[Reality of inpatient vasoactive treatment with prostacyclin derivatives in patients with acral circulation disorders due to systemic sclerosis in Germany]. / Versorgungsrealität der stationären vasoaktiven Therapie mit Prostazyklinderivaten bei Patienten mit akralen Durchblutungsstörungen bei systemischer Sklerose in Deutschland.

BACKGROUND: Raynaud's phenomenon and the frequently ensuing digital ulcerations represent an early and very distressing symptom in patients with systemic sclerosis (scleroderma, SSc) causing significant limitations in the ability to work and quality of life. The use of vasoactive drugs (especially intravenous prostacyclin derivatives) is recommended to reduce the risk of hypoxic tissue damage up to the loss of fingers. METHODS: In order to obtain information about the current state of treatment of patients with prostacyclin derivatives in routine clinical life in Germany, a survey was conducted among the centers affiliated to the German Network for Systemic Scleroderma (DNSS). In addition, a separate patient survey was conducted by the schleroderma self-help group (Sklerodermie Selbsthilfe e. V.), which only covered the symptoms Raynaud's syndrome, digital ulcers and the use of intravenous prostacyclin derivatives. RESULTS: Of the 433 patients surveyed 56% stated that they had already been treated with prostacyclin derivatives (iloprost/alprostadil) because of their illness and symptoms. A total of 61% received the treatment for severe Raynaud's phenomenon and 39% for digital ulcerations. Most respondents not only experienced an improvement in Raynaud's phenomenon and digital ulcers but also a significant improvement of limitations in everyday life. They also needed significantly less outside help and absenteeism from work was much lower. CONCLUSION: Patients consistently reported a positive effect of treatment with prostacyclin derivatives on Raynaud's phenomenon, acral ulcerations, pain and daily restrictions and felt well and safely cared for during inpatient treatment. These positive effects in the patients' perceptions provide crucial information supporting and confirming the current European and international treatment recommendations.

Therapeutic response to glucocorticoids, anticoagulation and plasma exchange in a patient with primary antiphospholipid syndrome presenting with purpura fulminans.

We report the case of a 25-year-old female patient who presented with purpura fulminans as a manifestation of primary antiphospholipid syndrome. Purpura fulminans is considered a rare cutaneous manifestation of antiphospholipid syndrome. Most frequently, it occurs in the context of catastrophic antiphospholipid syndrome and is associated with significant morbidity and mortality, either due to loss of affected extremities or thromboembolic damage to internal organs. After insufficient efficacy of parenteral anticoagulation and oral glucocorticosteroid treatment, we escalated treatment to high-dose intravenous glucocorticosteroid and five consecutive sessions of plasma exchange with good and sustained clinical response. At follow-up six months after admission, skin manifestations had healed with scarring, and no additional thrombotic events had occurred. Plasma exchange may hold promise as a therapeutic option in refractory or severe cases of antiphospholipid syndrome-related purpura fulminans with extensive cutaneous necrosis, although evidence is limited.

[Musculoskeletal manifestations of sarcoidosis]. / Muskuloskelettale Manifestationen der Sarkoidose.

Musculoskeletal manifestations in the context of sarcoidosis are frequently observed. The rheumatologist regularly encounters this disease in clinical practice. In the present review, we aim to give a current overview of the manifestations and treatments relevant to the practicing rheumatologist. The most frequently encountered manifestation is Lofgren's syndrome, which is characterized by bilateral ankle periarthritis, bilateral hilar lymphadenopathy, and erythema nodosum and has an excellent prognosis. Chronic arthropathy most commonly manifests as oligoarthritis, which sometimes hampers its differentiation from spondylarthropathies, especially when sacroiliitis, enthesitis or dactylitis are simultaneously present. Isolated vertebral granulomas are rare and require infectious and malignant disorders to be excluded, since there are no specific imaging findings that are exclusively found in vertebral sarcoidosis. The presence of granulomas in skeletal muscle is common in muscle biopsies, whereas clinically overt myopathy is present in only around 1-2% of patients. Therapeutic responses vary among the different clinical phenotypes. Non-steroidal anti-inflammatory drugs and low to medium dose glucocorticoids are the first-line therapy for musculoskeletal manifestations and often lead to adequate disease control in acute sarcoidosis. When these are ineffective or not tolerated, steroid-sparing agents are increasingly used in chronic sarcoidosis. Evidence for all medications used in sarcoid-related arthritis is comparatively scant. When supplementing vitamin D, the possible development of hypercalcemia, even at standard doses, needs to be considered; the optimal therapeutic levels for the prevention of medication-induced osteoporosis in sarcoidosis have not been firmly established.

