[Graves' orbitopathy: diagnosis, epidemiology and treatments]. / L'orbitopathie basedowienne: diagnostic, épidémiologie et principes de traitement.

Graves' orbitopathy is the most common extra-thyroid complication of Graves' disease and can be a potentially severe affection, therefore requiring multidisciplinary treatment support according to clinical activity and severity assessments. This review proposes to determine physiopathological mechanisms, epidemiology and therapeutic management of Graves' orbitopathy.

[Diagnostic approach and therapeutic management of hyperthyroidism]. / Démarche diagnostique et prise en charge thérapeutique de l'hyperthyroïdie.

Hyperthyroidism is a frequent clinical situation that can be expressed by various signs and it is generally easy to diagnose. This review proposes to explain the diagnostic approach that affects therapeutic management by separating diseases with homogeneous and nodular thyroid.

Effect of Interpregnancy Interval on Adverse Perinatal Outcomes in Southern China: A Retrospective Cohort Study, 2000-2015.

BACKGROUND: In January 2016, a universal two-child policy was introduced in China. The association of interpregnancy interval (IPI) with perinatal outcomes has not previously been assessed among Chinese population. We investigated the effect of IPI after live birth on the risks of preterm delivery, and small, and large for gestational age births in China. METHODS: We conducted a cohort study among 227 352 Chinese women with their first and second delivery during 2000 to 2015. IPI was calculated as months from first live delivery to conception of the second pregnancy. Poisson regression models with robust variance were fit to evaluate associations of IPI with risk of adverse perinatal outcomes, adjusted for potential confounders. RESULTS: Compared to IPI of 24- <30 months, IPI <18 months was associated with higher risks of preterm birth (PTB) and small for gestational age (SGA). For IPI <6 months, the adjusted relative risks (RR) for PTB and SGA were 2.04 (95% confidence interval [CI] 1.83, 2.27) and 1.43 (95% CI 1.31, 1.57), respectively. Women with IPI ≥60 months had higher risks of PTB and large for gestational age (LGA). For IPI ≥120 months, the adjusted RRs for PTB and LGA were 1.67 (95% CI 1.43, 1.94) and 1.10 (95% CI 0.97, 1.26). CONCLUSIONS: Women with IPI <18 months after live birth had higher risk of PTB and SGA, and IPI ≥60 months was associated with higher risk of PTB and LGA. These findings may provide information to Chinese couples about the appropriate interpregnancy interval for a second pregnancy.

Erythropoietin-stimulated endothelial cells support erythroid cell differentiation of CD34(+) haematopoietic progenitors.

BACKGROUND AND OBJECTIVES: Endothelial cells provide a unique medium for the proliferation and white lineage differentiation of haematopoietic progenitor cells (HPC). Whether this quality can be exploited to facilitate the differentiation of erythroid precursors is not yet known. MATERIALS AND METHODS: Haematopoietic progenitor cells derived from cord blood were cultured for 3 weeks in erythropoietin-stimulated supernatants with (n = 6) or without cyclosporine A (CSA, n = 6). Cell count, phenotype and morphology were assessed on a weekly basis, and the haemoglobin content was analysed. These cultures were compared with erythroid differentiation induced by cytokines only (n = 6). RESULTS: Endothelial supernatants combined with CSA led to equivalent numbers of CD71(+) erythroblasts after 1 week as cytokines only. The purity of glycophorin-positive, CD45-negative cells was higher in cells generated in endothelial supernatants than in cytokine-based media. Additional prostaglandin E2 induced a change from fetal to adult haemoglobin. CONCLUSION: For the generation of erythroblasts from HPC, endothelial supernatants are a simple and cost-effective alternative to culture conditions based on cytokines.

Evaluation of radiosurgery techniques--cone-based linac radiosurgery vs tomotherapy-based radiosurgery.

