A test of the nature of cosmic acceleration using galaxy redshift distortions.

Observations of distant supernovae indicate that the Universe is now in a phase of accelerated expansion the physical cause of which is a mystery. Formally, this requires the inclusion of a term acting as a negative pressure in the equations of cosmic expansion, accounting for about 75 per cent of the total energy density in the Universe. The simplest option for this 'dark energy' corresponds to a 'cosmological constant', perhaps related to the quantum vacuum energy. Physically viable alternatives invoke either the presence of a scalar field with an evolving equation of state, or extensions of general relativity involving higher-order curvature terms or extra dimensions. Although they produce similar expansion rates, different models predict measurable differences in the growth rate of large-scale structure with cosmic time. A fingerprint of this growth is provided by coherent galaxy motions, which introduce a radial anisotropy in the clustering pattern reconstructed by galaxy redshift surveys. Here we report a measurement of this effect at a redshift of 0.8. Using a new survey of more than 10,000 faint galaxies, we measure the anisotropy parameter beta = 0.70 +/- 0.26, which corresponds to a growth rate of structure at that time of f = 0.91 +/- 0.36. This is consistent with the standard cosmological-constant model with low matter density and flat geometry, although the error bars are still too large to distinguish among alternative origins for the accelerated expansion. The correct origin could be determined with a further factor-of-ten increase in the sampled volume at similar redshift.

Drugs acting as plasticizers in polymeric systems: a quantitative treatment.

The objective of the present study was to investigate and quantify the effects of ibuprofen, chlorpheniramine maleate and metoprolol tartrate on the thermal, mechanical and diffusional properties of polyacrylate-based films. Thin drug-containing films were prepared from organic Eudragit RS solutions and physicochemically characterized with respect to their glass transition temperature, mechanical properties and drug release kinetics in phosphate buffer pH 7.4. The apparent diffusion coefficient of the drug within the polymeric systems was determined by fitting an adequate solution of Fick's second law of diffusion to the experimentally determined release profiles. Importantly, the glass transition temperature of the films significantly decreased with increasing initial drug content, whereas the film flexibility and drug release rate increased. This clearly indicates that the three drugs act as efficient plasticizers for Eudragit RS. Interestingly, the mathematical analysis revealed that drug release was primarily controlled by diffusion. An increase in the initial drug content resulted in increased drug diffusivities and, thus, accelerated (absolute and relative) drug release rates. Importantly, quantitative relationships could be established between the drug diffusivity and the initial drug content. Based on this knowledge, the effects of the films' composition and thickness on the resulting drug release kinetics (also from coated solid dosage forms) can be predicted in a quantitative way.

Melanoma associated with subacute primitive fibrinolysis.

BACKGROUND: Surgery is the first treatment of a pigmented skin lesion when a melanoma is suspected. This excision is most of the time realized by the dermatologist as well as the second time surgery. Bleeding at the surgical site may have numerous aetiologies. Fibrinolysis is a rare but dramatic event. CASE REPORT: We report a case with delayed bleeding after excision of a melanoma. The patient was re-operated and a major haemorrhage followed so that a transfusion of blood and fresh frozen plasma was necessary. The biological investigations concluded to a subacute primitive fibrinolysis associated with the melanoma. The patient was first considered to have completely recovered when a blood-borne liver metastasis diffusion rapidly occurred. The patient deceased within a few months from a hepatic encephalopathy with hepatic metastases. DISCUSSION: We find only a few published cases of melanoma with fibrinolysis. Its association with other abnormalities, like a partial factor XIII deficiency, made these abnormalities even more difficult to identify. The relation between the subacute fibrinolysis, the melanoma and the liver infiltrative metastasis is difficult to establish.

A large population of galaxies 9 to 12 billion years back in the history of the Universe.

To understand the evolution of galaxies, we need to know as accurately as possible how many galaxies were present in the Universe at different epochs. Galaxies in the young Universe have hitherto mainly been identified using their expected optical colours, but this leaves open the possibility that a significant population remains undetected because their colours are the result of a complex mix of stars, gas, dust or active galactic nuclei. Here we report the results of a flux-limited I-band survey of galaxies at look-back times of 9 to 12 billion years. We find 970 galaxies with spectroscopic redshifts between 1.4 and 5. This population is 1.6 to 6.2 times larger than previous estimates, with the difference increasing towards brighter magnitudes. Strong ultraviolet continua (in the rest frame of the galaxies) indicate vigorous star formation rates of more than 10-100 solar masses per year. As a consequence, the cosmic star formation rate representing the volume-averaged production of stars is higher than previously measured at redshifts of 3 to 4.

