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Biomedical subjects

G A Müller

Publications and source records attributed to G A Müller.

At least 19 recordsLinked to original sources

Cystatin C--a marker for assessment of the glomerular filtration rate in patients with cisplatin chemotherapy.

BACKGROUND: Cystatin C has recently been proposed as an ideal marker for glomerular filtration rate (GFR). In this study, cystatin C serum levels were evaluated in comparison to serum creatinine concentrations and inulin clearances in patients with normal kidney function receiving cisplatin-based chemotherapy to assess the validity of cystatin C as an alternative endogenous marker of GFR. METHODS: Blood samples for the assessment of cystatin C, creatinine and inulin clearances were collected in patients before and after application of cisplatin in a clinical trial. Overall, 41 patients were included in the study, 35 of them were eligible receiving cisplatin in two different cisplatin-based chemotherapy schedules. RESULTS: A 21% increase of cystatin C serum levels was demonstrated in the placebo group after application of cisplatin. Analysis of inulin clearances revealed a 23% loss of inulin clearance in patients of the placebo arm. In contrast, significant changes could not be detected by analysis of serum creatinine levels. CONCLUSIONS: Cystatin C represents a more sensitive clinical marker than serum creatinine for the early assessment of GFR damage caused by cisplatin. Changes in cystatin C serum concentrations correlate well to GFR decrease as measured by inulin clearance.

Adult↗

[Plasma exchange therapy for steroid-unresponsive multiple sclerosis relapses: clinical experience with 16 patients].

Patients with severe multiple sclerosis (MS) relapses which do not respond sufficiently to corticosteroids can undergo escalating immunotherapy with plasma exchange. We review the course of 14 apheresis cycles in 13 adult patients and three pediatric cases from our center between 2004 and 2005. Nine cases were due to optic neuritis, five had experienced clinically isolated syndromes, and two suffered from Devic's disease. Of the adult patients, 71% had good or very good outcome. The mean time point of improvement was after the third plasmapheresis session, and early initiation of plasma exchange therapy (within 1 month after begin of relapse) was associated with better outcome. In pediatric MS, two of three patients showed clear improvement. These data argue for a very good therapeutic effect of plasma exchange if performed early and with adequate indication.

Activities of Daily Living↗

Prospective 7 year follow up imaging study comparing radiography, ultrasonography, and magnetic resonance imaging in rheumatoid arthritis finger joints.

OBJECTIVE: To perform a prospective long term follow up study comparing conventional radiography (CR), ultrasonography (US), and magnetic resonance imaging (MRI) in the detection of bone erosions and synovitis in rheumatoid arthritis (RA) finger joints. METHODS: The metacarpophalangeal and proximal interphalangeal joints II-V (128 joints) of the clinically dominant hand of 16 patients with RA were included. Follow up joint by joint comparisons for erosions and synovitis were made. RESULTS: At baseline, CR detected erosions in 5/128 (4%) of all joints, US in 12/128 (9%), and MRI in 34/128 (27%). Seven years later, an increase of joints with erosions was found with CR (26%), US (49%) (p<0.001 each), and MRI (32%, NS). In contrast, joint swelling and tenderness assessed by clinical examination were decreased at follow up (p = 0.2, p<0.001). A significant reduction in synovitis with US and MRI (p<0.001 each) was seen. In CR, 12 patients did not have any erosions at baseline, while in 10/12 patients erosions were detected in 25/96 (26%) joints after 7 years. US initially detected erosions in 9 joints, of which two of these joints with erosions were seen by CR at follow up. MRI initially found 34 erosions, of which 14 (41%) were then detected by CR. CONCLUSION: After 7 years, an increase of bone erosions was detected by all imaging modalities. In contrast, clinical improvement and regression of synovitis were seen only with US and MRI. More than one third of erosions previously detected by MRI were seen by CR 7 years later.

Adult↗

[Erdheim-Chester disease].

