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P Nawroth

Publications and source records attributed to P Nawroth.

At least 19 recordsLinked to original sources
PubMed2006

[Bone metastasis of prostatic cancer imitating Paget's sarcoma].

HISTORY AND CLINICAL FINDINGS: A 74-year-old man presented with bone pain of the right hip, night sweat and weight loss for 18 months. The diagnosis of Paget's disease was confirmed four months before admission, but pain and elevated serum alkaline phosphatase levels remained despite treatment with i.v. bisphosphonates. The physical examination showed no specific abnormalities. INVESTIGATIONS: Laboratory findings were elevated levels of serum alkaline phosphatase (AP), CA 19-9 and CEA. Radiological and tomographic images showed an aggressive periostal reaction consistent with Paget's sarcoma. The bone biopsy revealed the presence of prostatic cancer which was confirmed in a subsequent prostate biopsy. TREATMENT AND COURSE: Because of the multiple bone and lung metastases the disease proved to be incurable and the patient received palliative therapy with flutamide. He died 12 months later. CONCLUSION: In patients with Paget's disease lacking of response to bisphosphonate administration (permanently increased AP and sustained pain) radiological and clinical re-assessment of the diagnosis is indicated and may sometimes also include bone biopsy.

Adenocarcinoma↗
PubMed2006

Osseous integration of calcium phosphate in osteoporotic vertebral fractures after kyphoplasty: initial results from a clinical and experimental pilot study.

INTRODUCTION: This study evaluated the radiological changes at the bone-cement interface of calcium phosphate cement (CPC) and polymethylmethacrylate (PMMA) 12 months after kyphoplasty. In a pilot experiment, we additionally performed a histomorphometric analysis in osteopenic foxhounds to analyze the process of osseous integration of CPC and PMMA. METHODS: Twenty postmenopausal female patients with 46 vertebral compression fractures (VCF) were treated by kyphoplasty, utilizing CPC (N=28) or PMMA (N=18) for intravertebral stabilization. After a 12-month follow-up, we measured the density changes of border voxels at the bone-cement interface by computed tomography (CT) using dedicated software algorithms. We defined the border-voxel density (BVD) as a parameter of cement resorption at the interface. We also investigated the bone-implant interface in three osteopenic foxhounds by histomorphometry 3, 6, and 12 months after cement implantation. RESULTS: Twelve months after kyphoplasty, only CPC showed a significant decrease of the BVD compared to PMMA (p<0.01), indicating a slow progress of resorption at the interface. Histomorphometry of the dog vertebrae showed near total bone coverage of CPC implants, whereas the PMMA surface exhibited only 30% direct bone contact (p<0.01). We also observed a time-dependent increase in the number of discernable osteons close to the interface of CPC, but no bone tissue within PMMA (p<0.01). CONCLUSIONS: The decrease of the BVD 12 months after kyphoplasty may indicate osseous integration of CPC by: (1) the ingrowth of bone tissue and (2) osteonal penetration close to the interface.

Animals↗
PubMed2006

Effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy.

AIMS/HYPOTHESIS: Hyperglycaemia-induced mitochondrial overproduction of reactive oxygen species (ROS) is central to the pathogenesis of endothelial damage in diabetes. R-(+)-alpha-lipoic acid has advantages over classic antioxidants, as it distributes to the mitochondria, is regenerated by glycolytic flux, and has a low redox potential. METHODS: To assess the effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy, three groups of male Wistar rats were studied: non-diabetic controls, untreated diabetic controls, and diabetic rats treated with 60 mg/kg bodyweight R-(+)-alpha-lipoic acid i.p. for 30 weeks. Quantitative retinal morphometry included acellular occluded capillaries and pericyte numbers. The effects of R-(+)-alpha-lipoic acid on parameters of oxidative and nitrative stress, AGE and its receptor and nuclear factor kappa B (NFkappaB) were assessed by immunoblotting, and NFkappaB activation by electrophoretic mobility shift assay. Angiopoietin-2 and vascular endothelial growth factors were also determined by immunoblotting. RESULTS: After 30 weeks of diabetes, the number of acellular capillaries was significantly elevated in diabetic rats (57.1+/-10.6 acellular capillary segments [ac]/mm(2) of retinal area) compared with non-diabetic (19.8+/-5.1 ac/mm(2); p<0.001). Treatment with 60 mg/kg R-(+)-alpha-lipoic acid reduced the numbers by 88% (p<0.001 vs diabetic). Pericyte loss was also significantly inhibited in diabetic rats treated with R-(+)-alpha-lipoic acid (non-diabetic: 1,940+/-137 pericytes/mm(2)capillary area; untreated diabetic: 1,294+/-94 pericytes/mm(2)capillary area vs treated diabetic: 1,656+/-134 pericytes/mm(2); p<0.01). R-(+)-alpha-lipoic acid treatment reduced oxidative stress, normalised NFkappaB activation and angiopoietin-2 expression, and reduced vascular endothelial growth factor in the diabetic retina by 43% (p<0.0001). CONCLUSIONS/INTERPRETATION: R-(+)-alpha-lipoic acid prevents microvascular damage through normalised pathways downstream of mitochondrial overproduction of ROS, and preserves pericyte coverage of retinal capillaries, which may provide additional endothelial protection.