Performances of radiosurgery of intracranial lesions between cone-based Linac system and Tomotherapy-based system were compared in terms of dosimetry and time. Twelve patients with single intracranial lesion treated with cone-based Linac radiosurgery system from 2005 to 2009 were replanned for Tomotherapy-based radiosurgery treatment. The conformity index, homogeneity index (HI), and gradient score index (GSI) of each case was calculated. The Wilcoxon matched-pair test was used to compare the 3 indices between both systems. The cases with regular target (n = 6) and those with irregular target (n = 6) were further analyzed separately. The estimated treatment time between both systems was also compared. Significant differences were found in HI (p = 0.05) and in GSI (p = 0.03) for the whole group. Cone-based radiosurgery was better in GSI whereas Tomotherapy-based radiosurgery was better in HI. Cone-based radiosurgery was better in conformity index (p = 0.03) and GSI (p = 0.03) for regular targets, whereas Tomotherapy-based radiosurgery system performed significantly better in HI (p = 0.03) for irregular targets. The estimated total treatment time for Tomotherapy-based radiosurgery ranged from 24 minutes to 35 minutes, including 15 minutes of pretreatment megavoltage computed tomography (MVCT) and image registration, whereas that for cone-based radiosurgery ranged from 15 minutes for 1 isocenter to 75 minutes for 5 isocenters. As a rule of thumb, Tomotherapy-based radiosurgery system should be the first-line treatment for irregular lesions because of better dose homogeneity and shorter treatment time. Cone-based Linac radiosurgery system should be the treatment of choice for regular targets because of the better dose conformity, rapid dose fall-off, and reasonable treatment time.

A case report on the effect of fan beam thickness in helical tomotherapy of nasopharyngeal carcinoma.

The fan beam thickness (FBT) in helical tomotherapy is defined by a pair of collimators parallel to the rotational orbit of the radiation beam and is fixed for a specific patient treatment. The aim of this case study is to evaluate the dosimetric influence of changing the FBT in the treatment of a nasopharyngeal carcinoma (NPC) patient. The subject was a T2N1M0 stage NPC patient. The planning target volumes (PTVs) of the primary nasopharyngeal tumor and the left and right cervical lymphatics were delineated along with the organs at risk (OARs) in the corresponding computed tomography slices. Three treatment plans with FBT of 1.0 cm, 2.5 cm, and 5.0 cm (FBT-10, FBT-25, and FBT-50) were generated separately based on similar dose constraints and planning parameters. The dosimetric results of the PTV and OARs were collected and compared among the 3 treatment plans. The differences in the dose parameters of the PTVs were small among the 3 plans. The FBT-10 plan demonstrated the most homogeneous PTV doses with the smallest homogeneity indices (HIs). The FBT-50 plan delivered the highest dose to the OARs and the FBT-10 plan delivered the lowest. The differences between the 2 plans were more significant in the spinal cord, optic chiasm, optic nerves, and lens. This case study demonstrated that the variation of FBT in tomotherapy affected the quality of the treatment plan mainly in the OAR doses, but not so much in the PTV. Increasing the FBT reduced the effectiveness in the sparing of OARs.

Helical tomotherapy of nasopharyngeal carcinoma-any advantages over conventional intensity-modulated radiotherapy?

Helical tomotherapy uses different planning algorithm and dose delivery method from the linear accelerator (linac)-based intensity-modulated radiotherapy (IMRT). This study compared the dosimetric outcomes between the tomotherapy plans and conventional linac-based IMRT plans in the treatment of nasopharyngeal carcinoma (NPC). Fifteen stage II-III cancer (American Joint Committee on Cancer) NPC patients treated by tomotherapy were conveniently recruited. Apart from the tomotherapy plans, a 7-field 6-MV photon conventional IMRT plan was computed for each patient with the same CT dataset and reference from the dose constraints and target dose prescriptions of the tomotherapy plans using the XiO treatment planning system. Average values of the dose parameters including the conformity index (CI), homogeneity index (HI), maximum and minimum doses of the target volumes, and the maximum and mean doses of the organs at risk (OAR) were compared between the two treatment methods. Better dose coverage of the planning target volume (PTV) was demonstrated in the tomotherapy plans, in which the differences in the maximum and mean doses reached statistical significance (p < 0.05). Besides, the CI of the tomotherapy plans were significantly higher than the conventional linac-based plans for the nasopharynx PTV (NP-PTV) and neck lymphatics PTV (LN-PTV) (p = 0.017 and 0.010, respectively). The HI was significantly smaller in both NP-PTV and LN-PTV (p = 0.024 and < 0.001, respectively). Among the OAR, the brain stem and spinal cord doses in the tomotherapy plans were lower than that of the conventional IMRT plans. However, the doses to the other OAR did not show significant dosimetric differences. In the treatment of nasopharyngeal carcinoma, tomotherapy plans were superior to the 7-field conventional IMRT plans in PTV dose conformity and homogeneity and the sparing of the brain stem and spinal cord. However, no significant advantages were observed for the rest of the OAR.