HISTORY AND CLINICAL FINDINGS: A 55-year-old female was admitted complaining of musculoskeletal pain and weakness of both lower extremities for a number of years. Due to a hypothalamic mass of unknown aetiology a diabetes insipidus, a gonadotrophic, somatotrophic and a partially corticotrophic insufficiency had developed. INVESTIGATIONS: Laboratory investigations yielded elevated levels of several inflammatory parameters (C-reactive protein, blood sedimentation rate, fibrinogen and thrombocytes). Serological parameters indicating a systemic rheumatic disorder were absent. X-ray examination revealed combined osteolytic and osteoblastic lesions within the distal parts of both femora and within the proximal portions of both tibiae. MRI showed signal alterations and (99m)Technetium bone scan exhibited a considerably increased uptake. Histopathologically, a biopsy of the left tibia showed multifocal small infiltrates of foamy histiocytes indicating Erdheim-Chester disease (ECD). TREATMENT AND COURSE: Under treatment with glucocorticosteroids musculoskeletal complaints improved, but re-appeared following dose reduction. A therapeutic trial using methotrexat did not affect the complaints. CONCLUSION: The Erdheim-Chester syndrome is considered to belong to diseases with a proliferation of the monocytic-histiocytic and dendritic cellular system. In the presence of symmetric musculoskeletal symptoms associated with osteosclerotic and osteolytic lesions particularly occurring in the long bones of the lower extremities and concomitant with elevated serum markers of inflammation, the Erdheim-Chester disease should be taken into account. To date, no validated therapy exists.

Biopsy↗

Protease inhibitors in spontaneous cervical artery dissections.

BACKGROUND AND PURPOSE: Observations in patients with arterial aneurysms, fibromuscular dysplasia, and spontaneous cervical artery dissection (sCAD) indicate that protease inhibitor deficiency might boost the enzymatic destruction of arterial tissue and increase the risk of these arterial wall diseases. Here we present the first large investigation of the protease inhibitor hypothesis in patients with sCAD. METHODS: Eighty patients with sCAD were compared with 80 age- and sex-matched healthy individuals. Alpha1-antitrypsin (alpha1-AT) and alpha2-macroglobulin (alpha2-MG) levels, and alpha1-AT genotypes were assessed and compared between groups. RESULTS: alpha1-AT and alpha2-MG levels as well as alpha1-AT genotypes did not differ significantly between patients and controls. The frequency of Z alleles in the patient group was higher than in the control group and than in other cohorts from Europe; however, the difference remained nonsignificant. All patients with Z alleles had internal carotid artery dissections. CONCLUSIONS: Overall, this data does not support the hypothesis that protease inhibitor levels or alpha1-AT genotypes play an important role in the etiology of sCAD. The present data does not exclude that the Pi-Z allele might have an influence on subgroups of sCAD, such as internal carotid artery dissections.

Adult↗

First clinical evaluation of sagittal laser optical tomography for detection of synovitis in arthritic finger joints.

OBJECTIVE: To identify classifiers in images obtained with sagittal laser optical tomography (SLOT) that can be used to distinguish between joints affected and not affected by synovitis. METHODS: 78 SLOT images of proximal interphalangeal joints II-IV from 13 patients with rheumatoid arthritis were compared with ultrasound (US) images and clinical examination (CE). SLOT images showing the spatial distribution of scattering and absorption coefficients within the joint cavity were generated. The means and standard errors for seven different classifiers (operator score and six quantitative measurements) were determined from SLOT images using CE and US as diagnostic references. For classifiers showing significant differences between affected and non-affected joints, sensitivities and specificities for various cut off parameters were obtained by receiver operating characteristic (ROC) analysis. RESULTS: For five classifiers used to characterise SLOT images the mean between affected and unaffected joints was statistically significant using US as diagnostic reference, but statistically significant for only one classifier with CE as reference. In general, high absorption and scattering coefficients in and around the joint cavity are indicative of synovitis. ROC analysis showed that the minimal absorption classifier yields the largest area under the curve (0.777; sensitivity and specificity 0.705 each) with US as diagnostic reference. CONCLUSION: Classifiers in SLOT images have been identified that show statistically significant differences between joints with and without synovitis. It is possible to classify a joint as inflamed with SLOT, without the need for a reference measurement. Furthermore, SLOT based diagnosis of synovitis agrees better with US diagnosis than CE.

Adolescent↗

Diagnosis and follow up of aortitis in the elderly.