Development of a multi particulate extended release formulation for ZK 811 752, a weakly basic drug.

ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional mini matrix tablets decreased with increasing pH-values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Mini matrix tablets were prepared by direct compression of drug, matrix former (polyvinylacetate/polyvinylpyrrolidone; Kollidon SR) and excipients (lactose, calcium phosphate or maize starch). To solve the problem of pH-dependent solubility fumaric acid was added to the drug-polymer excipient system. The addition of fumaric acid was found to maintain low pH-values within the mini tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, micro environmental conditions for the dissolution of the weakly basic drug were kept constant and drug release was demonstrated to be pH-independent. Incorporation of water-soluble (lactose) or highly swellable (maize starch) excipients accelerated drug release in a more pronounced manner compared to the water-insoluble excipient calcium phosphate. Stability studies demonstrated no degradation of the drug substance and reproducible drug release patterns for mini matrix tablets stored at 25 degrees C/60% RH and 30 degrees C/70% RH for up to 6 months.

[Contact dermatitis with Hirudo medicinalis]. / Eczéma de contact à Hirudo medicinalis.

BACKGROUND: Hirudine is the first natural anti-coagulant ever described. It is used for its anti-coagulant properties in plastic surgery or for the treatment of post-phlebitic diseases. Natural hirudine is extracted from the saliva of the Hirudo medicinalis leech, but it can also be found in crushed leech and included in a cream (Hirucrème). Side effects to hirudine are considered to be rare. CASE REPORT: We report a contact eczema caused by an extract from the medicinal Hirudo medicinalis leech. This was confirmed by the patch tests. However, we noticed a negativity of these tests with two analogs of the recombinant hirudine. DISCUSSION: Several cases of contact dermatitis with Hirucreme have been described. The analogs of recombinant hirudine, which share similar biological activity, have a very close molecular structure. They are indicated via the systemic route for thrombopenia related to heparin for the prevention of severe thromboses. The negative patch tests does not allow definite conclusion, but they prove that these molecules do not always lead to cross-allergies.

[Drug hypersensitive syndrome caused by fluindione]. / Syndrome d'hypersensibilité médicamenteuse à la fluindione.

BACKGROUND: Fluindione (Previscan) is an oral anticoagulant prescribed in relay to heparin therapy for deep venous thrombosis, pulmonary embolism... The main complications with oral anticoagulants are bleeding. However, severe immuno-allergic complications, especially acute hepatitis, acute renal failure and acute bone marrow failure, have been described with phenindione therapy. OBSERVATIONS: The authors report herein the first five cases of drug-induced hypersensitivity syndrome due to fluindione. Clinical signs included erythroderma and severe systemic manifestations which occurred within 3 to 8 weeks after introducing the molecule. Sex ratio was four males for one female; their ages ranged from 53 to 84 years. Clinical signs included erythroderma (with photosensitivity in two patients), lymphadenopathy and fever evoking severe sepsis. In our observations, marked eosinophilia (5 cases), lymphocytosis, atypical lymphocytes (4 cases), hepatic cytolysis (4 cases), associated in 2 cases with hepatic cholestasis, and pulmonary signs were noted. Cutaneous eruption healed in about 3 to 6 weeks after withdrawal of the drug. In two cases, systemic steroids were required for the severity of systemic manifestations. Long after the acute episode and when steroids were stopped, patch testing with fluindione was still positive. DISCUSSION: To date, acute and/or severe skin diseases due to fluindione, associated or not with multisystemic involvement, have never been reported. This molecule is the most commonly used for the treatment of thromboembolic diseases. Patch testing is easy to perform and can help physicians find the responsible molecule. Moreover, skin manifestations are present only in 87 p. 100 of drug-induced hypersensitivity syndromes. Acute hepatitis and acute renal failure might be drug-induced hypersensitivity syndromes without cutaneous manifestations.

Role of drug exposure in aphthous ulcers: a case-control study.

