Regiospecific Oxidation of Chlorobenzene to 4-Chlororesorcinol, Chlorohydroquinone, 3-Chlorocatechol and 4-Chlorocatechol by Engineered Toluene o-Xylene Monooxygenases.

Toluene o-xylene monooxygenase (ToMO) was found to oxidize chlorobenzene to form 2-chlorophenol (2-CP, 4%), 3-CP (12%), and 4-CP (84%) with a total product formation rate of 1.2 ± 0.17 nmol/min/mg protein. It was also discovered that ToMO forms 4-chlorocatechol (4-CC) from 3-CP and 4-CP with initial rates of 0.54 ± 0.10 and 0.40 ± 0.04 nmol/min/mg protein, respectively, and chlorohydroquinone (CHQ, 13%), 4-chlororesorcinol (4-CR, 3%), and 3-CC (84%) from 2-CP with an initial product formation rate of 1.1 ± 0.32 nmol/min/mg protein. To increase the oxidation rate and alter the oxidation regiospecificity of chloroaromatics, as well as to study the roles of active site residues L192 and A107 of the alpha hydroxylase fragment of ToMO (TouA), we used the saturation mutagenesis approach of protein engineering. Thirteen TouA variants were isolated, among which some of the best substitutions uncovered here have never been studied before. Specifically, TouA variant L192V was identified which had 1.8-, 1.4-, 2.4-, and 4.8-fold faster hydroxylation activity toward chlorobenzene, 2-CP, 3-CP, and 4-CP, respectively, compared to the native ToMO. The L192V variant also had the regiospecificity of chlorobenzene changed from 4% to 13% 2-CP and produced the novel product 3-CC (4%) from 3-CP. Most of the isolated variants were identified to change the regiospecificity of oxidation. For example, compared to the native ToMO, variants A107T, A107N, and A107M produced 6.3-, 7.0-, and 7.3-fold more 4-CR from 2-CP, respectively, and variants A107G and A107G/L192V produced 3-CC (33 and 39%, respectively) from 3-CP whereas native ToMO did not. IMPORTANCE Chlorobenzene is a commonly used toxic solvent and listed as a priority environmental pollutant by the US Environmental Protection Agency. Here, we report that Escherichia coli TG1 cells expressing toluene o-xylene monooxygenase (ToMO) can successfully oxidize chlorobenzene to form dihydroxy chloroaromatics, which are valuable industrial compounds. ToMO performs this at room temperature in water using only molecular oxygen and a cofactor supplied by the cells. Using protein engineering techniques, we also isolated ToMO variants with enhanced oxidation activity as well as fine-tuned regiospecificities which make direct microbial oxygenations even more attractive. The significance of this work lies in the ability to degrade environmental pollutants while at the same time producing valuable chemicals using environmentally benign biological methods rather than expensive, complex chemical processes.

Estrogen receptor alpha mediates mandibular condylar cartilage growth in male mice.

OBJECTIVES: In the appendicular skeleton, estrogen via ERα signalling has been shown to mediate endochondral growth plate fusion in both males and females. However, the role of ERα in mediating growth of the mandibular condylar cartilage is unknown. Thus, this study focuses on the characterization of the mandibular condylar cartilage phenotype in young and adult male ERαKO mice. SETTING: Columbia University Medical Center. MATERIAL AND METHODS: WT and ERαKO C57BL/6 male mice were sacrificed at 49 days or 9 months for phenotypic analysis. Changes to MCC thickness, cell number and cell density were measured using histomorphometric methods. Cartilage-specific gene expression and OARSI scores were investigated for 49-day and 9-month-old male ERαKO and WT mice. RESULTS: In young mice, a significant increase in the number of mandibular condylar cartilage cells and a significant decrease in the expression of Col10, Runx2 and DMP1 were observed in the male ERαKO mice compared to WT. In 9-month-old mice, we found a similar increase in the number of cells but no change in osteoarthritic histological scoring in ERαKO mice compared to WT mice. CONCLUSION: In summary, estrogen plays a role in mediating mandibular condylar maturation in young male mice. However, according to this study, it does not play a role in mediating long-term growth or age-related mandibular condylar cartilage degeneration in males.

Priorities for cancer control in Spain.