OBJECTIVES: To evaluate the correlation of MRI and [(18)F]FDG-PET scans with the clinical course and inflammatory markers in patients with aortitis. METHODS: Eight patients with aortitis presenting with unspecific GCA-like symptoms were examined. Aortitis was diagnosed and followed up by [(18)F]FDG-PET and MRI. The aorta was divided into three vascular regions (ascending aorta, aortic arch, and descending aorta) to localise the aortic inflammation and compare both imaging techniques. RESULTS: were correlated with clinical and laboratory examinations. RESULTS: At diagnosis, 20/24 vascular regions from eight patients were positive by [(18)F]FDG-PET scan and 15/21 aortic regions by MRI. Patients were treated with corticosteroids and followed up for a mean (SD) of 13.3 (4.7) months. In [(18)F]FDG-PET, 11/20 (55%) initially pathological aortic regions returned to normal in the follow up examination, which correlated closely with the clinical and laboratory follow up examination. Conversely, in MRI, 14/15 initially affected vascular regions were unchanged. CONCLUSIONS: [(18)F]FDG-PET and MRI are both effective techniques for detecting early aortitis and have a high correlation with laboratory inflammatory measures. However, during the follow up examination, [(18)F]FDG-PET uptake decreased in line with the clinical symptoms and inflammatory serum markers, whereas MRI scans gave more static results.

Aged↗

Benign prostatic hyperplasia (BPH) requiring transurethral resection in freshly transplanted renal allograft recipients.

With recent progress in surgery and immunosuppression, more and more older men receive a kidney transplant. Thus, it is likely that the incidence of BPH in male transplant recipients is growing in parallel with age. Nonetheless, no data exist about diagnostic parameters for BPH in freshly transplanted male kidney allograft recipients. We evaluated whether established diagnostic and therapeutic criteria for BPH are valid for the evaluation of renal transplant recipients. BPH was diagnosed in 8 of 11 recipients older than 55 years. In all freshly transplanted renal allograft recipients, lower urinary tract symptoms (LUTS) were detected using an international prostate symptoms score (IPSS). This score was 9.6 +/- 7.1 in patients without BPH, and significantly higher with 21.1 +/- 4.3 in patients with BPH. In receiver-operating characteristics (ROC) curve analysis a cut-off of 15.5 was calculated to distinguish best between BPH and non-BPH giving an accuracy of 90.2%. Acute urinary retention (AUR) was the predominant sign, which occurred in all BPH patients but only in 6.9% in non-BPH patients. Bladder outlet obstruction (BOO) was also common with a reduced uroflow with 9.5 +/- 2.2 ml/sec in non-BPH and 3.0 +/- 1.8 ml/sec in BPH (8/11 BPH-patients developed AUR prior to measurement). By digital rectal examinations, benign prostate enlargement was estimated as minimal in 10 of 11 cases of BPH. In urethrocystoscopy kissing lobes were detected in all cases of BPH. Since medical treatment with alpha-receptor antagonists was not successful, a surgical procedure using a transurethral resection was performed without any complications in all cases. Symptoms did not recur after resection, and BOO improved with increased uroflow measurements with 12.3 +/- 4.8 ml/sec 8 days after resection. We conclude that LUTS and BOO are common in freshly transplanted renal allograft recipients. The sudden onset of outlet obstruction without the potentiality of adaptation of urinary bladder may effect lower urinary tract symptoms and bladder outlet obstruction. We conclude that an elevated IPSS over 15.5 in combination with AUR and typical urethrocystoscopy results are the best methods to diagnose BPH. Conversely, our results indicate that uroflowmetry and digital rectal examination are neither sensitive nor specific. In addition, once BPH has been diagnosed and treatment with receptor antagonists does not relieve urinary tract symptoms, surgical resection should be considered.

Humans↗

Molecular evidence of organic ion transporters in the rat adrenal cortex with adrenocorticotropin-regulated zonal expression.