BACKGROUND: Drug-induced aphthous ulcers have been the subject of several isolated and heterogeneous case reports for the last three decades. OBJECTIVES: To perform a case-control study to evaluate the risks linked to drug exposure in aphthous ulcers. METHODS: Eighty patients with typical clinical patterns of aphthous ulcers and 152 control patients who had had consultations for skin tumours were studied. A standardized questionnaire, concerning clinical features, life-style and medications taken during the last month, was completed for each patient. RESULTS: Case patients had a much higher intake of medications than control patients, respectively, 5.1 and 2. 8 medications per patient (P < 0.0001). Multivariate paired analysis showed an association between aphthous ulcers and two classes of drugs: non-steroidal anti-inflammatory drugs (P < 0.001) and beta-blockers (P = 0.002). Smoking could have a protective effect against aphthous ulcers (P < 0.001). CONCLUSIONS: Previous case reports and the results of this study suggest a real link between beta-blockers and aphthous ulcers. Our study did not confirm a role of other drugs but a few interesting case reports with positive reintroduction have to be considered. These results could be beneficial for patients, as healing may occur when the incriminated drug is discontinued.

[Cutaneous reactions or necrosis from interferon alpha: can interferon be reintroduced after healing? Six case reports]. / Réactions cutanées ou nécrose à l'interféron alpha: peut-on reprendre l'interféron? A propos de six cas.

PURPOSE: Alpha, beta or gamma interferon (INF) are cytokines produced by cells in response to antigenic stimulation. They are used to treat various hepatic, hematological, oncological and neurological diseases. Cutaneous reactions (rash, alopecia, labial herpes, erythema, or induration at the site of injection, and more rarely cutaneous necrosis) represent 5 to 12% of side-effects observed in patients receiving INF. The authors report six cases of local cutaneous reactions to alpha INF, five of which corresponded to cutaneous necrosis. This makes them question the relevance of INF reintroduction. METHODS: The study included 5 male and 1 female patients (mean age: 59.1 years; range: 42 to 74 years old). Three patients had chronic hepatitis C, while three others presented a blood disease. RESULTS: Cutaneous necrosis occurred after 1 to 10 months of treatment. The mean time to healing was 16.2 weeks. Reintroduction of the drug including injection in other sites did not lead to recurrence of necrosis in five out of the six cases. CONCLUSION: INF-induced cutaneous necrosis does not depend on the type of INF, the site of injection, the dose and may occur 2 months to 9 years after treatment implementation. The exact mechanisms involved in cutaneous necrosis remain unknown. Morbidity is due to a very long time to healing (4 to 6 months). Futhermore, healing sometimes requires prior surgery. Physicians should be aware of the potential occurrence of erythema in patients treated by INF, as it is the first sign of necrosis. The site of injection should then be modified. In case of necrosis, risk factors for thrombophilia, factors reducing microcirculation (DHE, beta-blockers, cigarette smoking) should be investigated. INF injections should be cautiously reintroduced in other sites with the help of a nurse in case of self-injections prior to the occurrence of necrosis. Regarding self-injections patients' training should be emphasized.

[Pretibial epidermolysis bullosa and hypothyroidism]. / Epidermolyse prétibiale de l'hypothyroïdie.

BACKGROUND: We report a case of primary non-autoimmune hypothyroidism causing pretibial epidermolysis bullosa. CASE REPORT: A 70-year-old man with primary non-autoimmune hypothyroidism developed blisters of different ages on the lateral aspect of both legs. Pathology reported blisters with subepidermal cleavage. Direct immunofluorescence was negative. Electron microscope examination showed a variable cleavage level and diffuse infiltration of a granulous and amorphous microfibrillar substance. After hormone replacement therapy, euthyroidism was associated with a reduction in the number of bullae and finally complete remission. After 12 months follow-up, the patient has not experienced recurrence. DISCUSSION: Recurrence-free clinical improvement after hormone replacement therapy suggests the diagnosis of hypothyroidism pretibial epidermolysis bullosae. Mochizuki et al. described a similar case which rapidly regressed after hormone therapy but where the electron microscope showed a different cleavage level. These bullae appear to result from a mechanical mechanism due to their localization in areas exposed to friction and also to the presence of bullae of different ages. This hypothesis is confirmed by the presence of a variable level of cleavage and a substance dense to electrons at electron microscopy as well as by the skin weakness. Our case confirms the reality of hypothyroidism pretibial epidermolysis bullosa. Thyroid hormones should be assayed in patients presenting pretibial bullae.

