[Treatment of uveitis-associated refractory ocular hypotony with topical ibopamine]

BACKGROUND: Ibopamine is a non-selective dopamine- and adrenalin-receptor agonist that has been shown to cause pupillary dilation and an increase in aqueous humour secretion. This novel drug can be used as a mydriatic agent, as a provocative test in open-angle glaucoma, and for the treatment of persisting ocular hypotony. HISTORY AND SIGNS: This 47-year-old man had a history of uveitis associated with Crohn's disease. Six years after deep sclerectomy for uveitic secondary glaucoma, he developed severe hypotony in his left eye with drop of visual acuity (VA). The hypotony did not respond to topical steroid treatment. 2 % Ibopamine solution was ordered t. i. d. concomitant to 1 % prednisolone acetate. THERAPY AND OUTCOME: Intraocular pressure (IOP) began to rise after 3 weeks of Ibopamine treatment and returned to normal (12 mmHg) with continuous recovery of VA after 8 weeks. Ibopamine was discontinued at an IOP of 16 mmHg after a course of 12 weeks. IOP and VA remained stable during the 12-month follow-up period. CONCLUSIONS: Ibopamine 2 % eye drops in combination with topical steroids are a therapeutic option in uveitis-associated ocular hypotony.

Antagonistic and synergistic effects of glucocorticoids and IL-7 on CD4+ T cell activation

Glucocorticoids (GCs) are steroidal compounds widely used to treat chronic and acute inflammatory diseases. In particular, GCs at pharmacological doses induce apoptosis of activated and naïve T cells, inhibit their proliferation and block pro-inflammatory cytokine secretion. At physiological concentrations, the effect of these steroids on T cell immunity are not yet fully understood, and various studies reported paradoxical roles exerted by GCs on T cell immunity. Here, we show that GCs surprisingly induce proliferation of activated CD4(+) T cells in the presence of IL-7, a cytokine secreted in the thymus and at mucosal sites. Increased proliferation is dependent on a GC-mediated survival of mitotic cells. Moreover, we observe a downmodulation of Th1 cytokine secretion in cells treated with GCs, an outcome which is not affected by the presence of IL-7. GCs exert thus a positive role in the presence of IL-7 by enhancing proliferation of CD4(+) T cells and simultaneously a negative role by suppressing pro-inflammatory cytokine production.

Optimization of corticosteroid induced osteoporosis in ovariectomized sheep. A bone histomorphometric study

During osteoporosis induction in sheep, side effects of the steroids were observed in previous studies. The aim of this study was to improve the induction regimen consisting of ovariectomy, calcium/vitamin D- restricted diet and methylprednisolone (-MP)- medication with respect to the bone metabolism and to reduce the adverse side effects. Thirty-six ewes (age 6.5 +/- 0.6 years) were divided into four MP-administration groups (n = 9) with a total dose of 1800 mg MP: group 1: 20 mg/day, group 2: 60 mg/every third day, group 3: 3 x 500 mg and 1 x 300 mg at intervals of three weeks, group 4: weekly administration, starting at 70 mg and weekly reduction by 10 mg. After double-labelling with Calcein Green and Xylenol Orange, bone biopsy specimens were taken from the iliac crest (IC) at the beginning and four weeks after the last MP injection, and additionally from the vertebral body (VB) at the end of the experiment. Bone samples were processed into stained and fluorescent sections, static and dynamic measurements were performed. There were no significant differences for static parameters between the groups initially. The bone perimeter and the bone area values were significantly higher in the VB than in the IC (Pm: 26%, p < 0.0001, Ar: 11%, p < 0.0166). A significant decrease (20%) of the bone area was observed after corticosteroid-induced osteoporosis (p < 0.0004). For the dynamic parameters, no significant difference between the groups was found. Presence of Calcein Green and Xylenol Orange labels were noted in 50% of the biopsies in the IC, 100% in the VB. Group 3 showed the lowest prevalence of adverse side effects. The bone metabolism changes were observed in all four groups, and the VB bone metabolism was higher when compared to the IC. In conclusion, when using equal amounts of steroids adverse side effects can be reduced by decreasing the number of administrations without reducing the effect regarding corticosteroid-induced osteoporosis. This information is useful to reduce the discomfort of the animals in this sheep model of corticosteroid-induced osteoporosis.