Experimental evidence suggested that secretion of steroid hormones from adrenocortical cells involves carrier-mediated transport: Cortisol release from, and uptake of p-[3H]aminohippurate into, bovine adrenocortical cells showed properties of the renal p-[3H]aminohippurate/anion exchanger OAT1. Other poly-specific transporters such as organic anion-transporting polypeptides (oatps) and organic cation transporters (OCTs) could also be involved in steroid hormone release. A homology-cloning procedure was established to detect these transporters in rat adrenal gland cDNA. PCR revealed the presence of OAT1, oatp1, oatp2, and oatp3. In situ hybridization localized OAT1 in the outer zona fasciculata, oatp3 in the zona glomerulosa, and oatp1 and oatp2 in the inner zona fasciculata and outer zona reticularis. An OCT2-specific probe produced signals in the zona glomerulosa and outer zona fasciculata. Pretreatment of rats with ACTH increased the expression of OAT1 mRNA that spread to all zones, and hypophysectomy strongly decreased it. A less pronounced regulation was detected for OCT2 and oatp3. Specific antibodies confirmed the localization of OAT1 in the outer zona fasciculata, supporting a possible role of OAT1 in cortisol release. The zonated distribution of transporters furthermore suggest that oatp1-3 and OCT2 may be important for the endocrine function of rat adrenocortical cells.

Adrenal Cortex↗

Human renal fibroblasts derived from normal and fibrotic kidneys show differences in increase of extracellular matrix synthesis and cell proliferation upon angiotensin II exposure.

Angiotensin II (Ang II) as a vasoactive hormone may be involved in progressive renal interstitial fibrosis. We investigated the influence of Ang II on cell proliferation and synthesis of extracellular matrix (collagen I, III and fibronectin) in human renal fibroblasts derived from normal (TK 173 cell line) and fibrotic (TK 188 cell line) kidneys which possess both Ang II type l and type 2 (AT1 and AT2) receptors. Incubation of the cells with Ang II increased the cell proliferation and the synthesis of extracellular matrix significantly in both cell lines. However, proliferation and extracellular matrix synthesis showed a greater increase in the cells derived from the fibrotic kidney. The Ang II mediated effect on cell proliferation and extracellular matrix synthesis was diminished in the presence of the AT1 receptor blocker losartan in both cell lines. No inhibition was observed using the AT2 receptor blocker PD123319. Ang II induced cell proliferation could be completely inhibited by incubation with human TGF-beta1 antibody. Incubation with Ang II did not affect TGF beta 1 production but in untreated cells TGF-beta 1 content was higher in the cells derived from the fibrotic kidney. This might be the reason for the more sensitive reaction on exposure to Ang II.

Angiotensin II↗

["Peculiar infection" with fever, splenomegaly and acute kidney failure in a 24-year-old forestry student].

When confronted by the combination of initial high fever associated with intense malaise, splenomegaly, elevated levels of transaminases, and acute renal failure, consideration must be given to the differential diagnosis of leptospirosis even in Germany. As a rule, the diagnosis is confirmed by serological testing based on the titer curve. Renal involvement is frequent, but usually has a good prognosis, especially if jaundice has not developed. Treatment with doxycycline or penicillin can shorten the disease course and exudation, possibly also the nephritis, or hinder it.

Acute Kidney Injury↗

No acute impact of haemodialysis treatment on free radical scavenging enzyme gene expression in white blood cells.

OBJECTIVE: Oxidative stress has been implicated in the side-effects caused by haemodialysis (HD) treatment. DESIGN: In the present study we have investigated whether gene expression of the enzymatic defence system provided by cellular glutathione peroxidase (GPx-1), phospholipid glutathione peroxidase (GPx-4), glutathione reductase (GSSG-R), glutathione synthethase (GSH-S), Cu/Zn-superoxide dismutase (SOD-1) and catalase (CAT) is affected by HD. The GPx-1, GPx-4, GSSG-R, GSH-S, SOD-1 and CAT mRNA were determined in white blood cells by quantitative reverse transcriptase-polymerase chain reaction with the LightCycler instrument and transcription elongation factor-2 as reference gene at the start (SD) and immediately after (ED) dialysis treatment (n = 36). In a subgroup (n = 10), messenger RNA (mRNA) expression was determined hourly during a 5 h HD. RESULTS: The expression of GPx-1, GPx-4, GSSG-R, GSH-S, SOD-1 and CAT mRNA was not affected by a single HD treatment. All mRNAs were significantly (P < 0.05) increased in HD patients [median (16. percentiles (perc.); 84. perc.)]: GPx-1: 2.18 (0.89; 3.23); GPx-4: 0.41 (0.26; 0.74); GSSG-R: 0.04 (0.02; 0.10); GSH-S: 0.04 (0.02; 0.08); SOD-1: 0.32 (0.20; 0.62); CAT: 0.12 (0.06; 0.18) when compared with healthy blood donors (GPx-1: 0.91 (0.60; 1.44); GPx-4: 0.27 (0.16; 0.43); GSSG-R: 0.02 (0.01; 0.02); GSH-S: 0.02 (0.02; 0.04); SOD-1: 0.15 (0.10; 0.18); CAT: 0.07 (0.04; 0.16). CONCLUSIONS: These results show that the HD procedure does not acutely affect the antioxidant defence system on the gene level but suggest that the chronic stress caused by uraemia and/or HD may cause gene induction of the enzymatic defence system.