[Interstitial nephritis in rheumatic diseases]. / Interstitielle Nephritis bei rheumatischen Erkrankungen.

Interstitial nephritis is responsible for about 12 % of end-stage renal disease in Germany. It comprises an etiologically heterogenous group of inflammatory renal disorders which primarily affect the renal interstitium and tubuli. Drugs, predominantly antibiotics, nonsteroidal anti-inflammatory drugs and proton pump inhibitors are causative in the majority of cases. Rheumatic diseases frequently affect the kidneys, either the glomeruli or the interstitial tissues. Inflammatory interstitial processes can be accompanied by complex functional tubular disorders. This review gives an overview about clinical and laboratory findings of interstitial nephritis in the context of rheumatic diseases. Sarcoidosis, tubulointerstitial nephritis and uveitis (TINU) syndrome, primary Sjogren's syndrome, and IgG4-related disease often show an interstitial nephritis when the kidneys are affected. Other diseases, such as systemic lupus erythematosus, systemic sclerosis, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and granulomatosis with polyangiitis are more rarely associated with predominant interstitial nephritis. Glucocorticoids are the mainstay of therapy for most cases; in refractory cases or when side effects occur, second-line immunosuppressants such as mycophenolate mofetil, azathioprine and others, rarely biologics, can be used.

[Endophthalmitis, liver abscess, and cerebral and pulmonary emboli in a 48-year-old Vietnamese man]. / Endophthalmitis, Leberabszess sowie zerebrale und pulmonale Embolien bei einem 48-jährigen Vietnamesen.

We present the case of a 48-year-old Vietnamese man with endophthalmitis, liver abscess, and pulmonary and cerebral septic emboli. Klebsiella pneumoniae was isolated as the causative organism; there were no laboratory findings suggestive of invasive fungal infection. Klebsiella pneumoniae invasive syndrome is a rare disease in Germany. This case report exemplifies the necessity of a dedicated diagnostic approach that takes into consideration factors such as ethnic origin and accompanying diseases of the patient.

Successful treatment of a mycophenolate mofetil-refractory proliferative lupus nephritis with Belimumab in a 19-year-old woman.

We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.

Ceruloplasmin expression in rat liver cells is attenuated by insulin: role of FoxO transcription factors.

The phosphoinositide 3'-kinase (PI3 K)/Akt pathway controls the activity of a number of proteins important in the regulation of apoptosis and cell proliferation. FoxO (forkhead box, class O) transcription factors, substrates of the Ser/Thr kinase Akt, control the expression of several target genes that are crucial to the defense against oxidative stress, the regulation of cell cycle, and apoptosis in mammalian cells. Here, expression of ceruloplasmin (CP), the major copper-containing protein in blood released by the liver, was investigated. We observed a significant downregulation of CP mRNA levels after insulin treatment in H4IIE rat hepatoma cells. The PI3K inhibitor wortmannin counteracted this insulin effect on CP mRNA levels, indicating that the PI3K/Akt cascade is involved in the regulation of CP expression. Stimulation of FoxO1 was induced in H4IIE rat hepatoma cells expressing a conditionally active FoxO1 construct, resulting in significant upregulation of CP mRNA levels. This upregulation was prevented in the presence of insulin. In parallel, mRNAs of established FoxO target genes were analyzed: like CP mRNA, selenoprotein P and glucose 6-phosphatase mRNAs were upregulated by FoxO1, which was prevented by insulin. The same effects of insulin on CP mRNA levels were detected in primary rat hepatocytes. Furthermore, CP release into cell culture media was analyzed with primary hepatocytes and found to be attenuated by insulin. In line with its insulin-mimetic effects on cultured cells, Cu (2+) imitated the effect of insulin on CP expression and caused a downregulation of CP mRNA levels in rat hepatoma cells.

Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress.