Insulin-like growth factors (IGFs), IGF binding proteins, and other endocrine factors in milk: role in the newborn

The role of colostrum and milk in the neonate has been chiefly recognized as a comprehensive nutrient foodstuff. In addition, the provision of colostrum-the first milk-for early immune capacity has been well documented for several species. Colostrum is additionally a rich and concentrated source of various factors that demonstrate biological activity in vitro. Three hypotheses have been proposed for the phenotypic function of these secreted bioactive components: (1) only mammary disposal, (2) mammary cell regulation, and (3) neonatal function [gastrointestinal tract (GIT) or systemic]. Traditionally, it was assumed that the development of the GIT is preprogrammed and not influenced by events occurring in the intestinal lumen. However, a large volume of research has demonstrated that colostrum (or milk-borne) bioactive components can basically contribute to the regulation of GIT growth and differentiation, while their role in postnatal development at physiological concentrations has remained elusive. Much of our current understanding is derived from cell culture and laboratory animals, but experimentation with agriculturally important species is taking place. This chapter provides an overview of work conducted primarily in neonatal calves and secondarily in other species on the effects on neonates of selected peptide endocrine factors (hormones, growth factors, in part cytokines) in colostrum. The primary focus will be on insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) and other bioactive peptides, but new interest and concern about steroids (especially estrogens) in milk are considered as well.

Hexose-6-phosphate dehydrogenase modulates 11beta-hydroxysteroid dehydrogenase type 1-dependent metabolism of 7-keto- and 7beta-hydroxy-neurosteroids

BACKGROUND: The role of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in the regulation of energy metabolism and immune system by locally reactivating glucocorticoids has been extensively studied. Experiments determining initial rates of enzyme activity revealed that 11beta-HSD1 can catalyze both the reductase and the dehydrogenase reaction in cell lysates, whereas it predominantly catalyzes the reduction of cortisone to cortisol in intact cells that also express hexose-6-phosphate dehydrogenase (H6PDH), which provides cofactor NADPH. Besides its role in glucocorticoid metabolism, there is evidence that 11beta-HSD1 is involved in the metabolism of 7-keto- and 7-hydroxy-steroids; however the impact of H6PDH on this alternative function of 11beta-HSD1 has not been assessed. METHODOLOGY: We investigated the 11beta-HSD1-dependent metabolism of the neurosteroids 7-keto-, 7alpha-hydroxy- and 7beta-hydroxy-dehydroepiandrosterone (DHEA) and 7-keto- and 7beta-hydroxy-pregnenolone, respectively, in the absence or presence of H6PDH in intact cells. 3D-structural modeling was applied to study the binding of ligands in 11beta-HSD1. PRINCIPAL FINDINGS: We demonstrated that 11beta-HSD1 functions in a reversible way and efficiently catalyzed the interconversion of these 7-keto- and 7-hydroxy-neurosteroids in intact cells. In the presence of H6PDH, 11beta-HSD1 predominantly converted 7-keto-DHEA and 7-ketopregnenolone into their corresponding 7beta-hydroxy metabolites, indicating a role for H6PDH and 11beta-HSD1 in the local generation of 7beta-hydroxy-neurosteroids. 3D-structural modeling offered an explanation for the preferred formation of 7beta-hydroxy-neurosteroids. CONCLUSIONS: Our results from experiments determining the steady state concentrations of glucocorticoids or 7-oxygenated neurosteroids suggested that the equilibrium between cortisone and cortisol and between 7-keto- and 7-hydroxy-neurosteroids is regulated by 11beta-HSD1 and greatly depends on the coexpression with H6PDH. Thus, the impact of H6PDH on 11beta-HSD1 activity has to be considered for understanding both glucocorticoid and neurosteroid action in different tissues.