Animals↗
PubMed2006

Distinct roles of Mac-1 and its counter-receptors in neonatal obstructive nephropathy.

Urinary tract obstruction during renal development leads to tubular atrophy and interstitial fibrosis. Inflammatory macrophages are crucial in this process, and beta2-integrins play a major role in leukocyte recruitment. We investigated the role of beta2-integrins and their major counter-receptors (intercellular adhesion molecule-1 (ICAM-1), receptor for advanced glycation endproducts (RAGE), junctional adhesion molecule (JAM)-C) in obstructive nephropathy in neonatal mice. Two-day-old beta2-integrin-deficient mice (Mac-1-/- and LFA-1-/-(deficient for leukocyte function-associated antigen-1)) and wild-type mice (C57BL/6) underwent unilateral ureteral obstruction (UUO) or sham operation. After 1, 5 or 12 days of obstruction, renal macrophage infiltration and tubulointerstitial damage were quantitated. Tissue abundance of Mac-1 and its ligands ICAM-1, RAGE and JAM-C was examined by Western blot and immunoprecipitation. Deficiency of either integrin was associated with reduced early macrophage invasion into the obstructed kidney. After 12 days of UUO, macrophage infiltration and tubulointerstitial injury were reduced only in Mac-1-/- but not in LFA-1-/- mice. Besides ICAM-1, an upregulation of two novel Mac-1 ligands, RAGE and JAM-C were observed, however, with distinct time courses. We conclude that beta2-integrins mediate macrophage infiltration in UUO. Mac-1 is the predominant leukocyte integrin involved in leukocyte recruitment after obstruction. ICAM-1 and its new ligands RAGE and JAM-C are sequentially activated in UUO. Blocking of Mac-1 and its ligands may confer synergistic renoprotective effects in neonatal obstructive nephropathy.

Animals↗
PubMed2005

[Integrated skills laboratory concept for undergraduate training in internal medicine].

BACKGROUND AND OBJECTIVE: An amendment to the German medical curriculum in April 2002 will place basic practical skills at the centre of medical training. We report here on the implementation and evaluation of an obligatory, tutor-guided, and integrated skills laboratory concept in the field of internal medicine. METHODS: To test the effectiveness of a skills laboratory training on OSCE performance a pilot study was carried out. The experimental group, of 77 students, participated in seven sessions of communication training, skills laboratory training, and bedside teaching, each lasting one and a half hours. The control group of 66 students had as many sessions but was only offered bedside-teaching. The evaluation of acceptance of skills' training as well as the related increase in individual competence is on-going (summer term 2004: n = 176 students). RESULTS: The integrated skills laboratory concept was rated at 3.5 (SD = 1.2) on a 5-point scale and was acknowledged as practice-oriented (M = 4.2; SD = 1.0) and relevant for doctors' everyday lives (M = 3.6; SD = 1.1). Increased levels of competence according to individual self-evaluations proved to be highly significant (p<.001), and results of the pilot study showed that the experimental group had a significantly better OSCE performance than the control group (p<.001). CONCLUSION: This pilot study shows that curriculum changes promoting basic clinical skills are effective and lead to an improved practical education of tomorrow's physicians. The integrated skills laboratory concept is well accepted and leads to a relevant increase in competence in the practice of internal medical. The presented skills laboratory concept in internal medicine is proving to be a viable and efficient learning tool.

