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Biomedical subjects

R Landgraf

Publications and source records attributed to R Landgraf.

At least 37 records · Page 2Linked to original sources
PubMed2003

Improved ultrasound examination of pancreas grafts in type 1 (insulin-dependent) diabetic patients using tissue harmonic imaging.

BACKGROUND: Combined kidney/pancreas transplantation is an established therapy for type 1 diabetic patients with end-stage renal disease. Ultrasound examinations are valuable noninvasive methods for postoperative monitoring of transplant recipients. Kidney grafts are easily to detect, whereas pancreas grafts are surrounded or covered by small bowel loops, which makes the examination much more difficult. PATIENTS AND METHODS: Thirty-three simultaneous pancreas and kidney recipients (SPK) were examined by conventional sonography at 3.4 MHz and THI sonography (pulse inversion, 2.3 MHz) by an investigator experienced in abdominal ultrasound. The images were graded by two "blinded readers" using a scale (1-best image quality, 2-second best, 3-worst) with regard to tissue penetration and detail characterization of the pancreas grafts. The graders were unaware of the sonographic technique, respectively. Statistical evaluation was performed by the Mann-Whitney U test. RESULTS: In 25 cases (78%) pancreas grafts were detected by conventional sonography. The detection rate was higher using THI sonography, namely 29 cases (91%). Grading for tissue penetration revealed a mean value of 2.05 +/- 0.5 for conventional and 1.94 +/- 0.5 for THI sonography (P =.27). Detail characterization of the pancreas grafts was determined to show a mean value of 2.50 +/- 0.5 for conventional sonography and a significantly better mean value of 1.78 +/- 0.6 for THI sonography (P <.0001). CONCLUSION: THI sonography improves the detection and the judgment of tissue characteristics of pancreas grafts. Penetration of ultrasound waves is not relevantly decreased by this new technique.

Adult↗
PubMed2003

The high-affinity non-peptide CRH1 receptor antagonist R121919 attenuates stress-induced alterations in plasma oxytocin, prolactin, and testosterone secretion in rats.

Evidence from basic and clinical research suggests that hyperactivity of central corticotropin-releasing hormone (CRH) circuits contributes to causality and course of affective disorders. Therefore, CRH receptor antagonists have attracted attention as potential therapeutics. We could previously show that the novel high-affinity non-peptide CRH 1 receptor antagonist R121919 significantly inhibits stress-induced corticotropin release and displays anxiolytic effects in rats selectively bred for high anxiety-related behavior. These animals are characterized by their innate hyper-reactivity of the hypothalamic-pituitary-adrenocortical system linked to an increased emotionality and therefore are suitable for the evaluation of CRH 1 receptor antagonists. Here we show that in addition to its effects on anxiety-related behavior and corticotropin secretion, R121919 attenuates the stress-induced release of corticosterone, prolactin, and oxytocin. Moreover, the decrease in plasma testosterone following exposure to stress is abolished by R121919. Our data indicate that antagonism of CRH 1 receptors may prevent stress-associated endocrine alterations.

Adrenocorticotropic Hormone↗
PubMed2003

Gastric emptying of solid and liquid meals in healthy controls compared with long-term type-1 diabetes mellitus under optimal glucose control.

BACKGROUND: Neuropathy of the enteric nervous system and hyperglycaemia are regarded as the main causes of diabetic gastroparesis. PATIENTS AND METHODS: In ten patients with Type-1 diabetes mellitus and sensomotoric neuropathy gastric emptying half times were compared with ten healthy controls by employing the 13C-octanoic acid and the 13C-sodiumacetate breath test, resp., following the intake of equally composed and isocaloric liquid and solid meals. Plasma glucose concentrations were controlled by permanent intravenous administration of insulin. RESULTS: In diabetes mellitus gastric emptying half times after the intake of the liquid meal (p < 0.05) but not after ingestion of the solid meal were slightly prolonged. Gastric emptying half times in patients and controls were not different when liquid and solid meals were compared. CONCLUSIONS: Acute hyperglycaemia appears to be more important than the neuropathy of the enteric nervous system in the pathophysiology of diabetic gastroparesis. The rate of gastric emptying is obviously not dependent on the phase of a meal, but rather on the composition and the caloric content.