Aged↗

[Long-term analysis of clinical disease activity and chronic organ damage in patients with systemic lupus erythematosus].

BACKGROUND: Systemic lupus erythematosus is a chronic inflammatory and systemic disease with multiple symptoms which is often characterized by a course of exacerbations. Over the last few decades the prognosis of SLE considerably improved with >90% patients living more than 10 years with their disease. AIM OF THE STUDY AND METHODS: The aim of this retrospective-descriptive analysis of 65 patients with the diagnosis of SLE (based on the ARA criteria) was to investigate the symptoms and the laboratory values at the time of diagnosis (TD) and over a period of 10 years (10Y) in the outpatient university clinic of the Department of Nephrology and Rheumatology at Goettingen. In addition to symptoms and laboratory values, disease activity, exacerbations, chronic organ failure, and medical therapy were to be investigated. RESULTS: The long-term analysis revealed a decline in the prevalence of ANAs (TD: 95.6%; >10Y: 78.6%), ds-DNA antibodies (TD: 78.0%; >10Y: 46.7%) and pathological levels of the complement component C3 (TD: 72.7%; >10Y: 42.9%) over time. The symptoms most prevalent at the time of first diagnosis such as the typical butterfly rash (TD: 50.0,%; >10Y: 36.8%), discoid skin lesions (TD: 38.8%; >10Y: 23.5%) were noted less often after a 10 year-disease course. On the contrary the frequency of arthralgias (TD: 61.2%; >10Y: 57.9%), myalgias (TD: 26.1%; >10Y: 26.3%) and fatigue (TD: 63.0%; >10Y: 64.7%) remained stable over time. The prevalence of arterial hypertension (TD: 17.2%; >10Y: 54.5%), proteinuria (TD: 33.3%; >10Y: 66.7%) and erythrocyturia (TD: 27.8%; >10Y: 44.4%) remarkably increased during the disease course. Besides renal damage, coronary artery disease (TD: 6.0%; >10Y: 23.0%) and neurological disease (e.g., cerebrovascular insults) (TD: 10.9%; >10Y: 26.3%) were noted more often after 10 years. Of patients, 56.9% developed one or several exacerbations of the disease. In all cases, clinical symptoms correlated with an increase in the level of ds-DNA-antibodies and a decrease of C3-complement component. Other medications included immunosuppressants, antihypertensive drugs and NSAIDs. High-dose steroids were preferred as the first diagnosis (TD: 44.4%; >10Y: 11.1%), while low-dose steroids were more often prescribed after a 10-years diseases course (TD: 6.7%; >10Y: 27.8%). CONCLUSIONS: There is a shift towards secondary organ damage with a decline of the inflammatory activity in patients with SLE after 10 years of disease. These consecutive diseases are due to the primary damage of SLE as well as to medical treatment (e.g., with steroids).

Adolescent↗

First steps toward the establishment of a German low-density lipoprotein-apheresis registry: recommendations for the indication and for quality management.