Spanish cancer strategy is being developed in the context of a decentralised health care system. The advantages and challenges posed by this system are reviewed, particularly vis-à-vis the need to build consensus among regional health services as regards priorities in cancer control. Analysis of the impact of cancer in Spain enables smoking prevention and obesity reduction to be highlighted, especially among adolescents, as targets for primary prevention. Two-yearly colorectal cancer screening using the faecal occult blood test and targeting persons aged 50-69 years is a new goal that should be pursued countrywide, as should population-based breast cancer screening. Insofar as health care is concerned, the focus is on promoting and consolidating multidisciplinary cancer care based on evidence-based clinical guidelines, and on ensuring that cancer patients enjoy prompt access to diagnosis and therapy. Psychosocial support, with experience gained in several health services, should be expanded. Palliative care must be consolidated as a necessary therapy for patients who require it. Finally, the important boost to cancer research witnessed in recent years should be sustained. The approach adopted is based on building a co-operative strategy among all of Spain's autonomous regions (Comunidades Autónomas), which must then apply the interventions in their respective health services. A shared understanding of the main priorities for cancer control, through a review of the evidence and a consensus embracing all stakeholders, including scientific societies and patients' associations, is an essential step in the implementation of cancer strategy in Spain.

[Herpetic recurrent upper limb lymphangitis]. / Lymphangite récurrente du membre supérieur d'origine herpétique.

Upper limb lymphangitis often complicates varied wounds on the hand or forearm and improvement is obtained in a few days with adapted antibiotic therapy. A 28-year-old woman presented since few years episodes of lymphangitis of the arm associated with vesicles on an erythematous base, on the palmar face of the first phalanx of the index finger, spontaneous relief within 10 days, without antibiotic therapy. Herpetic origin was confirmed on viral culture. No primary infection neither recurrence was noted. Because of the recurrences, a prophylactic treatment with valaciclovir was instituted. There was no reported recurrence at two years follow-up. Upper limb lymphangitis rarely complicates herpetic whitlow in immunocompetent patient. Clinicians should be aware of viral lymphangitis, which is often overlooked and associated with diagnostic errors and treatment delay.

Head-and-neck swelling: an under-recognized feature of giant cell arteritis. A report of 37 patients.

OBJECTIVE: To describe the frequency of occurrence and characteristics of head-and-neck swelling (HNS) in temporal (giant cell) arteritis (TA). METHODS: We analyzed the charts of patients with HNS retrieved from a single department series of 260 consecutive patients with TA and reviewed the published French-English literature. Patients with a swelling limited to the temporal fossa were excluded. RESULTS: A history of HNS was elicited in 17 patients in our series (i.e. 6.5%) and in 20 previously published patients. The swelling was an inaugural feature in most cases and was often transient. Ear-nose-and-throat (ENT )symptoms were observed in 80% of the cases, including jaw claudication or pain upon opening mouth in 22, causing trismus in 10. Two patients had permanent visual impairment and 1 had sudden hearing loss. The temporal artery biopsy yielded giant cell arteritis (GCA) in all the patients but 2. The HNS was often painful and mainly involved mainly the orbital region and face, particularly the lower part of the cheeks and maxillae, less often the neck and, rarely, the forehead and tongue. Concurrent localized limb swellings were also observed in 3 patients. The HNS disappeared in all the patients, either spontaneously or under steroid treatment, and recurred only in 6 patients. CONCLUSION: HNS is not exceptional in untreated TA and is strongly associated with ENT symptoms and a positive TAB, but not with visual loss or stroke. Such characteristics imply in these cases a prominent, widespread involvement of the external carotid artery system by giant cell arteritis.

[Adverse drug related events in a postemergency unit: prospective cohort study with 6 months follow up]. / Iatrogénie chez le sujet âgé de plus de 75 ans dans un service de posturgences. Etude prospective de cohorte avec suivi à six mois.

PURPOSE: To analyse iatrogenic events in elderly people and determine the part of unplanned admission in postemergency units directly related to thus iatrogenic events. METHODS: The authors conducted a prospective chart review on treatments and potentials adverse drug-related events of all elderly consecutively hospitalized between January and Marsh 2003 in a postemergency department. A 6 months prospective evaluation after discharge was made for all elderly with adverse drug-related event. RESULTS: One hundred (and) eighty-six elderly (mean age 83+/-5.7 years) were prospectively included. Eighty-one per cent are ambulatory with a self-medication administration in spite of a real disability (activity of daily-living: 4.5+/-1.8). The number of medications consumed ranged from 0 to 15 and averaged 6, with to different source of prescriptions in 34% of the cases. The treatment was recently modified in 41 cases (22%). Adverse drug related events accounted in 55 cases (29%) and hospitalization was directly related to iatrogenic event in 32 cases (17%). Adverse drug related events could be avoided in half cases. There was no death directly related with adverse drug reactions. Follow up after discharge was obtained in 47 cases and pointed out elderly disability: 34 were again hospitalized, 14 admitted in nursing home facilities and 12 died. Treatment was equivalent to our prescription only in 35% of the cases; on the other hand, we found only four elderly with medication directly related to previous adverse event. DISCUSSION: Theses results pointed out once again polymedication observed in frail elderly people leading to extreme difficulty to prescription due to polypathology. Prescription renewal could be related to adverse drug related events and precipitated elderly people in disability leading to institutionalization.