Adult↗
PubMed2005

[Oncogenic osteomalacia in a 49-year-old female patient].

HISTORY AND CLINICAL FINDINGS: A 49-year-old woman presented with increased bone and muscle pain of the left thigh and also of the left ribs since 1 1/2 year. 2 osteolytic regions on the left proximal femur were punctured but no tumour-like changes were found. INVESTIGATIONS: Laboratory tests showed a severe hypophosphataemia (0.33 mmol/l), increased serum alkaline phosphatase activity and moderate elevated parathyroid hormone. Renal loss of phosphate was measured under phosphate substitution. The bone mineral density (DXA) was decreased. With octreotid scintigraphy a somatostatine receptor positive tumour was detected on the right proximal thigh and magnetic resonance scanning confirmed localization of the tumour. TREATMENT AND COURSE: Treatment with oral phosphate and calcitriol improved the complaints presently. After total removal of a mesenchymal tumour, normalization of serum phosphate occurred and the patient did not require any medicine and did not have complaints anymore. CONCLUSION: In a case of uncertain hypophosphataemic osteomalacia in adults it is essential to search for a tumour after exclusion of the rare differential diagnoses to enable a causal treatment of a potentially oncogenic osteomalacia.

Alkaline Phosphatase↗
PubMed2005

The AGE/RAGE/NF-(kappa)B pathway may contribute to the pathogenesis of polyneuropathy in impaired glucose tolerance (IGT).

Binding of ligands to the receptor for advanced glycation end products (RAGE) results in activation of the transcription factor nuclear factor kappa B (NF-(kappa)B) and subsequent expression of NF-(kappa)B-regulated cytokines. This has been shown to be a relevant pathomechanism in diabetic polyneuropathies (PNP). To determine whether this pathway may contribute to the pathogenesis of PNP due to impaired glucose tolerance (IGT) we performed a pilot study to demonstrate the presence of the RAGE ligand N (epsilon)-(Carboxymethyl)lysine (CML), the receptor itself and N-(kappa)B in sural nerve biopsies of 4 patients with IGT-related PNP. Biopsies of either 4 patients with diabetic PNP and with Charcot-Marie-Tooth disease (CMT) I and II served as positive and negative controls, respectively. In IGT-related PNP and diabetic PNP, CML, RAGE, and NF-(kappa)B was found in the perineurium, epineurial vessels and in part in endoneurial vessels. CMT patients showed, if any, only weak staining for one or the other antigen. These data suggest that activation of the RAGE pathway may be one of the first steps in the pathogenesis of PNP even before chronic hyperglycemia occurs.

Aged↗
PubMed2005

Endothelin-1 levels in patients with Paget's disease of bone.

A locally accelerated bone turnover is the pathophysiological basis of Paget's disease of bone (PD) and may result in severe bone deformations and pain. Affected bone sites are hypervascularized. Secreted endothelial products such as endothelin-1 (ET-1), influence bone metabolism. We investigated a possible correlation between ET-1 plasma concentrations and bone metabolism in patients with PD and whether ET-1 plasma levels are regulated by i. v. bisphosphonate treatment. Plasma ET-1 levels were determined in 22 patients with PD and found to be significantly (p = 0.006) elevated (0.75 +/- 0.48 fmol/ml) compared to 19 healthy controls (0.20 +/- 0.24 fmol/ml). In a group of five patients with PD, plasma ET-1 levels were determined before and after treatment with i. v. pamidronate. On the average, ET-1 levels decreased by 21 % after pamidronate infusions (p = 0.045). The results suggest that bone metabolism in pagetic bone affects endothelial cell metabolism and may also be modulated by endothelial cell products. ET-1 plasma levels may indicate PD activity.

Aged↗
PubMed2005

RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages.