Sequential immunosuppressive therapy in progressive IgA nephropathy

BACKGROUNDS: Cyclophosphamide and high-dose steroids have been used as limited induction therapy in progressive IgA nephropathy (IgAN) to reduce the loss of renal function and proteinuria. We evaluated the effect of cyclophosphamide pulses (CyP) and mycophenolic acid (MPA) as sequential therapy on renal function in patients with progressive IgAN. METHODS: Twenty patients with progressive IgAN and advanced renal failure (median GFR 22 ml/min per 1.73 m2) and further disease activity (triangle downGFR -0.8 ml/min per month) after cyclophosphamide (CyP; n = 18) or steroid pulse therapy (n = 2) were treated with mycophenolate mofetil 1 g per day for a median of 27 months. RESULTS: The monthly loss of renal function was significantly reduced in linear regression analysis from -2.4 ml/min before CyP to -0.12 ml/min with CyP/MPA (p = 0.0009). Estimated renal survival time was significantly prolonged by a median of 65 months (p = 0.0014). Proteinuria decreased significantly from 1.7 to 0.4 g/l during MPA treatment (p = 0.015). In Cox regression analysis, only proteinuria >1.0 g/l was an independent risk factor for doubling of creatinine during CyP/MPA treatment (p = 0.03). CONCLUSION: A sequential therapy with CyP/MPA may arrest or slow down the loss of renal function and reduces proteinuria even in patients who passed the so called 'point of no return' with progressive IgAN.

Multimodal imaging in macular diagnostics: combined OCT-SLO improves therapeutical monitoring

BACKGROUND: Digital imaging methods are a centrepiece for diagnosis and management of macular disease. A recently developed imaging device is composed of simultaneous confocal scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT). By means of clinical samples the benefit of this technique concerning diagnostic and therapeutic follow-up will be assessed. METHODS: The combined OCT-SLO-System (Ophthalmic Technologies Inc., Toronto, Canada) allows for confocal en-face fundus imaging and high resolution OCT scanning at the same time. OCT images are obtained from transversal line scans. One light source and the identical scanning rate yield a pixel-to-pixel correspondence of images. Three-dimensional thickness maps are derived from C-scan stacking. RESULTS: We followed-up patients with cystoid macular edema, pigment epithelium detachment, macular hole, venous branch occlusion, and vitreoretinal tractions during their course of therapy. The new imaging method illustrates the reduction of cystoid volume, e.g. after intravitreal injections of either angiostatic drugs or steroids. C-scans are used for appreciation of lesion diameters, visualisation of pathologies involving the vitreoretinal interface, and quantification of retinal thickness change. CONCLUSION: The combined OCT-SLO system creates both topographic and tomographic images of the retina. New therapeutic options can be followed-up closely by observing changes in lesion thickness and cyst volumes. For clinical use further studies are needed.

Orbital manifestation of whipple's disease: an atypical case

BACKGROUND: Whipple's disease is a systemic disorder caused by an infection with a gram-positive bacillus, Tropheryma whipplei. Almost every organ system can be affected in Whipple's disease, resulting in varying clinical symptoms. CASE REPORT: As far as we are aware, this report of a 61-year-old male is the first presenting with a periorbital manifestation of the disease, with severe exophthalmos and optic nerve involvement, leading to rapid visual loss. This emergency case was successfully treated by a surgical orbital decompression combined with systemic use of antibiotics and steroids. CONCLUSION: Whipple's disease can affect the periorbital tissues and the optic nerve, causing massive exophthalmos and serious transient visual loss. In such a case surgical decompression of the affected orbit combined with antibiotics and steroids is a recommended valid treatment option.

