[Nail-fold capillaroscopy in dermatology]. / La capillaroscopie péri-unguéale en dermatologie.

Nail-fold capillaroscopy is a non-invasive tool to study the microcirculation and is increasingly being used in dermatology, angiology and rheumatology. More recently, the use of video-capillaroscopy has allowed computer storage of capillaroscopic images (video-capillaroscopy), enabling evaluation of changes in capillaroscopic abnormalities during the follow-up of patients with systemic sclerosis or mixed connective tissue disease. Qualitative and quantitative assessment of the nail-fold dermal capillaries and of their organization can readily distinguish between a normal capillaroscopic pattern in primary Raynaud phenomenon and a specific sclerodermic pattern in secondary Raynaud phenomenon carrying a very high risk of systemic sclerosis. Apart from its important role as a diagnostic tool for distinguishing between primary and secondary Raynaud phenomenon, capillaroscopy is now used to predict the risk of development of digital ulcers and of future visceral complications in patients with systemic sclerosis. Moreover, nail-fold capillaroscopy is essential for differential diagnosis between connective tissue diseases, for the etiologic diagnosis of digital necrosis and diffuse interstitial lung disease, and in sclerodermiform syndromes.

trans-4-Hydroxytamoxifen concentration and metabolism after local percutaneous administration to human breast.

trans-4-Hydroxytamoxifen (4-OHTAM), a very active metabolite of the antiestrogen tamoxifen, was percutaneously administered to the affected breast of nine patients before surgery for breast cancer in order to evaluate 4-OHTAM absorption through the skin and its subcellular localization and metabolism. After percutaneous administration of 80 muCi, [3H]-4-OHTAM was detected in breast tissue. It was especially concentrated in tumor tissue and nuclear and cytosolic fractions, in which it remained unmetabolized except for limited isomerization from the trans to the cis form. In contrast to breast tissue, concentrations of radioactivity remained low in plasma but with a high proportion of metabolites. In another experiment [3H]tamoxifen was percutaneously administered over the breast of 3 patients, resulting in tissue retention weaker and shorter than after [3H]-4-OHTAM. In addition [3H]-4-OHTAM was administered to either breast or abdominal skin; the appearance of radioactivity in plasma and urine was delayed after administration to the breast in comparison with administration to the abdomen. It therefore appears that 4-OHTAM passes through the skin and is concentrated in receptor structures of breast tissue, thus avoiding the hepatic metabolism subsequent to p.o. administration. We suggest that local percutaneous administration of this active antiestrogen could be useful in the treatment of hormone-dependent benign breast diseases.

Estradiol 17 beta-hydroxysteroid dehydrogenase activity in human breast fibroadenomas.

In the human endometrium, the presence of the progesterone-dependent enzyme 17 beta-hydroxysteroid dehydrogenase (E2DH) permits the conversion of an active estrogen, estradiol, into a less active one, estrone. This E2DH activity contributes to the antiestrogenic properties of progesterone. In the present study, E2DH activity was assayed in 54 surgically removed fibroadenomas. This benign breast disease was chosen since it offers rather homogeneous epithelial concentrations and still remains close to normal breast tissue from a pathological and hormonal point of view. E2DH activity was highest in fibroadenomas with high epithelial cell density. In addition, in these high epithelial cell density fibroadenomas (n = 18), E2DH activity increased markedly throughout the luteal phase of the menstrual cycle. Thus, it was 3- to 4-fold higher in fibroadenomas removed at the end of the luteal phase (1520 +/- 166 fmol/mg protein.h) than in those obtained during the follicular phase (375 +/- 95 fmol/mg protein.h). In addition, a striking increase in E2DH activity was observed in fibroadenomas from 5 patients treated with oral progestins (4080 +/- 650 fmol/mg protein.h) and 3 patients receiving progesterone topically applied upon the breast (3830 +/- 475 fmol/mg protein.h). E2DH activity, therefore, appears to be an important mechanism involved in the control by progesterone of estradiol action in breast tissue, as it is in the endometrium. It is also a good index of cellular differentiation and progesterone action at the molecular level. It is hypothesized that E2DH activity might be a specific marker of progesterone receptor itself and could be proposed in the evaluation of the hormone dependence of human breast tissue.