Seasonal variability in blood platelet 3H-imipramine binding in healthy controls: age and gender effects.

Binding of 3H-imipramine to blood platelet membranes was determined four times (once each season) in 26 healthy volunteers (11 men and 15 women), over the course of 1 year to determine possible seasonal variations. Blood platelets were obtained in April-May, July-August, October-November, and January-February. Significant seasonal variations in the maximum number of binding sites were found in women but not in men, with circannual peak in summer and a nadir in spring. The pattern of seasonal variations was not the same in men and women. The present results highlight the importance of monitoring for gender and season in binding studies. We found no significant correlation between 3H-imipramine binding parameters and age.

Changes in platelet 3-H-imipramine binding: influences of protein concentration of varying proportions of cytosol or intact platelets and displacing agents used.

Platelet 3-H-imipramine binding exhibits considerable variation, both interindividually and between several groups. The aim of this study was to measure 3-H-imipramine binding, simultaneously in platelet membranes vs. intact platelets vs. cytosol or intracytosolic protein in order to determine their effect on Bmax and Kd values. 3-H-imipramine binding was carried out at different protein concentrations. Our results indicate that the affinity constant is heavily influenced by the presence of cytosol and intact platelets in membrane preparations. Finally, we demonstrate a negative correlation between Bmax and protein concentration. Only perfect analytical conditions will allow platelet 3-H-imipramine binding to be a biological marker for affective disorders.

Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients.

OBJECTIVE: To determine the risk factors--especially the effects of thrombocytosis--for permanent visual loss in patients with temporal arteritis. METHODS: One hundred seventy-four patients with temporal arteritis (147 biopsy proven) were prospectively observed for the development of permanent visual loss. We used multivariate logistic regression analysis to determine which of 17 pretreatment characteristics were associated with visual loss. RESULTS: Visual ischemic manifestations occurred in 48 (28%) patients, including permanent visual loss in 23 (13%) patients. The independent predictors associated with an increased risk of permanent visual loss were a history of transient visual ischemic symptoms (odds ratio [OR] = 6.3; 95% confidence interval [CI]: 1.4 to 29; P = 0.02) and a higher platelet count (OR = 3.7 per SD; 95% CI: 1.8 to 7.9; P = 0.001). The presence of constitutional symptoms (OR = 0.14; 95% CI: 0.02 to 0.77, P = 0.01), polymyalgia rheumatica (OR = 0.04; 95% CI: 0.01 to 0.48, P = 0.02), and C-reactive protein level (OR = 0.35 per SD; 95% CI: 0.13 to 0.92, P = 0.03) were associated with a reduced risk. Upper limb artery involvement was excluded from the multivariate model, as no patients with that problem developed permanent visual loss. Of the 87 patients who presented with thrombocytosis (platelet count >400 x 10(9)/L), 32 (37%) developed ischemic visual symptoms, compared with 16 (18%) of those without thrombocytosis. CONCLUSIONS: An elevated platelet count is a risk factor for permanent visual loss in temporal arteritis. The finding of thrombocytosis in a patient with suspected temporal arteritis should emphasize the need for urgent treatment, with consideration of using inhibitors of platelet aggregation or anticoagulation therapy.

GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat.