[Pulmonary nodules in a patient on long-term steroid treatment]

We report on a patient who was chronically treated with steroids. She simultaneously developed pulmonary nocardiosis as well as a soft tissue infection and osteomyelitis by mycobacterium abscessus. Both infections are rare, but more frequently occur in immunocompromised hosts. The patient was healed after 12 month of adequate antibiotic treatment.

Prevalence of cholecystolithiasis and its management among kidney/pancreas-transplanted type 1 (insulin-dependent) diabetic patients

BACKGROUND: Simultaneous pancreas/kidney transplantation (SPK) should be the procedure of choice for (pre)uremic patients with type 1 diabetes. All standard immunosuppressive protocols for SPK include a calcineurin-inhibitor. Both calcineurin inhibitors, cyclosporine (CyA) and probably tacrolimus (FK506) too, are associated with the occurrence of cholelithiasis due to their metabolic side effects. PATIENTS AND METHODS: We evaluated the prevalence of cholelithiasis in 83 kidney/pancreas transplanted type I-diabetic patients (46 males, 37 females, mean age 42.8 +/- 7.5 years) by conventional B-mode ultrasound 5 years after transplantation. 56 patients received CyA (group 1) and 27 received tacrolimus (group 2) as first-line-immunosuppressive drug. Additional immunosuppression consisted of steroids, azathioprine or mycophenolate mofetil. Additionally, laboratory analyses of cholestasis parameters (gamma-GT and alcalic phosphatasis) were performed. RESULTS: In total, 23 patients (28%) revealed gallstones and 52 patients (62%) revealed a completely normal gallbladder. In eight patients (10%) a cholecystectomy was performed before or during transplantation because of already known gallstones. No concrements in the biliary ducts (choledocholithiasis) could be detected. In group 2 the number of patients with gallstones was slightly lower (22%) compared with group 1 patients (30%), but without statistical significance. - Cholestasis parameters were not increased and HbA1c values were normal in both groups of patients. CONCLUSION: The prevalence of biliary disease in kidney/pancreas transplanted type I-diabetic patients with 28% is increased in comparison to the general population (10-15%). Lithogenicity under tacrolimus seems to be lower as under cyclosporine based immunosuppressive drug treatment. We recommend regular sonographical examinations to detect an acute or chronic cholecystis as early as possible, which may develop occultly in these patients.

Clinical trials in head injury

Secondary brain damage, following severe head injury is considered to be a major cause for bad outcome. Impressive reductions of the extent of brain damage in experimental studies have raised high expectations for cerebral neuroprotective treatment, in the clinic. Therefore multiple compounds were and are being evaluated in trials. In this review we discuss the pathomechanisms of traumatic brain damage, based upon their clinical importance. The role of hypothermia, mannitol, barbiturates, steroids, free radical scavengers, arachidonic acid inhibitors, calcium channel blockers, N-methyl-D-aspartate (NMDA) antagonists, and potassium channel blockers, will be discussed. The importance of a uniform strategic approach for evaluation of potentially interesting new compounds in clinical trials, to ameliorate outcome in patients with severe head injury, is proposed. To achieve this goal, two nonprofit organizations were founded: the European Brain Injury Consortium (EBIC) and the American Brain Injury Consortium (ABIC). Their aim lies in conducting better clinical trials, which incorporate lessons learned from previous trials, such that the succession of negative, or incomplete studies, as performed in previous years, will cease.

Cell cycle-dependent regulation of extra-adrenal glucocorticoid synthesis in murine intestinal epithelial cells