Adult↗
PubMed2003

Born to be anxious: neuroendocrine and genetic correlates of trait anxiety in HAB rats.

This review summarises behavioural, neuroendocrine, and genetic characteristics of Wistar rats bred for either high (HAB) or low (LAB) anxiety-related behaviour. Compared to LABs, HAB animals show signs of extreme trait anxiety in a variety of behavioural tests; they further prefer passive coping strategies, indicative of a genetically linked depression-like behaviour, and show signs of increased stress vulnerability. All behavioural parameters associated with trait anxiety are robust and consistent. Resembling psychiatric patients, HAB rats respond to exposure to ethologically relevant stressors with a hyper-reactivity of the hypothalamic-pituitary-adrenal axis and show a pathological outcome of the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) challenge test. Experimental evidence indicates that over-expression and -release of vasopressin in the hypothalamic paraventricular nucleus is responsible for these behavioural and neuroendocrine phenomena, making the neuropeptide gene a candidate gene of trait anxiety/depression. Indeed, preliminary molecular genetic approaches succeeded in identifying polymorphisms in the promoter structure of the vasopressin gene. This may have implications for understanding the molecular basis for individual variations in trait anxiety and for psychopathology.

Animals↗
PubMed2003

[57-year-old patient with diplopia and headache].

A 57-year old patient presented with an 8 week history of headache and diplopia. Left-sided incomplete oculomotor nerve paresis was found, whereas further clinically relevant visual impairment was not seen. Magnetic resonance imaging of the head showed an extensive intra-, para- and suprasellar tumor which in combination with a markedly elevated serum prolactin level was identified as a macroprolactinoma. The symptoms began 7 years ago with a loss of libido and virility. The application of a dopamine agonist lead to a reduction of serum prolactin level to 0.5% of the initial value and a considerable tumor regression within three months. The development of oculomotor nerve paresis is an unusual manifestation of prolactinoma. By contrast, long-term medical history with slowly developing signs and symptoms of hypogonadotropic hypogonadism are often to be found in men. The delayed diagnosis is responsible for the high percentage of macroprolactinomas in male subjects.

Diagnosis, Differential↗
PubMed2002

The tumour necrosis factor-alpha induced vascular permeability is associated with a reduction of VE-cadherin expression.

BACKGROUND: Vascular permeability is controlled by endothelial cell-to-cell junctions. Vascular endothelial (VE)-cadherin, the major component of adherence junctions (AJ) in the endothelium, is the target of the permeability-increasing agent tumour necrosis factor-a (TNF-alpha). We investigated whether TNF-alpha regulates the synthesis of VE-cadherin on the transcriptional level. MATERIALS AND METHODS: Human endothelial cells, isolated from aorta (aEC) and umbilical cord (HUVEC), were exposed to TNF-alpha (200 U/ml) for 6 h or 12 h, with and without subsequent incubation with TNF-alpha for 24 h. VE-cadherin mRNA was evaluated by semi-quantitative RT-PCR. The VE-Cadherin protein expression was analyzed by flow cytometry (FACS). RESULTS: The VE-cadherin amplification curve of TNF-alpha treated cells was shifted to the right compared to controls, indicating a lower mRNA amount. The number of cycles at which half-maximal amplification (N50) was achieved, was lower for control aEC (30.7) than for TNF-alpha treated aEC (33.0). The N50 of HUVEC treated with TNF-alpha for 12 h and 12 h + 24 h medium (N50 = 32.1), was higher compared to controls (N50 = 29.7) and cells treated with TNF-alpha for 6 h (N50 = 30.8). As determined by FACS analysis, incubation with TNF-alpha caused a small decrease of VE-cadherin protein expression from 7.44 to 6.05 mean channel intensity. CONCLUSION: Our results indicate that TNF-alpha affects VE-cadherin gene expression on the transcriptional level, inducing a downregulation of the VE-cadherin expression.