Leg ulcers and hydroxyurea: forty-one cases.

BACKGROUND: Hydroxyurea is an antitumor agent used to treat chronic myeloproliferative disorders. Leg ulcerations have been reported in patients undergoing long-term hydroxyurea therapy for myeloproliferative diseases. To better define this dermatological adverse effect of hydroxyurea therapy and to try to understand the pathophysiological process of this disease, we collected medical information for such patients in a multicenter retrospective study. OBSERVATIONS: Forty-one patients (mean age, 67 years) developed leg ulcerations while undergoing hydroxyurea therapy (mean therapy duration, 5 years). The sex ratio was 1, and there was no underlying vascular disease. Hematologic abnormalities were identified. Complete recovery from the ulcerations occurred quickly after withdrawal of treatment in 33 (80%) of the cases. CONCLUSIONS: This longest-reported series of patients confirms the role of hydroxyurea therapy in the onset of leg ulcerations. Healing or improvement requires cessation of treatment. Cutaneous atrophy and impaired wound healing may explain the relationship between hydroxyurea and leg ulcers. In addition, the megaloblastic erythrocytes resulting from the presence of hydroxyurea may circulate poorly through the capillary network. A prospective study in hematologic centers would be valuable.

Long-term follow-up study of 164 patients with definite systemic sclerosis: classification considerations.

To evaluate the usefulness of recently proposed schemes of classification for systemic sclerosis an extensive cross-sectional study of a series of 164 consecutive patients with long-term systemic sclerosis was undertaken. There were 47 cases of proximal sclerosis, 93 of distal sclerosis and 24 of complete CREST syndrome. The study included clinical, visceral, immunological and follow-up data. In addition, a quantitative clinical score was calculated for each patient, thus providing indications for prognosis. Data were expressed according to three conventional systems of classification: The ARA system, the diffuse versus limited systemic sclerosis system and the early cutaneous involvement system. The most reliable indications of severe outcome were: proximal sclerosis, trunk skin involvement, presence of anti Scl 70 autoantibody, pulmonary and/or heart involvement and age. Diagnosis and prognosis were not generated by the same items. Prognosis indicators proved more accurate for groups than for individuals. Mortality was 1 death per 149 patient X years of follow-up from diagnosis. We conclude that the ARA criteria for classification should be recognized as a standard, but patients with complete CREST syndrome should be included in the distal group. Other systems of classification, principally 2-way versus 3-way criteria, allow different subsets of patients that correlate with prognosis and the severity of the disease, and could be used for therapeutic purposes.

Importance of cutaneous postural reflex vasoconstriction in patients with atherosclerotic occlusive disease of the lower extremities.

OBJECTIVE: The present study was designed to measure the cutaneous postural vasoconstrictive reflex (PVR) in normal controls and patients with atherosclerotic occlusive disease of the lower extremities, and to determine its diagnostic and prognostic relevance. EXPERIMENTAL DESIGN: The postural vasoconstrictive reflex was recorded in 34 patients with atherosclerotic occlusive disease of the lower limbs and 27 normal controls, using laser-Doppler flowmetry. Patients also had ankle and toe pressure measurements and transcutaneous oximetry (TcPO2). SETTING: University hospital. RESULTS: The PVR on the pulp of the big toe was 20+/-7 arbitrary perfusion units in normal controls, 9.4+/-12 in patients with claudication, and -19 +/- 5 in patients with rest pain and/or gangrene, who differed from the claudicant and control groups (p=0.001 and 0.0001 respectively). The sensitivity of negative PVR in the big toe was 89% for the diagnosis of rest pain and/or gangrene, and its specificity, 83%. The severity of foot ischaemia and PVR values exhibited a significant inverse correlation (r=-0.56, p<0.0001). All patients with a poor outcome, ie. death and/or major amputation within 100 days of follow-up, had a negative PVR, and all patients with a positive PVR had a good 100-day prognosis without even a minor amputation. CONCLUSIONS: Laser-Doppler provides useful additional information in the assessment of foot ischaemia severity by showing that postural vasoconstriction is impaired in patients with severe atherosclerotic occlusive disease of the lower limbs, resulting in increased skin microcirculatory flow during leg dependency.