The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole.

AIMS: Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated. METHODS: This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration. RESULTS: Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin C(max) by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 +/- 128 to 678 +/- 189 ng ml(-1) and increased AUC by 4.6-fold (4.1, 5.2) from 1666 +/- 808 to 7378 +/- 3011 ng ml(-1) h. Sotrastaurin half-life was nearly doubled from 5.9 +/- 1.7 to 10.6 +/- 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations. CONCLUSIONS: The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered.

Total serum homocysteine levels do not identify cognitive dysfunction in multimorbid elderly patients.

OBJECTIVES: Total blood homocysteine (Hcys) and folate levels have been investigated in association with cognitive dysfunction in healthy but not in multimorbid elderly patients. We hypothesized that total serum Hcys is an adequate marker to identify multimorbid elderly patients with cognitive dysfunction assessed by the Short Cognitive Performance Test (SKT) and Mini-Mental State Examination (MMSE). DESIGN: Cross-sectional study. SETTING: The study center was an acute geriatric hospital. PARTICIPANTS: A total of 189 multimorbid elderly patients were recruited. METHODS: Cognitive dysfunction was determined according to the SKT and MMSE. Biochemical parameters (Hcys, folate, vitamin B12, hemoglobin), nutritional status (BMI, Mini Nutritional Assessment, nutritional intake), and activities of daily living were assessed. RESULTS: According to the SKT, 25.4% of patients showed no cerebral cognitive dysfunction, 21.2% had suspected incipient cognitive dysfunction, 12.7% showed mild cognitive dysfunction, 9.0% had moderate cognitive dysfunction, and 31.7% of patients were demented. The median plasma Hcys value was elevated by approximately 20% in multimorbid elderly patients, independent of cognitive dysfunction. Serum folate and vitamin B12 concentrations were within normal ranges. We did not find significant differences in nutritional status, activities of daily living, numbers of diseases or medications, or selected biochemical parameters between the SKT groups. CONCLUSION: Elevated serum Hcys levels with normal plasma folate and vitamin B12 concentrations were observed in multimorbid elderly patients. The plasma Hcys level did not appear to be an important biological risk factor for cognitive dysfunction in multimorbid geriatric patients.

An audit of postoperative intravenous patient-controlled analgesia with morphine: evolution over the last decade.

The development and refinement of an acute pain service based on the increased availability of clinical evidence would be expected to improve the quality of postoperative pain control. This report reviews the application of postoperative patient-controlled analgesia (PCA) using intravenous morphine in a single institution between 2002 and 2005. More than 5000 patients were evaluated and the results were compared with a similar study performed 10 years ago. Prescription of PCA had increased by more than threefold. Morphine consumption from post-operative day 1 to day 3 (19.1 vs. 26.1, 8.6 vs. 18.1 and 4.5 vs. 19.0 microg/kg/h, respectively), demand-to-delivery ratio (1.35-1.76 vs. 2.4-2.8) and the incidence of respiratory depression (0.06% vs. 2%) were significantly reduced (p<0.001), but there was no improvement in pain relief. A substantial proportion of patients still experienced postoperative nausea (47%) and vomiting (18.5%) despite a reduction in morphine consumption. Most patients ranked PCA as good and only 0.3% were dissatisfied. We conclude that, in our institution over the last decade, PCA has become more popular for postoperative pain management but with no attendant improvement in pain relief or reduction in side effects. Using PCA alone may result in poorer quality postoperative analgesia. Our findings add to the growing body of evidence that postoperative pain management has not substantially improved despite increased adoption of acute pain services.

[Does an association between increased homocystein levels and cognitive dysfunction also exist in multimorbid geriatric patients]. / Besteht auch bei multimorbiden geriatrischen Patienten ein Zusammenhang zwischen erhöhten Homocysteinspiegeln und kognitiven Defiziten?

