[Cost of systemic lupus erythematosus for adult patients with active and treated disease in France (LUCIE study)]. / Coût du lupus systémique en France des patients adultes avec une maladie active et traitée (étude LUCIE).

PURPOSE: To evaluate in France the annual direct medical cost of adult patients with active systemic lupus erythematosus (SLE) on medication and estimate the cost of a flare. METHODS: A two-year, observational, retrospective, multicenter study, carried out between December 2010 and February 2011. Patients' characteristics, SLE disease activity and severity, rate of flares, healthcare consumption (medications, hospitalisations, etc.) were evaluated. Medical costs were assessed from the national Health Insurance perspective. Cost predictors were estimated using multivariate regression models. RESULTS: Eight centres specialized in SLE management included 93 eligible patients (including 50.5% severe). The mean age was 39.9 (11.9) years and 93.5% were women. At baseline, the mean SLE duration was 9.8 (6.6) years. The mean scores of the SELENA-SLEDAI instrument and the SLICC/ACR index were higher in severe patients (9.8 vs 5.6, and 1.2 vs 0.4 respectively; P<0.001). Over the study period, 51% of patients received the combination containing at least corticosteroids or immunosuppressants. The mean annual direct medical cost of severe patients was €4660 versus €3560 for non-severe patients (non-significant difference). The cost of medications (61.8% of the annual cost) was higher in severe patients (€3214 vs €1856; P<0.05). Immunosuppressants and biologics represented 26.5% and 4.6% of the annual total cost respectively. Patients experienced on average 1.10 (0.59) flares/year, of which 0.50 were severe flare. The occurrence of a new severe flare incremented the annual cost of €1330 (P<0.05). CONCLUSION: Medications represented the major component of the annual direct medical cost. Severe flares increase significantly the cost of SLE care management.

Patterns of systemic lupus erythematosus expression in Europe.

OBJECTIVES: To analyse the differences in disease expression of European SLE patients based on gender, age at diagnosis, and ethnicity. METHODS: A two-year, retrospective, multicentre, observational study was carried out in five countries (France, Germany, Italy, Spain and the UK). Patients' clinical manifestations including disease activity, organ involvement, organ damage and flares were analysed. RESULTS: Thirty-one centres enrolled 412 consecutive eligible patients (90.5% of women), with active disease, stratified by disease severity (half severe and half non-severe). Baseline characteristics included; mean (SD) age: 43.3 (13.6) years, SLE duration: 10.7 (8.0) years and age at disease diagnosis: 32.6 (13.0) years old. The mean (SD) SELENA-SLEDAI and SLICC/ACR scores were: 8.1 (6.7) and 0.82 (1.36), respectively. Over half of patients experienced flares (54.9%). The average number of annual flares was 1.01 (0.71) flares/year. In males compared to females, the renal system was more frequently active (53.8% vs 30.0%, p=0.002), the mean SLICC/ACR score was higher (1.15 vs 0.79, p=0.039) and the pulmonary system was more likely to be damaged (12.8% vs 3.8%, p=0.010). Furthermore, patients diagnosed at younger age displayed more renal system activity (young: 56.3% vs adult: 33.4% vs elder: 8.9%, p<0.001) and renal damage (25.0% vs 6.9% vs 2.2%, p=0.018) compared to the others. The annual number of flares (1.13 vs 1.05 vs 0.81 flares/year, p<0.0001), including the occurrence of severe flares (0.58 vs 0.51 vs 0.20, p<0.0001), was also higher in these patients. Conversely, greater organ damage was observed in patients diagnosed at an older age compared to the others. The mean SLICC/ACR score was higher (1.31 vs young: 0.88 and adult: 0.78, p<0.001) in patients diagnosed in the older age groups. The pulmonary (13.3% vs younger: 0% vs adult: 3.7%, p=0.030) and cardiovascular (17.8% vs younger: 0% vs adult: 2.9%, p<0.001) systems were more frequently damaged in these patients. Black African descents showed greater disease activity compared to Caucasian patients. They flared more often (77.1% vs 48.6%, p=0.001) and experienced a greater number of annual flares (1.57 vs 0.89 flares/year, p<0.0001), mainly more severe flares (0.89 vs 0.38/year, p<0.0001). They also were more likely to experience renal system damage. CONCLUSION: The study showed clearly two patient subsets. The disease was the most active in Black African descents, and this phenomenon has never been described before in continental Europe. The disease was also more active in patients diagnosed at a younger or adult. Greater disease damage was observed in males and in patients diagnosed at an older age.