Abstract High-mobility group box chromosomal protein 1 (HMGB1) is a protein with both intranuclear functions and extracellular cytokine-like effects. In this report, we study possible candidate receptors for HMGB1 on macrophages (Mphi) and define pathways activated by HMGB1 binding. Bone marrow Mphi were prepared from Dark Agouti (DA) rats and stimulated in vitro with HMGB1. The kinetics of tumour necrosis factor (TNF) production, NO production, activation of p38 mitogen-activated protein kinase (MAPK), p44/42 MAPK- and SAPK/JNK-signalling pathways, nuclear translocation of nuclear factor kappa B (NF-kappaB) and HMGB1-induced upregulation of major histocompatibility complex (MHC) class II and CD86 were analysed. Mphi from interleukin (IL)-1 receptor type I-/-, Toll-like receptor 2 (TLR2-/-) and RAGE-/- mice were used to investigate the role of these receptors in HMGB1 signalling. HMGB1 induced TNF and NO production by Mphi, phosphorylation of all investigated MAP kinase pathways and NF-kappaB translocation, and expression of MHC class II was increased. Mphi from RAGE-/- mice produced significantly lower amounts of TNF, IL-1beta and IL-6, while IL-1RI-/- and TLR2-/- Mphi produced cytokine levels comparable with wildtype controls in response to HMGB1 stimulation. We conclude that HMGB1 has the potential to induce a proinflammatory phenotype in Mphi, with RAGE as the major activation-inducing receptor.

Animals↗
PubMed2005

No association of the 94T/G polymorphism in the adiponectin gene with diabetic complications.

AIM: This study examined a possible association of the T/G polymorphism at nucleotide 94 in the adiponectin gene with the prevalence of diabetic complications. METHODS: The study was performed in 696 patients with type 1 diabetes and type 2 diabetes. Genotyping was performed by means of polymerase chain reaction and subsequent cleavage by using SmaI restriction endonuclease. RESULTS: The 94G/G genotype was significantly more prevalent in patients with type 2 diabetes (2.2%) than in type 1 diabetics (0.0%) (p = 0.02), whereas no differences were found for frequencies of the 94T/T and the 94G/T genotypes, respectively. In patients with type 1 diabetes, 45 of 239 patients were heterozygous for the 94T/G polymorphism (carrier rate (CR): 18.8%; allele frequency (AF): 0.094). In type 2 diabetics, 71 of 457 patients were heterozygous and 10 patients were homozygous for the 94G/G genotype (CR: 17.7%; AF: 0.10). No association with diabetic nephropathy, diabetic neuropathy or diabetic retinopathy was found for either genotype in patients with type 1 and type 2 diabetes. CONCLUSIONS: The 94T/G polymorphism in the adiponectin gene is not associated with diabetic complications. The significance of a higher prevalence of the G allele in type 2, compared to type 1 diabetes remains to be clarified.

Adult↗
PubMed2004

[Oral diabetes treatment. Which substance is indicated at which time?].

The prevalence of type 2 diabetes continues to show a clear upward trend in Germany. In earlier days it was considered the "harmless diabetes of old age," but has become increasingly recognized as a disease carrying a high risk of vascular sequelae as well as shortening the diabetic's remaining life expectancy if adequate therapy is not initiated. In addition to correcting hyperglycemia, treatment consists in effective management of concomitant risk factors such as hypertension, dyslipidemia, and adiposity resulting from faulty nutrition and lack of exercise. In the large majority of overweight type 2 diabetics, metformin is the oral antidiabetic agent of first choice provided the patient does not exhibit renal insufficiency, which represents the most important contraindication. This recommendation for monotherapy of overweight type 2 diabetics is supported by an endpoint study. In contrast, no equivalent evidence is available on any of the possible options for oral combination therapy.

Administration, Oral↗
PubMed2004

Fluid shear of low magnitude increases growth and expression of TGFbeta1 and adhesion molecules in human bone cells in vitro.