[Drug-induced hypersensitivity syndrome in internal medicine: diagnostic and therapeutic traps. Eight observations]. / Syndrome d'hypersensibilité médicamenteuse en pratique interniste: pièges diagnostique et thérapeutique. Huit observations.

PURPOSE: Drug-induced hypersensitivity syndrome (DIHS) is an acute and severe drug reaction. Manifestations include severe skin lesions, fever, nodal enlargement, blood eosinophilia and multisystemic involvement. The severe systemic manifestations of DIHS are responsible for a 10% mortality rate. The pertinence of corticosteroid therapy is discussed. METHODS: The authors report eight retrospective cases of DIHS obtained from the PMSI (Programme de Médicalisatiopn des Systèmes d'Information) between November 1991 and November 1998. RESULTS: The series consisted of five male and three female patients (mean age: 52.6 years; range: 23-83 years). The interval between the introduction of the drug and the onset of the reaction varied from two to eight weeks. Due to severe systemic manifestations, three patients were given corticosteroid therapy. Healing of skin and systemic disorders resolved with a mean delay of 4.4 weeks (range: 1 to 56 weeks). CONCLUSION: DIHS can be a diagnostic trap, as there are no diagnostic criteria for DIHS. Only the association of multiple arguments such as the time to the occurrence of symptoms, clinical similarity to many infectious illnesses, hypereosinophilia, atypical lymphocytosis, etc. may help guide diagnosis. DIHS can also be a therapeutic trap, as prompt withdrawal of the offending drug is essential to minimize morbidity. Although still controversial in the literature, the pertinence of corticosteroid therapy may be discussed in case of severe systemic effects. Patch testing can be a valuable tool to determine the responsibility of a drug; however it proves to be useful only when positive.

[Tolerance and feasibility of adjuvant treatment of stage II malignant melanoma with high-dose interferon-alpha]. / Tolérance et faisabilité du traitement adjuvant du mélanome malin stade II par interféron alpha à fortes doses.

BACKGROUND: The use of high-dose interferon alpha as adjuvant therapy has been shown for the first time to improve recurrence-free and overall survival in stage II malignant melanoma. The aim of our work was to evaluate the toxicity of this therapeutic scheme during a 1-year period in 13 patients with malignant melanoma. PATIENTS AND METHODS: Thirteen patients, mean age 56 years, with stage II melanoma were included. Interferon alpha was administered at the dose of 20 MU per m2 body surface area five days per week for four weeks during the induction phase and at the dose of 10 MU subcutaneously three times a week for 48 weeks in the maintenance phase. Patients underwent clinical assessment daily and had blood tests twice a week during the induction phase. Weekly blood tests and monthly examinations were then performed during the maintenance phase. Clinical and biological toxicity was evaluated in accordance with the WHO scores. Grade 3 toxicity led to a 30 p. 100 dose reduction and treatment was interrupted in case of grade 4 toxicity. RESULTS: A flu-like syndrome (grade 1-2) and digestive disorders, nausea, anorexia related to dysgeusia or dry mouth were observed in most of the patients during the induction phase and persisted in 30% of the patients during the maintenance phase. Six patients developed a state of depression (grade 2-3) which persisted during the maintenance phase, inciting us to prescribe an antidepressor regimen for all our patients. One patient developed major reversible alopecia at dose reduction. Nine patients had grade 1 or grade 2 neutropenia and four had grade 3 neutropenia. Seven patients developed grade 1-2 thrombocytopenia, six had elevated transaminase levels (grade 1-2) and two moderately elevated CPK. CONCLUSION: At the end of the induction phase of interferon alpha therapy in 13 patients with malignant melanoma, 8/13 had received 100 p. 100 of the theoretical dose and 11/13 had received 80 p. 100. At the end of the treatment protocol, 5/10 patients had received 100 p. 100 of the theoretical dose and 8/10 more than 80 p. 100. The proposed protocol appears to be feasible without major risk. Rigorous clinical and biological surveillance is mandatory.