Antigens, CD↗
PubMed2002

Hypothalamic and hippocampal release of serotonin in rats bred for hyper- or hypo-anxiety.

Microdialysis for measurement of serotonin in the paraventricular nucleus of the hypothalamus (PVN) and the dorsal hippocampus was performed under both basal and stimulated conditions, known to elicit differential behavioral and neuroendocrine responses in rats with inborn high (HAB) or low (LAB) anxiety-related behavior. We studied the release of hypothalamic and hippocampal serotonin in response to elevated platform exposure and forced swim stress, a mild emotional and a combined emotional and physical stressor, respectively. The data suggest that serotonin release patterns may depend on the inborn level of anxiety, the brain area dialyzed, and the stressor the animals were exposed to. Under basal conditions, no differences in serotonin release in either the PVN or dorsal hippocampus were observed between HAB and LAB rats. While in the PVN open platform exposure failed to change the release of serotonin, forced swim stress induced an increase in both HAB (p = 0.0001) and LAB (p = 0.01) rats with a significantly greater effect in the former (p = 0.027). In the dorsal hippocampus, only LABs, but not HABs, responded to the elevated platform exposure by enhancing the release of serotonin (p = 0.01). Also, forced swim stress increased hippocampal serotonin only in LAB (p = 0.002), but not HAB, rats probably indicating an involvement of hippocampal serotonin in locomotion and active stress coping. It remains to be shown to what extent the differences in serotonin release contribute to neuroendocrine and behavioral differences between HAB and LAB rats.

Animals↗
PubMed2002

Weight in adolescents with type 1 diabetes mellitus during continuous subcutaneous insulin infusion (CSII) therapy.

Continuous subcutaneous insulin infusion (CSII) has become increasingly popular as a form of intensified insulin therapy in adolescents with type 1 diabetes mellitus (DM). One reported drawback was increased weight gain in adolescents after initiation of insulin pump therapy. In a prospective, longitudinal, non-randomized and case controlled study, we followed 12 adolescents (mean age 13.6 yr, 8 males, 4 females) from 6 months before the start of CSII to 12 months on CSII. These 12 adolescents with DM on CSII were matched for age, gender, HbA1c, duration of DM, and body mass index (BMI) with 12 adolescents who continued on multiple injection therapy (MIT). In addition, six of the 12 adolescents on CSII intended to control their weight by means of the insulin pump. These six vs six adolescents within the CSII group were further analyzed for weight development and eating habits. Clinical indications for CSII were dawn phenomenon, night-time hypoglycemia and patient request for more flexibility in DM management. All patients had been in satisfactory metabolic control on MIT. After 12 months of CSII, the daily insulin requirement remained significantly lower than 18 months before (0.79 +/- 0.11 vs 1.02 +/- 27 U/kg/d, p = 0.034) and number of daily meals was lower (4.1 +/- 0.9 vs 6.5 +/- 0.7, p = 0.006). Mean initial HbA1c was 7.4% in the MIT and CSII patients, and remained comparable between these two groups. BMI was not different between the CSII and MIT group over the entire study period. However, those adolescents on CSII who intended to control their weight by means of the insulin pump were able to achieve relative weight loss during the,first 6 months on CSII. Two patients of the CSII group had one severe hypoglycemic episode with loss of consciousness. In conclusion, CSII does not lead to weight gain by itself, but allows sufficient weight control without a negative effect on metabolic control. The general threat of weight gain in patients who switch to insulin pump therapy must be pointed out, and the role of eating habits and caloric content of food should play a central role in insulin pump educational programs.

Adolescent↗
PubMed2001

Artificial nucleases.