Efficacy and safety of collagenase Clostridium histolyticum injection for Dupuytren contracture: report of 40 cases.

BACKGROUND: Dupuytren's disease (DD) is a fibroproliferative pathology that affects the palmar aponeurosis causing the development of nodules and collagen cords and the progressive flexion of the fingers. The standard procedure is surgical fasciectomy, followed by high recurrence rates. Collagenase Clostridium histolyticum (CCH) injection represents an innovative noninvasive approach to the treatment of DD. This prospective study was designed to examine the efficacy and safety of CCH injection performed in the outpatient, using local anesthesia. MATERIALS AND METHODS: Forty patients [32 metacarpophalangeal (MP), 8 proximal interphalangeal (PIP)] with Dupuytren's contracture of at least 20° for MP joint and any degree for PIP joint were included. The mean age was 66. All joints were treated with a single vial of collagenase injection and manual breaking of the cord 24 h after. All adverse effects (AEs) were monitored. Patients were checked 7, 30, 90, and 180 days after the injection. Primary endpoint was a reduction in digit contracture within 0°-5° of normal extension. Secondary endpoints were the improvement of range of motion, the evaluation of AEs incidence, and cost-effectiveness of collagenase treatment. RESULTS: About 67.5 % of patients obtained a clinical success. At 6 months, a further 7.5% attained the same result. The mean contracture of treated joints was 5.3º for MP and 6.8° for PIP joints. Twenty-three patients had one or more mild-to-moderate side effects. CONCLUSIONS: The use of collagenase appears to be an effective and safe method for the treatment of Dupuytren's contracture. Therapeutic success was achieved in a significant percentage of patients. The incidence of side effects was higher, but they were local reactions of short duration. The use of a single collagenase vial in patients treated in day surgery appears more cost-effective than surgery.

Eperisone versus tizanidine for treatment of chronic low back pain.

AIM: Many therapies exist for treatment of chronic low-back pain (LBP) including the use of muscle relaxant and analgesic drugs. The aim of this paper was to compare efficacy and tolerability of eperisone and tizanidine in combination treatment with tramadol in chronic LBP. METHODS: Sixty patients affected by chronic LBP associated with contractures of paravertebral muscles were randomized in two groups: Group E (30 patients) treated with eperisone; Group T (30 patients) treated with tizanidine. Both groups received tramadol retard 100 mg/day. VAS at rest and with effort were used at baseline (T0) and after 5 (T5), 10 (T10), 15 (T15) and 30 (T30) days of treatment. The Summed Pain Intensity Difference (SPID), the SPID percentage (SPID%) and the Total Pain Relief (TOTPAR), at rest (-r) and with effort (-e) were calculated. RESULTS: In both groups a statistically significant reduction in VAS-r and VAS-e was observed during the treatment; similar reductions occurred in both groups at every timepoint. SPID-r and -e, SPID%-r and -e and TOTPAR-r and -e resulted similar between groups. A significant difference between groups occurred for incidence of somnolence: 16.6% for Group E versus 43.3% for Group T. Treatment was stopped due to adverse events in 5 patients of Group E and in 9 patients of Group T, without statistically significant difference. CONCLUSION: Both associations assumed for one month, have shown effective for LBP at rest and with effort. Eperisone/tramadol, reducing discontinuation and allowing a better adherence to the therapy, may be considered a viable option for the treatment of chronic LBP.

Management of French patients with type 2 diabetes mellitus in medical general practice: report of the Mediab observatory.

OBJECTIVES: The Mediab study was conducted to estimate the medical care in French patients with type 2 diabetes mellitus managed by general practitioners on an ambulatory basis, but consIdered as requiring new treatment implementation. METHODS: Five thousand one hundred and fourty eight diabetic patients without any treatment or treated with lifestyle measures either alone or combined with an oral antIdiabetic agent given as monotherapy were included in a cross-sectional study that was conducted on a nationwIde basis by using the ORP (R) methodology. The 4088 patients in whom HbA1c was determined with a reliable method were further classified into 3 categories according to whether HbA1c was<=6.5% (group I, n=525), ranging between 6.6 and 8% (group II, n=1699) or > 8% (group III, n=1864). RESULTS: A large proportion of patients (45.6%) exhibited HbA1c > 8%. Adherence to diet and regular physical activity were progressively decreasing while prevalence of diabetic complications was steadily increasing from group I to III, i.e. when diabetic control was worsening. The complications suffered from severe "underreporting". When complications were reported, the odds-ratio analysis showed that retinopathy is influenced by both the magnitude of glucose excess and the diabetes duration, while renal diseases and macroangiopathy depend mainly on diabetes duration. 38.1% of patients visited a diabetologist, but most of these patients were referred to the speciaList after the inclusion visit. CONCLUSIONS: Despite the development of guIdelines, a large percentage of patients remains poorly-controlled. Future actions should be based on: (i) better collaboration between general practitioners and diabetologists (ii) better detection of complications that suffer from severe "underreporting", (iii) reinforcement of lifestyle recommendations and of pharmacological treatments by shifting from mono- to multi-drug therapy, at earlier stages of the disease.