Measurement of the cutaneous blood flow reserve in normal humans by laser-Doppler flowmetry.

AIM: To assess the normality of the cutaneous blood flow reserve (CR). METHODS: To explore the feasibility and reproducibility of laser-Doppler flowmetry for CR measurement, we prospectively measured CR in 17 healthy subjects on the dorsum of the foot and pulp of the big toe. CR was defined as the sum of the venoarteriolar reflex (VAR), i.e. postural vasoconstriction, and postischemic reactive vasodilation (H), expressed as % of the resting supine flux and assessed by using laser-Doppler flowmetry. RESULTS: For the dorsal foot, VAR%+/-SEM was 61+/-14, H%, 752.5+/-214 and CR, 813.5+/-217. On the pulp of the big toe, VAR% was 61.6+/-4.7, H%, 588.2+/-174 and CR, 649.9+/-176. CR measurement variability was assessed by calculating the inter-individual coefficient of variation of CR, which was 1.1 for both the dorsal foot and pulp of the big toe. Reproducibility was assessed by calculating the CR intraclass correlation coefficient, which was 0.49 for the dorsal foot and 0.64 for the pulp of the big toe. CONCLUSIONS: The CR is proposed as a new parameter for assessing the microvascular integrity and contractile reserve of the skin. Laser-Doppler flowmetry is suitable for this non-invasive evaluation. The method displayed large variability, and its reproducibility varied from moderate for the dorsal foot, to substantial for the toe. Further studies are necessary to demonstrate its clinical usefulness.

[Reestablishment of the clinical diagnosis in vascular acrosyndromes]. / Réhabilitation de la clinique dans les acrosyndromes vasculaires.

Raynaud's phenomenon (RP) is very frequent with a prevalence of 4% in a general population. Its evaluation has to be simple noninvasive and cheap. The only difficulty is to differentiate early primary RP from secondary RP that may evolve principally to a connective tissue disorder. Two questions have to be solved 1--Is it a primary or a secondary RP? 2--In case of secondary RP how to obtain a more precise diagnosis? Clinical examination alone is able to give a response for question 1 with 76% of reliability. Information has to be collected about sex, age at onset, occupation, uni or bilaterality of the disability, thumb involvement and drug consumption. Physician has to examine skin carefully, pulses, arterial bruits, heart, lungs, the time of return of color of digits after squeezing the blood out of the hand by clenching with and without compression of the radial and/or the cubital artery. Inquiries should be made about visceral involvement: oesophageal dysfunction, dyspnea, sicca syndrome, thyroiditis or polyneuritis that rule out a primary form of Raynaud's phenomenon.

[Distal arteritis of the legs: lumbar sympathectomy]. / Artérite distale des membres inférieurs: sympathectomie lombaire.

Among atheromatous occlusive arterial disease of the lower limbs, chronic sub-popliteal arterial occlusions refer an heterogenous group of patients. In this medical condition, lumbar sympathectomy constitutes a classical possible treatment. Actually, the beneficial effect of sympathectomy has never been confirmed by controlled randomised trials. In this particular and uncomfortable situation, it is only possible to list non indications for sympathectomy: asymptomatic patient, claudication, critical ischemia, limb salvage, and combination with vascular surgery. Lumbar sympathectomy deserves a controlled evaluation in patients with a small foot ischemic ulceration without hemodynamic critical ischemia i.e. systolic toe pressure > 30 mm Hg and/or ankle systolic pressure > 50 mm Hg.

[Leg volumetry: a precise method for quantification in phlebology]. / La volumétrie: une méthode précise de quantification en phlébologie.