BACKGROUND: Total blood homocysteine (Hcys) and folate have been investigated in association with cognitive dysfunction (CD) in healthy but not in multimorbid elderly patients. We hypothesized that total Hcys and folate are adequate markers to identify multimorbid elderly patients with CD. METHODS: According to the Short Performance Cognitive Test (SKT) CD was determined in a cross-sectional study with 189 (131 f/58 m) multimorbid elderly patients with a mean age of 78.6 +/- 7.3 yrs. Besides the analyses of biochemical parameters (Hcys, folate, vitamin B(12), hemogram) nutritional status (BMI, Mini Nutritional Assessment) as well as activities of daily living were assessed. Daily nutritional intake was measured with a 3-day nutrition diary. For analysis, we used the nutritional software program DGE-PC professional. RESULTS: According to SKT 25.4% showed no cerebral cognitive dysfunction, 21.2% had a suspicion about incipient cognitive dysfunction, 12.7% showed mild, 9.0% moderate, 31.7% of patients severe cognitive deficits. Median plasma Hcys was about 20% elevated in multimorbid elderly patients independent of CD. Serum folate and vitamin B(12) levels were within range, though dietary folate intake (97 [80-128] microg/d) was reduced about 75% (recommendation 400 microg/d). Significant correlations between vitamin intake and plasma/serum levels of Hcys, folate and vitamin B(12) were not present. We did not find significant differences between SKT groups of nutritional status, activities of daily living, index of diseases, medications, or selected biochemical parameters. CONCLUSION: We analysed elevated serum Hcys levels in multimorbid elderly patients with normal plasma folate and vitamin B(12) concentration and CD. Plasma Hcys or serum folate did not appear as an important biological risk factor on CD in multimorbid elderly patients.

Methylprednisolone therapy in deceased donors reduces inflammation in the donor liver and improves outcome after liver transplantation: a prospective randomized controlled trial.

OBJECTIVE: To investigate potential beneficial effects of donor treatment with methylprednisolone on organ function and outcome after liver transplantation. SUMMARY BACKGROUND DATA: It is proven experimentally and clinically that the brain death of the donor leads to increased levels of inflammatory cytokines and is followed by an intensified ischemia/reperfusion injury after organ transplantation. In experiments, donor treatment with steroids successfully diminished these effects and led to better organ function after transplantation. METHODS: To investigate whether methylprednisolone treatment of the deceased donor is applicable to attenuate brain death-associated damage in clinical liver transplantation we conducted a prospective randomized treatment-versus-control study in 100 deceased donors. Donor treatment (n = 50) consisted of 250 mg methylprednisolone at the time of consent for organ donation and a subsequent infusion of 100 mg/h until recovery of organs. A liver biopsy was taken immediately after laparotomy and blood samples were obtained after brain death diagnosis and before organ recovery. Cytokines were assessed by real-time reverse transcriptase-polymerase chain reaction. Soluble serum cytokines were measured by cytometric bead array system. RESULTS: After methylprednisolone treatment, steroid plasma levels were significantly higher (P < 0.05), and a significant decrease in soluble interleukins, monocyte chemotactic protein-1, interleukin-2, interleukin-6, tumor necrosis factor-alpha, and inducible protein-10 was observed. Methylprednisolone treatment resulted in a significant downregulation of intercellular adhesion molecule-1, tumor necrosis factor-alpha, major histocompatibility complex class II, Fas-ligand, inducible protein-10, and CD68 intragraft mRNA expression. Significantly ameliorated ischemia/reperfusion injury in the posttransplant course was accompanied by a decreased incidence of acute rejection. CONCLUSIONS: Our present study verifies the protective effect of methylprednisolone treatment in deceased donor liver transplantation, suggesting it as a potential therapeutical approach.

Total serum homocysteine levels do not identify cognitive dysfunction in multimorbid elderly patients.