Deformation of the bone matrix by mechanical strain causes fluid shifts within the osteocytic canaliculi which affect osteocytic cell metabolism. We applied low fluid shear (1 - 63 micro Pa for 10 - 48 h) to human osteoblastic cells (HOB) in vitro to study its impact on cell proliferation and differentiated functions. Proteins involved in translating the physical force into a cellular response were characterised. Low fluid shear stress stimulated proliferation of HOB 1.2-fold when stress was applied intermittently for 24 h. Shear stress also increased differentiated cellular properties such as alkaline phosphatase (ALP) activity (121 % of control), fibronectin (FN) and fibronectin receptor (FNR) expression (290 % and 200 %, respectively). Prostaglandin E (2) (PGE (2)) and TGFbeta1 release into the medium were significantly stimulated when shear stress was applied for 6 - 12 h and 24 - 48 h, respectively. TGFbeta1 + 2 neutralising antibodies or the presence of indomethacine inhibited the mitogenic effect of fluid shear and reduced ALP activity to its control level. Furthermore, TGFbeta treatment induced a dose-dependent increase in FN and FNR expression. Therefore, fluid shear stress of low magnitude (a) suffices to affect HOB metabolism and (b) regulates anchorage of HOB via FN and FNR by stimulating osteoblastic PGE (2) and TGFbeta secretion.

Aged↗
PubMed2004

Reduction of postprandial hyperglycemia in patients with type 2 diabetes reduces NF-kappaB activation in PBMCs.

AIMS/HYPOTHESIS: Short-lasting hyperglycemia results in activation of the transcription factor NF-kappaB in peripheral blood mononuclear cells. We therefore studied whether the postprandial increase in glucose is sufficient to induce mononuclear NF-kappaB activation and whether blunting postprandial hyperglycemia with the alpha-glucosidase inhibitor acarbose reduces NF-kappaB activation. METHODS: 20 patients with type 2 diabetes were included in a double-blind randomized trial receiving 100 mg acarbose or placebo three times a day over a period of eight weeks. Peripheral blood mononuclear cells were isolated before and 120 minutes after a standardized breakfast. NF-kappaB binding activity was estimated by electrophoretic mobility shift assay and NF-kappaB-p65; translocation was determined by Western blot. RESULTS: Eight weeks of treatment with acarbose significantly reduced postprandial hyperglycemia (p = 0.004 when compared to placebo), postprandial mononuclear NF-kappaB-binding activity (p = 0.045) and nuclear translocation of NF-kappaB-p65 (p = 0.02). CONCLUSION: Reduction of postprandial glucose peak levels by acarbose reduces postprandial mononuclear NF-kappaB activation.

Acarbose↗
PubMed2004

Variants in the human beta 1-, beta 2-, and beta 3-adrenergic receptor genes are not associated with morbid obesity in children and adolescents.

AIM: beta-adrenergic receptors (beta-ARs) are of key importance for the regulation of lipolysis and thermogenesis by catecholamines. Genetic defects in expression or function of beta(1)- beta(2)- and/or beta(3)-AR could affect energy homeostasis and predispose an individual towards the development of obesity. We therefore investigated the possible association of polymorphisms in the beta-adrenergic receptor genes with early onset obesity. METHODS: Frequencies of the following variants were assessed in extremely obese children and healthy underweight controls: Gly/Ser in codon 49 and Arg/Gly in codon 389 of the beta(1)-AR, Arg/Gly in codon 16 and Gln/Glu in codon 27 of the beta(2)-AR, Trp/Arg in codon 64 of the beta(3)-AR. RESULTS: The Ser49 allele in the beta(1)-AR gene was found at a frequency of 0.131 in obese and 0.136 in lean subjects (p = 0.835), while the Gly389 allele in the beta(1)-AR had a frequency of 0.319 in obese and 0.328 in lean subjects (p = 0.802). Gly16 in the beta(2)-AR was found with a frequency of 0.590 in obese and 0.611 in lean subjects (p = 0.591) and the Glu27 allele in the beta(2)-AR had a frequency of 0.380 in obese and 0.420 in lean subjects (p = 0.298). CONCLUSION: We did not detect significant differences for allele and carrier frequencies of individual polymorphisms. Together with previously obtained data on genotype distribution of a beta(3)-AR variant in the same study group, no significant differences were found between obese and lean subjects for the distribution of individuals with variants in none, one, two or all three beta-ARs. Our data make it unlikely that polymorphisms in beta-ARs are involved in the pathogenesis of early onset obesity.