New recommendations for the indication of treatment with selective extracorporeal plasma therapy low-density lipoprotein apheresis (LDL-apheresis) in the prevention of coronary heart disease are urgently needed. The following points are the first results of the ongoing discussion process for indications for LDL-apheresis in Germany: all patients with homozygous familial hypercholesterolemia with functional or genetically determined lack or dysfunction of LDL receptors and plasma LDL cholesterol levels >13.0 mmol/L (>500 mg/dL); patients with coronary heart disease (CHD) documented by clinical symptoms and imaging procedures in which over a period of at least 3 months the plasma LDL cholesterol levels cannot be lowered below 3.3 mmol/L (130 mg/dL) by a generally accepted, maximal drug-induced and documented therapy in combination with a cholesterol-lowering diet; and patients with progression of their CHD documented by clinical symptoms and imaging procedures and repeated plasma Lp(a) levels >60 mg/dL, even if the plasma LDL cholesterol levels are lower than 3.3 mmol/L (130 mg/dL). Respective goals for LDL cholesterol concentrations for high-risk patients have been recently defined by various international societies. To safely put into practice the recommendations for LDL-apheresis previously mentioned, standardized treatment guidelines for LDL-apheresis need to be established in Germany that should be supervised by an appropriate registry.

Cholesterol, LDL↗

Up-regulation of the human serum and glucocorticoid-dependent kinase 1 in glomerulonephritis.

Glomerulonephritis is paralleled by excessive formation of transforming growth factor-beta (TGF-beta), which participates in the pathophysiology of the disease. Recently, a novel downstream target of TGF-beta has been identified, i.e. the human serum and glucocorticoid-dependent kinase 1 (hSGK1), a serine/threonine kinase participating in the regulation of Na(+) transport. The present study was performed to elucidate transcriptional regulation of hSGK1 in glomerulonephritis. To this end, in situ hybridization was performed in biopsies from patients with clinical diagnosis of glomerulonephritis. hSGK1 transcript levels were moderately enhanced in 5 out of 9 patients and strongly enhanced in 4 out of 9 patients. Distal nephron epithelial cell hSGK1 transcript levels were low or absent in 7 of the 9 patients but markedly enhanced in 2 of the 9 patients. In conclusion, glomerulonephritis leads to glomerular and in some cases to epithelial up-regulation of hSGK1 transcription.

Adult↗

Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation.

Type IV collagen is a major component of basement membranes and it provides structural and functional support to various cell types. Type IV collagen exists in a highly complex suprastructure form and recent studies implicate that protomer (the trimeric building unit of type IV collagen) assembly is mediated by the NC1 domain present in the C-terminus of each collagen alpha-chain polypeptide. Here we show that type IV collagen contributes to the maintenance of the epithelial phenotype of proximal tubular epithelial cells, whereas type I collagen promotes epithelial-to-mesenchymal transdifferentiation (EMT). In addition, the recombinant human alpha1NC1 domain inhibits assembly of type IV collagen NC1 hexamers and potentially disrupts the deposition of type IV collagen, facilitating EMT in vitro. Inhibition of type IV collagen assembly by the alpha1NC1 domain up-regulates the production of transforming growth factor-beta1 in proximal tubular epithelial cells, an inducer of EMT. These results strongly suggest that basement membrane architecture is pivotal for the maintenance of epithelial phenotype and that changes in basement membrane architecture potentially lead to up-regulation of transforming growth factor-beta1, which contributes to EMT during renal fibrosis.

Animals↗

Chronic renal transplantation: a model for the hyperhomocysteinemia of renal insufficiency.

Renal transplant recipients (RTR) are considered representative of patients with chronic renal insufficiency (CRI) in general with respect to both reduced, progressively declining renal function, and increased risk for cardiovascular disease (CVD). In accord with this argument, we hypothesized that total (t) plasma concentrations of the putatively atherothrombotic amino acid homocysteine (Hcy) would be equivalent in RTR and CRI patients with comparable renal function. We determined plasma tHcy, folate, pyridoxal 5'-phosphate, and B12 concentrations, in addition to serum creatinine and albumin concentrations, in 86 chronic, stable RTR, and 238 patients with CRI. Within comparable ranges of serum creatinine (i.e. RTR=0.6-4.2 mg/dl; CRI=0.7-4.1 mg/dl), tHcy concentrations did not differ between the two groups (RTR=15.0 micromol/l; CRI=14.9 micromol/l, P=0.899). ANCOVA revealed that renal function, gauged as a simple creatinine measurement, was the major independent determinant of plasma tHcy concentrations, accounting for approximately 80-90% of the total variability in tHcy predicted by the full model (i.e. full model R(2)) containing, in addition to creatinine, the seven other potential explanatory variables. If controlled trials confirm that tHcy-lowering treatment reduces CVD events rates in RTR, these results should be applicable to CRI patients in general.

Adult↗