OBJECTIVES: Total blood homocysteine (Hcys) and folate levels have been investigated in association with cognitive dysfunction in healthy but not in multimorbid elderly patients. We hypothesized that total serum Hcys is an adequate marker to identify multimorbid elderly patients with cognitive dysfunction assessed by the Short Cognitive Performance Test (SKT) and Mini-Mental State Examination (MMSE). DESIGN: Cross-sectional study. SETTING: The study center was an acute geriatric hospital. PARTICIPANTS: A total of 189 multimorbid elderly patients were recruited. METHODS: Cognitive dysfunction was determined according to the SKT and MMSE. Biochemical parameters (Hcys, folate, vitamin B12, hemoglobin), nutritional status (BMI, Mini Nutritional Assessment, nutritional intake), and activities of daily living were assessed. RESULTS: According to the SKT, 25.4% of patients showed no cerebral cognitive dysfunction, 21.2% had suspected incipient cognitive dysfunction, 12.7% showed mild cognitive dysfunction, 9.0% had moderate cognitive dysfunction, and 31.7% of patients were demented. The median plasma Hcys value was elevated by approximately 20% in multimorbid elderly patients, independent of cognitive dysfunction. Serum folate and vitamin B12 concentrations were within normal ranges. We did not find significant differences in nutritional status, activities of daily living, numbers of diseases or medications, or selected biochemical parameters between the SKT groups. CONCLUSION: Elevated serum Hcys levels with normal plasma folate and vitamin B12 concentrations were observed in multimorbid elderly patients. The plasma Hcys level did not appear to be an important biological risk factor for cognitive dysfunction in multimorbid geriatric patients.

Reticulocytes and their immature fraction do not detect acute rejection after kidney transplantation.

BACKGROUND: Early detection of an acute rejection episode is an important problem in monitoring transplant patients. Erythropoietin (EPO) production is diminished in patients suffering from chronic renal insufficiency or acute rejection. Therefore, a decrease of reticulocyte counts and of young reticulocytes might indicate the emergence of an acute rejection episode. This pilot study examined the value of reticulocyte parameters as indicators of acute rejection episodes. PATIENTS AND METHODS: Reticulocyte parameters were examined in 25 renal transplant patients. Initial immunosuppressants therapy was based on a combination of methylprednisolone, mycophenolatmofetil, cyclosporine and antithymocyte globulin or basiliximab, CellCept, cyclosporine, and ATG or Simulect. During the first 3 weeks after the procedure, blood samples were collected three times per week. Complete blood counts were performed on XE-2100 analyzers (Sysmex). Acute rejection was biopsy-proven. RESULTS: Acute rejection episodes were not accompanied by significantly altered reticulocyte parameters. During the first weeks, the reticulocyte count or the immature fraction, respectively, did not differ between patients with delayed versus immediate onset of renal function: reticulocyte count 1.70 +/- 1.06% vs 1.58 +/- 1.10% and ratio of immature (high fluorescent) reticulocytes 22.8 +/- 7.9% vs 17.6 +/- 9.4%). CONCLUSION: Reticulocyte counts and determination of the immature reticulocyte fraction were not significantly altered by an acute rejection episode. Various influences modulate the release of EPO and reaction of erythropoiesis upon an EPO stimulus.

Rapid immunochromatographic strip test for the detection of albuminuria and brief literature review on albuminuria screening.

Albuminuria is a powerful predictor of cardiovascular events in diabetic and hypertensive patients as well as in the general population. In the present study we evaluated the diagnostic performance of the new PreventID Albumin test, a semi-quantitative immunochromatographic dipstick device for the rapid detection of low concentrations of urinary albumin (microalbuminuria). 88 randomly selected fresh urine samples from the central clinical laboratory of the Charité, Berlin/Germany were analysed. The diagnostic accuracy of the PreventID Albumin test for the detection of urinary albumin excretion >18 mg/l was assessed by comparing the results with urinary albumin excretion determined by immunoturbidimetry as golden standard. In comparison with immunoturbidimetry the PreventID Albumin test had a sensitivity of 96.2% and specificity of 97.1%. False negative results were found in 2.3% and false positive results were obtained in 1.1% of specimens. These findings suggest that the PreventID Albumin test may be a useful and valid method for the screening of albuminuria. However, it should not be regarded as a diagnostic test. Positive results should be followed by quantification of urinary albumin or albumin/creatinine ratio by a laboratory based method.

Monoclonal anti-interleukin-5 treatment suppresses eosinophil but not T-cell functions.