UNLABELLED: Chronic venous insufficiency is usually quantified by venous pressure measurement, which is an invasive method. Air plethysmography has also been used, but it is expensive, time consuming and only suitable for sophisticated research laboratories. Leg volumetry might be suitable for routine use, as it is simple, inexpensive, fast, non invasive and can be performed by non medical personnel. Here, we only evaluated its practicability, accuracy and reproducibility. PATIENTS: The study group included 28 legs of 14 healthy volunteers, and 22 legs of 11 patients suffering from varicose veins. METHOD: The device used was a plexiglass boot, 50 cm high, 20 cm wide. It was filled with water at 24 +/- 2 degrees C. The leg was immersed and the volume of water displaced recorded. RESULTS: Normal legs displaced a volume of 2,449 +/- 153 ml (mean +/- SD), range: 2,080-2,720, and variability 6.2%. Patients' legs displaced a volume of 2,576 +/- 290, range: 2,110-3,120, (p = 0.05 vs normals) and variability 11.2%. Accuracy was 0.7%, as from 2 consecutive measurements of the same patients' legs by 2 different observers. Intra-individual variability was 1.3%, as recorded in 12 repeated measurements of the same leg on different mornings. In normal legs, the difference between morning and evening volumes was statistically significant (18 +/- 15 ml, p = 0.0001), a finding consistent with the deterioration of the venous function in normal extremities during daily activities. CONCLUSION: This simple, cheap, objective, non-invasive reproducible and accurate method of leg volume measurement might be useful in routine practice for chronic venous insufficiency quantification.

[Limitations of cold tests in Raynaud's disease]. / Limites des tests au froid au cours des phénomènes de Raynaud.

Vascular reactivity is an hemodynamic parameter, hard to quantify because its reproducibility is usually unpredictable. Cold is the most common stress used to trigger vasoconstriction in human clinical practice. Cold tests are urgently needed to fulfill the following purposes: A physiological tool to investigate cold reactivity in vascular diseases and secondly an objective means of judging and comparing the action of drugs thought to be effective in treating Raynaud's phenomenon. At present, cold tests exhibit poor reliability: The large number of tests proposed reflects the lack of agreement in this respect. Sensitivity, specificity and reproducibility fluctuate from one lab to another. It seems illusory to compare the diagnostic value of any cold test with that of clinical examination, for mathematical reasons, ie, the low prevalence of Raynaud's phenomenon in the general population (4%). At present, most of the positive results obtained in clinical trials of drugs which are effective in Raynaud's phenomenon are not correlated with the results of the cold tests.

[Action of nifedipine on the post-ischemic cold hyperemia reaction in Raynaud's phenomenon]. / Action de la nifedipine sur la réaction d'hyperhémie post-ischémique au froid dans le phénomène de Raynaud.

PURPOSE OF THE STUDY: To determine the effects of Nifedipine on cold stress reactive hyperemia in patients with Raynaud's phenomenon. DESIGN: Open trial comprising an observation period without treatment and a treatment period with Nifedipine. SETTING: Referral-based angiology department in a university hospital. PATIENTS: 26 patients with definite Raynaud's phenomenon were included; 6 patients were withdrawn (3 for side effects, 1 for pregnancy, 2 for protocol inobservance). INTERVENTIONS took place after one week of observation and one week of treatment with Nifedipine per os 20 mg 3 times daily. At day 0, 7 and 14, cold stress was performed to measure cold reactive post-ischemic hyperemia. MAIN RESULTS: During the Nifedipine period, the number of attacks, their intensity and resulting total disability decreased significantly, and hyperemia increased significantly. CONCLUSIONS: Our study confirms improvement in Raynaud's phenomenon with Nifedipine. This calcium-channel inhibitory drug also improves cold reactive hyperemia. This new cold test is inexpensive and easy to perform and appears to be suitable for assessing hemodynamic objective improvement in drug trials concerning Raynaud's phenomenon.

[Treatments of progressive systemic sclerosis]. / Evolution des traitements de fond de la sclérodermie.