Phase II trial of thalidomide in renal-cell carcinoma.

BACKGROUND: Thalidomide has been reported to yield anti-tumor activity in cancer. We performed a phase II trial of this drug in patients with metastatic renal cell carcinoma to determine its efficacy. PATIENTS AND METHODS: Patients with proven metastatic renal cell cancer, measurable progressive disease and a performance status of 0-2 were enrolled in this study. Thalidomide was given daily at a starting dose of 400 mg, followed by a 400 mg increment to 800 mg and then to 1200 mg with 6-12 weeks at each dose level. The response rate at 6 months was the primary end point. Toxicity, overall survival, tumor vascularization depicted on color Doppler ultrasonography and serum vascular endothelial growth factor, basic fibroblast growth factor, interleukin-12 and tumor necrosis factor-alpha levels were secondary end points. RESULTS: Forty patients were enrolled. Two partial responses were observed (5%) and disease remained stable in nine patients after 6 months. Median survival was 10 months. Toxicity was high, with frequent manifestations of fatigue, constipation and lethargy. The incidence of neuropathy detected on electromyography (EMG) attained 70% at 6 months, and 100% in patients on thalidomide for 12 months. Nine patients developed venous thromboembolism during the first 12 weeks of treatment, and three of them experienced pulmonary embolism. One unexpected (and unexplained) death occurred. CONCLUSIONS: Despite undisputed, albeit marginal, activity in renal cell cancer, high-dose thalidomide cannot be recommended using this schedule since the level of toxicity is high.

Impaired beta-cell regeneration in perinatally malnourished rats: a study with STZ.

We investigated the mechanisms implicated in beta-cell mass reduction observed during late fetal and early postnatal malnutrition in the rat. Beta-cell regeneration, including proliferation and neogenesis, was studied after neonatal beta-cell destruction by streptozotocin (STZ). STZ was injected at birth and maternal food restriction was continued until weaning. Beta-cell mass, proliferation, and islet number were quantified by morphometrical measurements on pancreatic sections in STZ-injected normal (C-STZ) and malnourished (R-STZ) rats, with noninjected C and R rats as controls. At day 4, only 20% of the beta cell-mass remained in C-STZ rats. It regenerated to 50% that of noninjected controls, mainly through active neogenesis, as shown by the entire recovery of islet number/cm(2), and also through moderately increased beta-cell proliferation. In contrast, beta-cell mass from R-STZ animals poorly regenerated, despite a dramatic increase of beta-cell proliferation, because islet number/cm(2) recovered insufficiently. In conclusion, perinatal malnutrition impairs neogenesis and the capacity of beta-cell regeneration by neogenesis but preserves beta-cell proliferation, which remains the elective choice to increase beta-cell mass. These results provide an explanation for the impaired capacity of malnourished animals to adapt their beta-cell mass during aging or pregnancy, which aggravate glucose tolerance.

Application of the obligate aerobic yeast Yarrowia lipolytica as a eucaryotic model to analyse Leigh syndrome mutations in the complex I core subunits PSST and TYKY.

We have used the obligate aerobic yeast Yarrowia lipolytica to reconstruct and analyse three missense mutations in the nuclear coded subunits homologous to bovine TYKY and PSST of mitochondrial complex I (proton translocating NADH:ubiquinone oxidoreductase) that have been shown to cause Leigh syndrome (MIM 25600), a severe progressive neurodegenerative disorder. While homozygosity for a V122M substitution in NDUFS7 (PSST) has been found in two siblings with neuropathologically proven Leigh syndrome (R. Triepels et al., Ann. Neurol. 45 (1999) 787), heterozygosity for a P79L and a R102H substitution in NDUFS8 (TYKY) has been found in another patient (J. Loeffen et al., Am. J. Hum. Genet. 63 (1998) 1598). Mitochondrial membranes from Y. lipolytica strains carrying any of the three point mutations exhibited similar complex I defects, with V(max) being reduced by about 50%. This suggests that complex I mutations that clinically present as Leigh syndrome may share common characteristics. In addition changes in the K(m) for n-decyl-ubiquinone and I(50) for hydrophobic complex I inhibitors were observed, which provides further evidence that not only the hydrophobic, mitochondrially coded subunits, but also some of the nuclear coded subunits of complex I are involved in its reaction with ubiquinone.