Female rats were allowed to pace sexual interactions in a bilevel chamber, where a sexually vigorous male was tethered to the bottom level. Exploratory behaviors (sniffing, rearing), locomotor activity (expressed as number of level changes and periods of inactivity) as well as items of sexual motivation (latency to descend to the male's level, approaches towards the male and genital exploration) were recorded. In addition, sexual receptivity was evaluated in a non-paced situation. A test for motor impairment was also performed. The GABA transaminase inhibitor gamma-acetylene GABA reduced exploratory behaviors at doses much lower than those needed to reduce receptivity. The GABA reuptake inhibitor SKF 100330A did not affect any behavior category at doses of 15 and 30 mg/kg, but had a sedative action at 60 mg/kg. This was shown as impaired motor coordination and an almost total absence of activity in the bilevel chamber. Receptivity was not impaired, however. The mixed GABAA/ GABAB agonist progabide reduced exploratory behaviors and receptivity without producing motor impairment at a dose of 400 mg/kg. The GABAA agonist THIP impaired motor coordination and reduced receptivity and exploratory behaviors at a dose of 10 mg/kg. A larger dose, 20 mg/kg, had a strong sedative action. Only a small proportion of the animals descended to the males level. The GABAB agonist baclofen reduced receptivity at a dose that had no effect on motor coordination or exploratory behaviors. None of the drugs had a specific effect on sexual motivation. Whenever behaviors reflecting motivation were reduced, there were also other behavioral effects indicative of sedation. These data show that GABA receptor agonists, particularly the GABAB agonist baclofen, reduce sexual receptivity at doses that have only slight effect on motor functions or exploratory behaviors. In contrast, non-specific enhancement of GABAergic activity by a transaminase or reuptake inhibitor have effects on motor functions and exploratory behaviors at doses much lower than those needed to reduce receptivity.

Induction chemotherapy with carboplatin and ftorafur in advanced head and neck cancer. A randomized study.

From 1987 to 1989, 42 patients with locally advanced squamous cell carcinoma of the head and neck (Stages III-IV, Mo) were randomized to receive radiotherapy (Group A) or three courses of induction chemotherapy followed by radiotherapy (Group B). There were 36 evaluable patients, 17 in Group A and 19 in Group B. The radiotherapy regimen was the same for both groups, 66-74 Gy total tumor doses with standard fractionation scheme of 2 Gy/day. The chemotherapy regimen was a combination of carboplatin 400 mg/m2 by intravenous bolus injection on day 1, and Ftorafur 1,000 mg/m2 orally once a day for 14 days. Cycles were given every 4 weeks. The complete response rate in Group A was 65%; in group B it was 31.5% after induction chemotherapy and 84% after radiotherapy. The 42-month actuarial overall survival rates were 34% for Group A and 47% for Group B (P = NS). Patients from both groups with a complete response had a significantly longer survival time than those with a partial response (P less than 0.001). No significant differences in disease-free survival were found between the two treated groups. The chemotherapy regimen was well tolerated, with moderate hematologic and gastrointestinal toxicity. Increased in radiation toxicity by chemotherapy was not observed.

Do the conventional clinicopathologic parameters predict for response and survival in head and neck cancer patients undergoing neoadjuvant chemotherapy?

AIMS AND BACKGROUND: Neoadjuvant chemotherapy for head and neck carcinoma is still an important treatment modality. The prognostic value of patient and tumor parameters has been extensively evaluated in several trials, yielding mixed results. We report the prognostic factors emerging from a group of patients undergoing neoadjuvant chemotherapy. PATIENTS AND METHODS: From April 1986 to June 1992, 149 consecutive patients received cisplatin-5-fluorouracil-based neoadjuvant chemotherapy. After four courses of chemotherapy, patients underwent local-regional treatment with surgery, radiation or both. A variety of patient and tumor characteristics were evaluated as predictors for response to chemotherapy and survival. RESULTS: The complete response, partial response and no response rates to NAC were 52%, 33% and 15%, respectively. No parameters predicted response to chemotherapy. At a maximum follow-up of 87 months, overall survival was 39% and disease-free survival was 49%. Variables shown to be predictors of survival in univariate analyses were age, performance status, histology, site, T, N, stage, and response to chemotherapy. Using the Cox regression analysis, only complete response to induction chemotherapy (P = 0.0006), performance status (P = 0.03), stage (P = 0.01), age (P = 0.03) and primary tumor site (P = 0.04) emerged as independent prognostic factors for survival. CONCLUSIONS: Complete response to chemotherapy was confirmed as the strongest prognostic factor influencing survival. However, conventional clinicopathologic factors did not predict response, hence, potential prognostic biologic and molecular factors for response must be sought. At present, much effort must be made for the improvement of the complete response rate, which seems to be a requisite to prolong survival.

Dietary treatment of lymphedema by restriction of long-chain triglycerides.