Adolescent↗
PubMed2003

Discrimination of patients with and without vertebral fractures as measured by ultrasound and DXA osteodensitometry.

This study compares dual X-ray absorptiometry (DXA) measurements of the hip and spine with quantitative ultrasound (QUS) parameters measured simultaneously at the calcaneal and phalangeal bone in 174 patients with and without vertebral fractures. The aim of this study was to compare the ability of DXA and QUS measurements to discriminate patients with and without osteoporotic vertebral fractures and to evaluate whether QUS measurements in addition to the DXA measurements improve the clinical discrimination between patients with and without osteoporotic vertebral fractures. T-scores determined by DXA measurements at the spine and hip and QUS measurements at the calcaneus provide similar information regarding the discrimination of women with and without vertebral fractures. Phalangeal QUS measurements did not discriminate between patients with and without vertebral fractures. The discriminative power of the combined use of DXA and calcaneal QUS measurements to discern between patients with and without vertebral fractures increases in women. In contrast, the combined use of DXA and phalangeal QUS measurements resulted in decreased discriminative power as compared to DXA measurements alone. The number of fractures was higher in the quartiles with lower T-scores of the DXA and calcaneal QUS measurements whereas no difference was seen in the T-score quartiles of the phalangeal QUS device. These findings suggest that DXA and QUS measurements at weight-bearing skeletal sites provide useful information for assessing women with an anamnestic risk of osteoporotic bone loss. For DXA and calcaneal QUS measurements in men as well as for phalangeal QUS, however, a clinical algorithm remains to be established to understand the diagnostic implications and related therapeutic consequences of the obtained measurements.

Absorptiometry, Photon↗
PubMed2002

[Fibrous dysplasia: differential diagnosis from Paget's disease].

HISTORY AND CLINICAL FINDINGS: A 27-year-old woman presented with chronic diffuse bone pain and skeletal deformities. Since the age of 3 years she had occipital hyperostosis. Since aged 13 years she had symptoms indicating spinal root involvement due to hyperkyphosis. For the last 6 years there was evidence of destructive and hyperplastic changes in the region of the middle ribs. Alkaline phosphatase (APL) had been elevated (> 250 U/l) for several years. Three years before the present admission the patient had been hospitalized elsewhere because of bone pain and had received intermittent infusions of pamindronate to a total of 600 mg. INVESTIGATIONS: Laboratory tests showed moderate rise in bone-specific APL and osteocalcin. Conventional x-ray examinations and computed tomography showed lesions in the occipital bone, sella turcica and ethmoid air cells. Several thoracic vertebral fractures were demonstrated. Skeletal scintigraphy indicated enrichment in the occipital and supraorbital regions, as well as in vertebrae and ribs. Dual energy x-ray absorptiometry (DEXA) showed osteopenia. Bone biopsy from the occipital lesion revealed fibrous dysplasia. TREATMENT AND COURSE: The diagnosis of fibrous dysplasia having been confirmed, cyclical treatment with i.v. pamidronate was given for 6 months. It was well tolerated and lessened the pain without changing the objective findings. CONCLUSION: In case of uncertain radiological and scintigraphic findings in the differential diagnosis of fibrous dysplasia, Paget's disease or bone tumor, it is essential to obtain a biopsy and, if available, perform gene analysis.

Absorptiometry, Photon↗
PubMed2001

Characterization of a novel EGFP reporter mouse to monitor Cre recombination as demonstrated by a Tie2 Cre mouse line.

The use of the Cre/loxP system has greatly empowered the field of gene targeting. Here we describe the successful establishment of a novel knock-in EGFP reporter mouse line to monitor Cre-induced recombination in the vast majority of cell types. The value of this reporter mouse line is demonstrated by the use of a novel Tie2Cre transgenic mouse line that facilitates gene targeting in endothelial and hematopoietic cells. High efficiency of recombination was found in all endothelial cells and in the majority of hematopoietic cells but was absent in other tissues. Furthermore, in the second generation, the Tie2Cre mouse can be used to get 100% recombination of one allele, whilst allowing tissue specific in the second, therefore offering excellent efficiency.

Alleles↗