Age-dependent inability of the endocrine pancreas to adapt to pregnancy: a long-term consequence of perinatal malnutrition in the rat.

We have recently shown that maternal food restriction during late pregnancy decreased beta-cell mass in the offspring at birth. Prolonged maternal malnutrition until weaning led to irreversible decrease of beta-cell mass in the adult male progeny. During pregnancy, the maternal endocrine pancreas demonstrates an acute and reversible increase in beta-cell mass. The aim of this work was to investigate whether perinatal malnutrition could have long-lasting effects on glucose homeostasis and the adaptation of the endocrine pancreas to a subsequent pregnancy. This study was conducted on 4- and 8-month-old female rats malnourished during their perinatal life and on age-matched control animals. Oral glucose tolerance tests (OGTT), pancreatic insulin content, and islet mass quantitation after dithizone staining were performed on the same animals. Four-month-old nonpregnant previously malnourished animals showed normal glucose tolerance but a significant decrease in insulin secretion during OGTT. These animals were, however, still able to adapt pancreatic insulin contents and doubled their islet mass in late gestation. At 8 months of age, insulin content before pregnancy was reduced to half that of controls. Moreover, it did not show the characteristic increase during gestation that could still be observed in pregnant control females. In those control animals, the islet mass increased regularly until late gestation (14.1+/-1.8 mg at day 20.5, vs. 9.8+/-1.2 mg, nonpregnant), whereas in previously malnourished animals the islet mass remained throughout pregnancy similar to the nonpregnant values (8.5+/-1.4 mg at day 20.5 vs. 8.9+/-3.6 mg, nonpregnant). In conclusion, early malnutrition has dramatic consequences on the capacity of the endocrine pancreas to meet the increased insulin demand during pregnancy and aging.

Effect of ageing on beta-cell mass and function in rats malnourished during the perinatal period.

AIMS/HYPOTHESIS: In a recently developed rat model, maternal food restriction from day 15 of pregnancy until weaning induced low birth weight and a 70% reduction of beta-cell mass in the offspring at day 21 after birth. Subsequent renutrition from weaning was insufficient to fully restore beta-cell mass in young adult rats. The aim of this study is to investigate the long-term consequences of early malnutrition on beta-cell mass and function. METHODS: Oral glucose tolerance tests were done in 3- and 12-month-old animals and beta-cell mass and apoptosis were determined by morphometrical measurements on pancreatic sections. The specific impact of postnatal malnutrition was studied by comparing control animals (C group) with animals malnourished during their fetal life only (R/C group), and animals malnourished during fetal life and until weaning (R group). RESULTS: In 3-month-old R/C animals beta-cell mass reached 8.0 +/- 1.5 mg with no further increase until 12 months (8.1 +/- 1.5 mg), compared with 9.3 +/- 1.9 mg in control rats. Twelve-month-old R/C animals showed normal plasma insulin responses and borderline glucose tolerance. In R animals, apoptosis reached 1.9 +/- 0.4% of the beta cells at 3 months, compared with 0.7 +/- 0.5% in control rats, and beta-cell mass did not increase between 3 and 12 months (4.7 +/- 0.8 mg at 12 months). In aged control and R animals, apoptosis affected 8% of the beta cells. At 12 months only, R animals showed profound insulinopenia and marked glucose intolerance. CONCLUSION/INTERPRETATION: In conclusion, perinatal malnutrition profoundly impairs the programming of beta-cell development. In animals with decreased beta-cell mass the additional demand placed by ageing on the beta cells entails glucose intolerance since beta-cell mass does not expand and apoptosis is increased.

Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat.

We have recently shown that maternal food restriction during late pregnancy in rats decreased beta-cell mass in the offspring at birth, without altering beta-cell proliferation. The aim of the present work was to determine: 1) whether sustained maternal undernutrition until weaning (R group) more dramatically alters beta-cell mass in the offspring and if normal food supply from weaning until adulthood could reverse the deleterious effects and; 2) if altered beta-cell proliferation was responsible for the decreased beta-cell mass. Beta-cell fraction and proliferative capacity were determined during the suckling period and at adult age after ad libitum feeding from weaning in the R animals and in age-matched controls (C group). At day 21, the offspring born and nursed by food-restricted mothers (R animals) showed a 66% reduction in beta-cell mass and number, which did not increase from birth to weaning, although beta-cell proliferation remained normal. At 3 months of age, R animals had 35% decreased beta-cell fraction, with a 50% decrease in the head of the pancreas. In that area, beta-cell proliferation was similar to that of the controls. In the tail of the pancreas, beta-cell fraction was only slightly impaired but beta-cell proliferation was increased by 37%, as compared with the controls. This increase was associated with a shift in islet size distribution towards medium and large islets compared with the head of pancreas from these R animals. No regional variations of beta-cell fraction, proliferation or islet size distribution were observed in adult control animals. In conclusion, prolonged malnutrition until weaning impairs beta-cell development but not beta-cell proliferation. Subsequent re-nutrition is followed by increased beta-cell proliferation but this is insufficient to fully restore beta-cell mass.