Glucocorticoids are anti-inflammatory steroids with important applications in the treatment of inflammatory diseases. Endogenous glucocorticoids are mainly produced by the adrenal glands, although there is increasing evidence for extra-adrenal sources. Recent findings show that intestinal crypt cells produce glucocorticoids, which contribute to the maintenance of intestinal immune homeostasis. Intestinal glucocorticoid synthesis is critically regulated by the transcription factor liver receptor homologue-1 (LRH-1). As expression of steroidogenic enzymes and LRH-1 is restricted to the proliferating cells of the crypts, we aimed to investigate the role of the cell cycle in the regulation of LRH-1 activity and intestinal glucocorticoid synthesis. We here show that either pharmacological or molecular modulation of cell cycle progression significantly inhibited expression of steroidogenic enzymes and synthesis of glucocorticoids in intestinal epithelial cells. Synchronization of intestinal epithelial cells in the cell cycle revealed that expression of steroidogenic enzymes is preferentially induced at the G(1)/S stage. Differentiation of immature intestinal epithelial cells to mature nonproliferating cells also resulted in reduced expression of steroidogenic enzymes. This cell cycle-related effect on intestinal steroidogenesis was found to be mediated through the regulation of LRH-1 transcriptional activity. This mechanism may restrict intestinal glucocorticoid synthesis to the proliferating cells of the crypts.

Obesity in long-term survivors of childhood acute lymphoblastic leukemia

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) with current cure rates reaching 80% emphasizes the necessity to determine treatment related long-term effects. The present study examines the prevalence of and the risk factors for overweight and obesity in a cohort of ALL survivors treated and living in the French speaking part of Switzerland. METHODS: In this retrospective two-center study, height and weight of 54 patients diagnosed with ALL in first complete remission and treated with chemotherapy only were recorded at specified time points during treatment and off-therapy. Body mass index (BMI) and its age- and gender-adjusted standard deviation score (BMI-SDS) were calculated for the patients and their parents separately. Overweight and obesity were defined by a threshold of BMI-SDS >1.645 and BMI-SDS >1.96, respectively. RESULTS: At last follow-up, 16 (30%) of the 54 survivors were overweight and 10 (18%) were obese. The off-treatment period was most at risk with 11 of the 16 becoming overweight and 9 of the 10 becoming obese during that period. Overweight/obesity at diagnosis and abnormal maternal BMI were significantly associated with abnormal weight at follow-up, while age at diagnosis, gender, cumulative dose of steroids and paternal BMI showed no association. CONCLUSIONS: Consistent with published evidence from other regions of the developed and developing world, there is a significant prevalence of obesity in young ALL survivors in the French speaking part of Switzerland. Factors significantly associated with this late effect were mostly related to the familial background rather than to the treatment components.

Acute respiratory distress syndrome secondary to antisynthetase syndrome is reversible with tacrolimus

Polymyositis and interstitial lung diseases, predominantly nonspecific interstitial pneumonia (NSIP), are known to be frequent in antisynthetase syndrome, where anti-aminoacyl-tRNA synthetase antibodies are often identified. An unusual case of acute respiratory distress syndrome, secondary to such proven NSIP of cellular type with predominant CD8 lymphocytes, is described herein. The patient described in the present case study initially had a poor recovery with high dose of steroids, but this was followed by a good improvement after the prescription of tacrolimus and a low dose of prednisone. A precise diagnosis in similar circumstances may be life-saving, allowing the successful application of new immunosuppressants.

Otologic manifestations in Samter's syndrome

OBJECTIVE: It was the aim of this study to investigate the prevalence of otologic manifestations in a cohort of Samter's syndrome patients (nasal polyps with chronic rhinosinusitis, aspirin intolerance and asthma). METHODS: We analyzed a retrospective and prospective case review from 1995 to 2005, performed in the otorhinolaryngology outpatient clinic of a tertiary referral center. Ear history, clinical examinations, treatment and outcome were evaluated using office and hospital records in 23 cases. All subjects completed a questionnaire. RESULTS: In 6 cases (26%), otological manifestations with ear pressure and conductive hearing loss occurred during an advanced stage of Samter's syndrome (>5 years after onset of the first nasal symptoms) partially responsive to systemic steroids. CONCLUSION: Recognition of the association between Samter's syndrome and otological disease is important (26% of the cases) because it could also be responsive to systemic steroids which prevent progression to irreversible hearing loss or infectious otomastoiditis.