Two patients suffering from idiopathic unilateral lower limb lymphedema were treated with a diet in which long-chain triglycerides (LCT) were drastically restricted. From the beginning of the treatment, a distinct improvement was observed in both patients, with reduction of the affected limb perimeters, decrease of edema tension, and decrease of skin turgescence. Patient A underwent weight loss, and the reduction of the diameter of the affected limb was greater than that in the nonaffected limb. In patient B, whose weight remained stable during the study, the diameter of the affected limb underwent a remarkable diminution, while no changes were detected in the nonaffected limb. To the authors' knowledge, this is the first report of dietary treatment of idiopathic lymphedema, these being preliminary results of an ongoing study in a group of patients suffering from lymphedema treated with a low LCT diet.

[Systemic lupus erythematosus and herpes virus infection: three new observations]. / Lupus érythémateux disséminé et herpes viridae: à propos de trois observations.

INTRODUCTION: Systemic lupus erythematosus is still of unknown origin. Viruses have long been postulated to play a role in its pathogenesis particularly cytomegalovirus and Epstein-Barr virus. EXEGESE: We describe three patients who presented acute onset of systémic lupus erythematosus concurrently with recent viral infection (two with cytomegalovirus and one with Epstein-Barr virus). CONCLUSION: The peculiar clinical events emphasize the difficulty of diagnosis at the onset of the disease and suggest possible role of these viruses in the pathogenesis of SLE.

[Risk factors for irreversible cerebral ischemia complications from Horton's disease: prospective study of 178 patients]. / Facteurs prédictifs de complications céphaliques ischémiques irréversibles au cours de la maladie de Horton: étude prospective sur 178 patients.

PURPOSE: To search for risk factors of developing irreversible cranial ischemic complications (ICIC) in patients with giant cell arteritis (GCA) and to explore whether two subsets of patients (high risk and low risk of developing ICIC) can be defined. METHODS: One-hundred seventy-eight consecutive patients with temporal arteritis (149 biopsy-proven) were diagnosed and followed up in a department of Internal Medicine between 1976 and 1999. The patients were separated into two groups, according to the presence or absence of ICIC, with comparison of 17 clinical and biological parameters prospectively recorded for each patient using a pre-established comprehensive questionnaire. RESULTS: ICIC occurred in 25 patients (14%), with amaurosis in 22 cases. Suggestive symptoms and/or signs of temporal arteritis were present in 92% of the patients, lasting 50 days (median) before the onset of ICIC. Forty-three patients (24%) complained of transient visual ischemic symptoms (TVIS), which preceded acute blindness in 11 cases. A multivariate logistic regression, from which 28 cases with upper limb artery involvement were excluded for technical reasons (no CCII in any case, thus predicting perfectly the lack of ischemic risk, P = 0.02), indicated that the only independent variables associated with the ischemic risk were: a history of TVIS (P = 0.05), the lack of signs of polymyalgia rheumatica (PMR; P = 0.02), lower blood levels of fibrinogen (P = 0.024) and higher mean blood platelets levels (P = 0.006). However, these five variables predicted only 30% of the variability of the model. Sensitivity, specificity, positive and negative predictive values of the model reached respectively 36, 96, 64 and 88%. Overall, 86% of the cases were correctly classified with respect to the ischemic risk. CONCLUSION: The rate of ICIC should be reduced by an earlier recognition of the usual signs of temporal arteritis. Several independent risk factors of ICIC have been identified. However, the logistic model failed to predict accurately the ischemic risk in 14% of the cases, indicating that as yet unrecognised factors probably exist that play a role in the occurrence of ICIC. Nevertheless, regarding the strong association between platelet levels and ICIC, patients with thrombocytosis should receive initially both corticosteroids and antiplatelet agents.

[Non-simultaneous malignant lymphoma and antiphospholipid syndrome: 4 cases]. / Lymphomes malins et syndrome des antiphospholipides non simultanés: quatre observations.