Postnatal somatic growth and insulin contents in moderate or severe intrauterine growth retardation in the rat.

A rat model of perinatal malnutrition was designed to study the role of nutrition in postnatal somatic growth and insulin stores until adulthood. Maternal food restriction (50%) from day 15 of pregnancy resulted in intrauterine growth retardation (IUGR) in the offspring. The outcome of moderate or severe IUGR was investigated. Neonates with moderate IUGR normally nourished postnatally showed normal body and organ weights and normal insulin contents in adulthood. Offspring with severe IUGR normally nourished postnatally also rapidly recovered normal body and pancreatic weights, but liver and kidney weights were significantly reduced at adult age. Malnutrition until weaning in offspring with severe IUGR induced marked growth retardation (50%) in body and organ weights at weaning. Although pancreatic weight recovered at adult age, body, liver and kidney weights were irreversibly affected, despite several months of normal nutrition. Furthermore, severe IUGR at birth resulted in decreased insulin content at adult age, irrespective of postnatal nutrition. In conclusion, this animal model demonstrates that normalization of adult size can be dissociated from organ growth and also that altered insulin stores in adulthood are more dependent on the severity of IUGR at birth than on postnatal catch-up in organ growth.

In utero undernutrition impairs rat beta-cell development.

The role of nutrition on the development of the endocrine pancreas was studied in a rat model obtained by maternal food restriction. A 50% food restriction was applied to female rats from day 15 of pregnancy and resulted in intrauterine growth-retardation (IUGR) in the offspring. At day 1 postnatal, beta-cell mass was significantly decreased in IUGR pups as compared to controls (0.70 +/- 0.06 vs 1.07 +/- 0.06 mg, p < 0.0001), as well as insulin content. This change in beta-cell mass can be attributed to a reduced number of islets, since the density of insulin-positive aggregates in pancreatic sections of IUGR rats was 20% lower than in controls. Proliferative capacity of beta cells, as measured by 5-bromo-2-deoxyuridine (BrdU) labelling index, was not altered in growth-retarded animals. Body as well as pancreatic weight were fully recovered in IUGR pups after 21 days of normal feeding by control mothers. However, these animals retained a 25% decrease in insulin content, 40% decrease in beta-cell mass (1.58 +/- 0.18 vs 2.78 +/- 0.42 mg, p < 0.001) and a strong reduction in the density of insulin positive aggregates per cm2, as compared to controls, suggesting that the total islet number was likely to be reduced. Beta-cell proliferative capacity remained normal. In conclusion, in utero undernutrition in rats does not impede postnatal growth but durably impairs beta-cell development. Impairment of beta-cell differentiation might be suggested.

Role of CCK in the regulation of secretion and adaptation in the pig pancreas.

The effect of cholecystokinin (CCK) on the pancreas was investigated in the pig in two experiments. Fifteen pigs were fed a diet containing 17 or 48% protein with or without MK329 (4.5 mg per meal). MK329 enhanced the postprandial peak of plasma CCK during the first 30 min, but pancreas adaptation to high protein was not affected. Sixteen pigs were divided into two groups: 12 pigs were infused with CCK-8 + secretin for 1 h and four pigs received a standard meal. In both groups, pancreatic secretion tests were performed under infusion of the vehicle alone or with MK329. After CCK + secretin, MK329 (65-500 micrograms/kg/h) did not alter CCK plasma levels and reduced the early pancreatic protein response by about 30%. Enzyme outputs in pancreatic juice were modestly affected by MK329. After the meal, MK329 (500 micrograms/kg/h) doubled the postprandial peak of plasma CCK and lowered the pancreatic protein output by 35-40% for the first 30 min. We suggest that (a) pancreatic adaptation to high dietary protein is not mediated via CCK-A receptors and (b) the stimulation of pancreatic protein secretion by a meal or by exogenous CCK-8 is mediated partly by CCK-A receptors.