Progressive Systemic Sclerosis (PSS) is still an incurable disease but there are treatments for it, and the list of proposed treatments is long. The methodology of trials concerning PSS is complex, due to the low prevalence of the disease and therefore its financial interest for pharmaceutical companies, the lack of simple end points for efficacy, and the large number of clinical expressions with various prognoses. These causes explain why most open studies are fiercely positive, and why controlled studies are so rare. The progress made during the last 10 years concern 1) the diagnosis, which is now made earlier due to capillaroscopy and antibody assays, especially of anticentromere antibodies, 2) better knowledge of the prognosis, due to the classification of PSS into limited and the diffuse forms which have different prognoses, and 3) the recognition of a serious complication of the disease, ie. pulmonary hypertension, which can now be detected by non-invasive methods. All these improvements will also improve the methodology of future trials of drugs for treating PSS. In this ocean of uncertainties, some treatments have a valid background, and 3 visceral locations of PSS can be efficiently treated: renal involvement, with angiotensin-converting enzyme inhibitors, respiratory involvement, with D-penicillamine, and pulmonary hypertension, with prostacyclin derivatives. Corticosteroids are suspected to increase the risk of renal complications. Calcium blockers are considered a useful symptomatic treatment of the associated Raynaud's phenomenon and of the risk of digital necrosis, and may also constitute a treatment of PSS itself. A recent trial conducted by the French Microcirculation Society and its acrosyndrome Study Group considered the effects of an oral derivative of prostacyclin. Beneficial effects were: a reduction of the risk of digital necroses, improved overall wellbeing, less necessity for hospitalizations, fewer giant capillaries, and a dramatic fall in the level of von-Willebrand factor.

[Cannabis and tobacco: cofactors favoring juvenile obliterative arteriopathy]. / Cannabis et tabac. Co-facteurs favorisant l'artériopathie oblitérante juvénile.

The causal effect of cannabis, associated or not with smoking, in juvenile thromboangiitis disorders such as Leo Buerger disease, has been suggested. We describe here a case of a 30-year-old woman who smoked cannabis and developed intermittent claudication of the lower limbs. Female sex and proximal localization of the lesions (external iliac artery) are not usually described in "cannabis arteritis". Cannabis would be involved not only in the pathogenesis of juvenile obstructive arteriopathy, but also in the development of atheromatous lesions in the young subject.

Cutaneous microvascular effects of mid-term hormone replacement therapy in healthy postmenopausal women: a prospective placebo controlled trial.

OBJECTIVE: To study the mid-term effects of Hormone Replacement Therapy (HRT) on cutaneous microcirculatory blood flow and reactivity in healthy postmenopausal women. DESIGN: In a double-blind placebo controlled randomized study, 16 healthy postmenopausal women received either placebo or HRT (micronized estradiol: 1 mg/day, day 1-28, promegestrone: 0.25 mg/day, day 14-28). This regimen was completed 6 times. Cutaneous microcirculatory blood flow was recorded by laser-Doppler velocimetry on the foot dorsum, in the supine and then dependent positions, and after post-ischemic hyperemia. RESULTS: At day 0, the two groups were similar and none of the following data differed significantly between treated and placebo group: (supine flux: 11.8 +/- 1.8 u vs. 13.2 +/- 3.9, venoarteriolar reflex: 5.6 +/- 1.3 vs. 6 +/- 3.3, and post-ischemic hyperemia: 35.2 +/- 3.9 vs.48.3+/-11). At the end of the study (day 26-28 of 6th cycle), the supine flux was 9.8 +/- 2.1 in the HRT group vs.12.9 +/- 6 in the placebo group (NS), the venoarteriolar reflex, 1.2 +/- 2 vs. 7+/-1.7 (p=0.04), and post ischemic hyperemia, 31.8 +/- 5.4 vs. 39.5 +/- 4.6 (NS). Intragroup values did not change significantly for any of the microcirculatory parameters measured, which remained stable throughout the 6 months of the study. Intergroup values for these parameters did not change either, except for the venoarteriolar reflex, which was lower at the end of the study in the HRT (EP period, cycle 6 day 26-28) than placebo group (p=0.04). CONCLUSIONS: HRT does not impair the resting supine cutaneous microcirculation blood flow or post-ischemic hyperemia.