield and usefulness of such campaigns.

Multiple squamous cell carcinomas in a psoriatic patient following high-dose photochemotherapy and cyclosporin treatment: response to long-term acitretin maintenance.

Cumulative toxicity is a well known limitation of antipsoriatic treatments. In particular, the induction of multiple squamous cell carcinomas following long-term PUVA treatment is well established. In the present report, a psoriatic patient is described who was treated for more than 14 years with photochemotherapy (PUVA) and who received excessive amounts of topical corticosteroids. The patient developed, in total, 34 squamous cell carcinomas. In all, three squamous cell carcinomas developed during long-term PUVA treatment, and 21 carcinomas appeared during 16 months of treatment with cyclosporin. Subsequently, a marked inhibition of the occurrence of new tumours occurred during prolonged treatment with acitretin, and no new tumours have appeared during the last 4 years of continuous treatment with this retinoid at a dose of 60 mg/day. Modulation of the expression of PUVA-induced squamous cell carcinomas by cyclosporin and acitretin are discussed. The present report lends support to the hypothesis that cyclosporin causes an increased occurrence of PUVA-induced carcinomas, whereas acitretin (60 mg/day) is of value in preventing the occurrence of new squamous cell carcinomas in patients who were treated with long-term PUVA.

Validation of the supine venous pump function test: a new non-invasive tool in the assessment of deep venous insufficiency.

1. A new non-invasive test was developed to assess calf muscle pump function: the supine venous pump function test. The technique uses strain-gauge plethysmography and is performed in the supine position. The method is superior to other non-invasive methods because basically the most essential haemodynamic parameter, venous pressure decrease, is used by properly converting venous volume measurements into venous pressure. The validity of this test was established by comparison with invasive venous pressure measurements and by determining the reproducibility. Additionally, normal values were determined. 2. In 28 extremities the supine venous pump function test was performed simultaneously with invasive venous pressure measurements. The reproducibility of the test was assessed in 10 randomly chosen volunteers. In 34 volunteers normal values were obtained and 26 patients with clinical venous insufficiency were examined. 3. Comparison of the two methods revealed a correlation coefficient of r = 0.98 (P < 0.001). A mean difference of 3.9%pf between both methods was found with limits of agreement of -6.3%pf to 14.1%pf. The coefficient of repeatability was 13%pf and the coefficient of variation was 9%. The normal range was found to be > 60%pf. The mean pump function in the patient group was 45%pf. 4. The limits of agreement are small enough to be confident that the supine venous pump function test can be used instead of invasive venous pressure measurements to assess calf muscle pump function in clinical practice. The reproducibility of the test is good.

Total skin examination during screening for malignant melanoma does not increase the detection rate.

Total skin examination during public screening for malignant melanoma is often advocated, but the benefit of this approach has not been established properly. We assessed the yield of examination of the entire skin, in addition to examination of intentionally shown skin lesions, in people attending melanoma screening clinics in southern Limburg, the Netherlands, in 1993. Of the 4146 attenders, 2910 (70%) showed a specific skin spot. Additional examination of the entire skin was offered to 1385 people. There were 1221 evaluable cases. Fourteen presumptive diagnoses of malignancies were encountered: seven malignant melanomas, all with low clinical suspicion, and seven basal cell carcinomas. Histology revealed three basal cell carcinomas. No malignant melanomas were confirmed by histology. It is concluded that additional total skin examination during screening for malignant melanoma is not worthwhile, except perhaps for persons presenting lesions that are suspicious of melanoma or dysplastic naevi.

Skin cancer screening focusing on melanoma yields more selective attendance.

BACKGROUND: Screening theoretically reduces death and morbidity from malignant melanoma. The rationale of screening for nonmelanoma skin cancer is more debatable, since mortality is very low. METHODS: We organized a screening campaign in Southern Limburg, the Netherlands, in 1993. Press releases and public announcements referred only to melanoma. The results were compared with similar campaigns in Arnhem and Eindhoven, the Netherlands, in 1990; these, however, addressed skin cancer in general. RESULTS: There were 4146 people attending the 1993 screenings, compared with 2463 in 1990. The proportion of screenees with lesions suggestive of melanoma increased from 1.1% in 1990 to 1.7% during the 1993 campaign (P = .04). The proportion of dysplastic nevi rose from 2.1% to 7.7% (P < .001). Nonmelanoma skin cancers were less often encountered (3.7% in 1990 vs 2.6% in 1993; P = .009). Actinic keratoses were also less numerous (6.3% vs 1.5%; P < .001). CONCLUSION: Screening concentrating on melanoma increases the rates of lesions suggestive of melanoma and dysplastic nevi, whereas the proportions of basal and squamous cell carcinomas and actinic keratoses decrease. These findings may have important implications with regard to the cost-effectiveness of skin cancer screening efforts.