Influx of eosinophils in airway mucosa and airway lumen is a hallmark of bronchial asthma. In-vitro data and animal studies indicate that the T-helper (Th) type-2 cell cytokine, interleukin (IL)-5, plays an important role in eosinophil maturation, differentiation, recruitment, and survival. The objective of this study was to determine whether intravenous treatment with monoclonal anti-IL-5 would affect the number of peripheral blood eosinophils, their activation status, T-cell activation or the pattern of Th1 and Th2 cytokine production. Over a period of 6 months, 19 asthmatics were investigated in a double-blind, placebo-controlled, multicentre study with mepolizumab (SB 240563) anti-IL-5 antibody administered three times. Before each infusion and 12 weeks after the last infusion, peripheral blood leukocytes were examined, qualitative and quantitative distribution of eosinophils and lymphocyte subpopulations, frequencies of IL-2, -3, -4, -5, -10, -13, interferon-gamma-producing CD4 T-cells and serum eosinophil cationic protein (ECP) levels were determined. Treatment with mepolizumab resulted in a marked, rapid and sustained decrease of eosinophil numbers (median values from 300 to 45 per microL) paralleled by decreased levels of serum ECP (median values from 15 to 5 microg x L(-1)). Distribution of T-cell subsets and T-cell cytokine production were not altered during antibody treatment. In conclusion, administration of mepolizumab to asthmatic patients markedly reduces peripheral blood eosinophils without altering the distribution and activation status of lymphocytes.

Simultaneous biatrial computerized mapping during permanent atrial fibrillation in patients with organic heart disease.

INTRODUCTION: Activation patterns during permanent atrial fibrillation (AF) in patients with organic heart diseases are unclear. METHODS AND RESULTS: We studied six patients with permanent AF and organic heart diseases undergoing surgery. The duration of AF averaged 4.9+/-7.6 years. Computerized epicardial mappings of the right atrial (RA) free wall and the left atrial (LA) posterior wall were simultaneously performed with 224 bipolar electrodes at 3-mm spatial resolution. In the RA, large wavefronts and conduction blocks were frequently observed. The lines of block correlated with the crista terminalis and large pectinate muscles. In contrast, the LA had rapid repetitive activities originated from corners of the electrode plaque, near the four pulmonary veins (PVs). On average, 2.8+/-1.2 sites of rapid repetitive activities were identified per patient. They activated continuously, intermittently, or alternately during AF. The mean activation cycle length in the RA (196+/-22 msec) was significantly longer than that in the LA (179+/-26 msec; P = 0.004). The maximum dominant frequency in the LA was higher than that in the RA (6.41+/-1.18 Hz vs 5.66+/-0.55 Hz; P = 0.049). The maximum dominant frequency was consistently located in areas with rapid repetitive activations near the PVs. CONCLUSION: During human permanent AF associated with organic heart diseases, the activation cycle length was shorter in the LA posterior wall than in the RA free wall. Rapid repetitive activities are consistently observed in the LA posterior wall, at or near the PVs.

Effects of endothelin receptor antagonists on the progression of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease in European countries and is associated with an enhanced renal synthesis of endothelin (ET)-1. ETs are - beside their potent vasoconstrictor properties - very potent profibrotic acting paracrine hormones especially in the kidney. METHODS: We analyzed in rats with streptozotocin-induced diabetes the effects of an ETA-type (ETA) receptor antagonist (LU 135252) in comparison to a combined ETA/ETB receptor antagonist (LU 224332) on the expression of interstitial and glomerular collagen type I, III and IV as well as on fibronectin and laminin by quantitative immunohistochemistry using a computer-aided image analysis system. Global glomerular matrix deposition was analyzed after PAS staining. In addition to the morphometric examination of the kidneys, we also investigated GFR, urinary albumin and total protein excretion. The diabetic rats were treated for 36 weeks. RESULTS: Treatment with either LU 135252 or LU 224332 normalized the amount of PAS-positive material within the glomeruli. The expression of glomerular fibronectin and type IV collagen was increased 36 weeks after induction of diabetes. The overexpression of these two matrix proteins within the glomeruli of diabetic rats was completely abolished by both ET receptor antagonists, whereas protein excretion was only reduced by about 50% as compared to diabetic rats without treatment. CONCLUSION: The present study indicates that ETA receptor antagonists as well as combined ETA/ETB receptor antagonists reduce proteinuria and completely normalize the renal matrix protein expression in hyperglycemic rats with streptozotocin-induced diabetes. The antifibrotic effect seems to be mediated via the ETA receptor. ET receptor antagonists might be a new approach in the treatment of diabetic nephropathy.