OBJECTIVE: We report four cases of non-synchronous antiphospholipid syndrome (APS) and malignant lymphoma, which highlight the complex relationship that seems to exist between these illnesses. METHODS: In a retrospective study conducted in two departments (internal medicine and clinical hematology) of a university hospital, we collected all observations of patients with both APS and malignant lymphoma diagnosed throughout the past decade. RESULTS: An association of APS with malignant lymphoma was recorded in three female and one male patient, median age 42.5 years at the time of diagnosis of the first disease. In each case, the primary APS was diagnosed, with arterial thrombotic events in three cases and venous thrombotic events in one case. One patient had isolated IgG anticardiolipin antibody, whereas the others had a combination of IgG anticardiolipin antibody and lupus anticoagulant with or without IgG anti-beta 2 glycoprotein I antibody. One patient also had an acquired inhibitor to factor VIII:C and a chronic C virus hepatitis. The mean time apparently separating the two illnesses ranged from 18 months to 9 years, but in two cases the diagnosis of APS was delayed due to a progressive, atypical, neurological onset. In two instances, the APS took place at a distance from a cured malignant lymphoma (Hodgkin's disease and nodal large cell B-cell lymphoma), whilst in the others it preceded a B-cell lymphoma (nodal and cutaneous, small cells and primary hepatic, large cells). Treatment resulted in complete haematological response in both cases, with disappearance of anticardiolipin antibody and lupus anticoagulant in the latter following a double autologous peripheral blood stem cell transplantation. In addition, late carcinomas (breast, kidney, thyroid) were seen in two patients. CONCLUSIONS: Our data indicate that the diagnosis of a malignant lymphoma should be considered in patients with a primary APS and peripheral lymph node enlargement or unexplained constitutional symptoms. Conversely, a late onset of arterial or venous thrombotic diathesis after a malignant lymphoma may indicate not only late relapse of malignant lymphoma but also a subsequent APS.

[Diabetes insipidus revealing primary malignant non-Hodgkin's lymphoma of bone]. / Diabète insipide révélateur d'un lymphome malin non Hodgkinien primitivement osseux.

INTRODUCTION: Diabetes insipidus is a very rare, occasionally misleading, revealing symptom of non Hodgkin's malignant lymphoma. We report a case of this uncommon association and a review of the literature is done. EXEGESIS: Soon after a transient attack of diplopia due to a 6th cranial nerve palsy, idiopathic cerebral diabetes insipidus was diagnosed in a 32-year-old immunocompetent man. As anterior hypopituitarism was absent, the patient was discharged and treated with desmopressin acetate. Six months later, recurrence of diploplia together with raised erythrocyte sedimentation rate was observed and B cell lymphoma was observed in the iliac bone and skull, with extension into the right cavernous sinus. Both tumoral lesions led to important uptake of gallium-67. After a 26-month follow-up following intensive chemotherapy including autologous peripheral stem cell transplantation and local radiotherapy, lymphoma symptoms had disappeared, but the patient's condition had only partially improved with regard to diabetes insipidus. The association of lymphoma and diabetes insipidus which has only been reported in 14 cases is discussed. CONCLUSION: Since endocrine symptoms are often preceding hematological diagnosis, malignant lymphomas should systematically be viewed as potential etiology of diabetes insipidus. Magnetic resonance imaging which is more sensitive than computerized tomography in revealing brain lymphomas is mandatory. Gallium scan imaging might help guide the diagnosis in some instances.

[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.

[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.

[Disease associations in 250 patients with temporal (giant cell) arteritis]. / Maladie de Horton: associations morbides chez 250 malades.

INTRODUCTION: Miscellaneous disorders have been described in association with temporal (giant cell) arteritis (TA), most often anecdotally, except with arteriosclerosis. METHOD: In a retrospective study, we reported our personal experience of disease associations in a series of 250 patients diagnosed with TA and followed-up in the department between 1976 and 2003. RESULTS: Disease associations were found in 43 patients, i.e. 17% of cases: concurrent malignancy (23 patients: 17 cancers and 6 blood diseases), primary Gougerot-Sjögren's syndrome (6 cases), endocrine disease other than Hashimoto's thyroiditis (7 cases: 3 hyperparathyroidism [HPP], 3 hyperthyroidism, 1 association HPP + hyperthyroidism), polyneuropathy (3 cases), essential thrombocythaemia (2 cases), anti-neutrophilic cytoplasmic (anti-myeloperoxidase) antibodies (2 cases), and miscellaneous associations (1 case of RS3PE syndrome, nephrotic syndrome, myasthenia, sarcoidosis, and macro-creatine kinase type 2). More than one disease associated was present 5 patients. In 77% of the patients, there was a strong temporal association between TA and the alternate illness. No systemic necrotizing vasculitis or rheumatoid arthritis was observed in any patient. CONCLUSION: In our experience, there was a frequent, non-fortuitous, association between TA and malignancy. Auto-immune conditions were rare, but the prevalence of Gougerot-Sjögren's syndrome might have been underestimated. Hyperthyroidism and HPP are not exceptional and must be recognised in order to avoid severe bone loss induced by corticosteroids.