Oxidative stress is an important determinant not only in the pathogenesis of Alzheimer's disease (AD), but also in insulin resistance (InsRes) and diabetic complications. Forkhead box class O (FoxO) transcription factors are involved in both insulin action and the cellular response to oxidative stress, thereby providing a potential integrative link between AD and InsRes. For example, the expression of intra- and extracellular antioxidant enzymes, such as manganese-superoxide dismutase and selenoprotein P, is regulated by FoxO proteins, as is the expression of important hepatic enzymes of gluconeogenesis. Here, we review the molecular mechanisms involved in the pathogenesis of AD and InsRes and discuss the function of FoxO proteins in these processes. Both InsRes and oxidative stress may promote the transcriptional activity of FoxO proteins, resulting in hyperglycaemia and a further increased production of reactive oxygen species (ROS). The consecutive activation of c-Jun N-terminal kinases and inhibition of Wingless (Wnt) signalling may result in the formation of ß-amyloid plaques and τ protein phosphorylation. Wnt inhibition may also result in a sustained activation of FoxO proteins with induction of apoptosis and neuronal loss, thereby completing a vicious circle from oxidative stress, InsRes and hyperglycaemia back to the formation of ROS and consecutive neurodegeneration. In view of their central function in this model, FoxO proteins may provide a potential molecular target for the treatment of both InsRes and AD.

Regulation of glucose-6-phosphatase gene expression by insulin and metformin.

The biguanide derivative metformin is a potent anti-diabetic drug widely used in the treatment of type 2 diabetes mellitus. Its major effect on glucose metabolism consists in the inhibition of hepatic glucose production. Since the mechanisms of metformin action are only partially understood at the molecular level, we studied the regulation of the gene promoter activity of glucose-6-phosphatase (G6Pase), the central hepatic gluconeogenic enzyme, by this drug. We have found that both metformin and insulin inhibit the basal and dexamethasone/cAMP-stimulated G6Pase promoter activity in hepatoma cells. Since one of the pharmacological targets of metformin is AMP-activated protein kinase (AMPK) and activation of AMPK is known to inhibit hepatic glucose production by the suppression of G6Pase gene transcription, we studied the effect of AMPK in this context. Under nonstimulated conditions, the inhibitory effect of both insulin and metformin was partially counteracted to a similar extent by treatment with compound C, a specific inhibitor of AMPK. In contrast, under conditions of stimulation with dexamethasone and cAMP, treatment with compound C reversed the inhibitory effect of metformin on G6Pase promoter activity to a similar extent as compared to nonstimulated conditions, whereas the effect of insulin was almost resistant to treatment with the AMPK-antagonist. These data indicate a differential AMPK-dependent regulation of G6Pase gene expression by insulin and metformin under basal and dexamethasone/cAMP-stimulated conditions.

Avian Clock gene polymorphism: evidence for a latitudinal cline in allele frequencies.

In comparison with most animal behaviours, circadian rhythms have a well-characterized molecular genetic basis. Detailed studies of circadian clock genes in 'model' organisms provide a foundation for interpreting the functional and evolutionary significance of polymorphic circadian clock genes found within free-living animal populations. Here, we describe allelic variation in a region of the avian Clock orthologue which encodes a functionally significant polyglutamine repeat (ClkpolyQcds), within free-living populations of two passerine birds, the migratory bluethroat (Luscinia svecica) and the predominantly nonmigratory blue tit (Cyanistes caeruleus). Multiple ClkpolyQcds alleles were found within populations of both species (bluethroat: 12 populations, 7 alleles; blue tit: 14 populations, 9 alleles). Some populations of both species were differentiated at the ClkpolyQcds locus as measured by F(ST) and R(ST) values. Among the blue tit, but not bluethroat populations, we found evidence of latitudinal clines in (i) mean ClkpolyQcds repeat length, and (ii) the proportions of three ClkpolyQcds genotype groupings. Parallel analyses of microsatellite allele frequencies, which are considered to reflect selectively neutral processes, indicate that interpopulation allele frequency variation at the ClkpolyQcds and microsatellite loci does not reflect the same underlying demographic processes. The possibility that the observed interpopulation ClkpolyQcds allele frequency variation is, at least in part, maintained by selection for microevolutionary adaptation to photoperiodic parameters correlated with latitude warrants further study.