The oxidation of DNA and RNA provides a facile approach for investigating the interaction of nucleic acids with proteins and oligonucleotides. In this article, we have outlined our understanding of the mechanism of DNA scission by 1,10-phenanthroline-copper(I) in the presence of hydrogen peroxide. We also discuss results obtained by using 1,10-phenanthroline-oligonucleotide conjugates in probing the size of the transcriptionally active open complex. Finally, we outline an effective method for converting DNA-binding proteins into site-specific modification agents by using 1,10-phenanthroline-copper(I).

Base Sequence↗
PubMed2001

Identification of a heregulin binding site in HER3 extracellular domain.

HER3 (also known as c-Erb-b3) is a type I receptor tyrosine kinase similar in sequence to the epidermal growth factor (EGF) receptor. The extracellular segment of this transmembrane receptor contains four domains. Domains I and II are similar in sequence to domains III and IV, respectively, and domains II and IV are cysteine-rich. We show that the EGF-like domain of heregulin (hrg) binds to domains I and II of HER3, in contrast to the EGF receptor, for which prior studies have shown that a construct consisting of domains III and portions of domain IV binds EGF. Next, we identified a putative hrg binding site by limited proteolysis of the recombinant extracellular domains of HER3 (HER3-ECD(I-IV)) in both the presence and absence of hrg. In the absence of hrg, HER3-ECD(I-IV) is cleaved after position Tyr(50), near the beginning of domain I. Binding of hrg to HER3-ECD(I-IV) fully protects position Tyr(50) from proteolysis. To confirm that domain I contains a hrg binding site, we expressed domains I and II (HER3-ECD(I-II)) and find that it binds hrg with 68 nm affinity. These data suggest that domains I and II of HER3-ECD(I-IV) act as a functional unit in folding and binding of hrg. Thus, our biochemical findings reinforce the structural hypothesis of others that HER3-ECD(I-IV) is similar to the insulin-like growth factor-1 receptor (IGF-1R), as follows: 1) The protected cleavage site in HER3-ECD(I-IV) corresponds to a binding footprint in domain I of IGF-1R; 2) HER3-ECD(I-II) binds hrg with a 68 nm dissociation constant, supporting the hypothesis that domain I is involved in ligand binding; and 3) the large accessible surface area (1749 A) of domain L1 of IGF-1R that is buried by domain S1, as well as the presence of conserved contacts in this interface of type 1 RTKs, suggests that domains L1 and S1 of IGF-1R function as a unit as observed for HER3-ECD(I-II). Our results are consistent with the proposal that HER3 has a structure similar to IGF-1R and binds ligand at a site in corresponding domains.

Amino Acid Sequence↗
PubMed2001

Anxiolytic and anti-stress effects of brain prolactin: improved efficacy of antisense targeting of the prolactin receptor by molecular modeling.

We provide the first evidence that prolactin is a neuromodulator of behavioral and neuroendocrine stress coping in the rat. In virgin female and male rats, intracerebral infusion of ovine prolactin (oPRL) into the lateral cerebral ventricle (intracerebroventricular) exerted an anxiolytic effect on the elevated plus-maze in a dose-dependent manner (0.1 and 1.0 microg/5 microl; p < 0.01). In contrast, downregulation of the expression of the long form of brain prolactin receptors by chronic intracerebroventricular infusion of an antisense oligodeoxynucleotide (ODN) (osmotic minipump, 0.5 microg. 0.5 microl(-1). hr(-1); 5 d) increased anxiety-related behavior on the plus-maze compared with mixed bases-treated and vehicle-treated rats (p < 0.01), again demonstrating an anxiolytic effect of PRL acting at brain level. Furthermore, in jugular vein-catheterized female rats, the stress-induced increase of corticotropin secretion was decreased after chronic intracerebroventricular infusion of oPRL (osmotic minipump, 1.0 microg. 0.5 microl(-1). hr(-1); p < 0.05) and, in contrast, was further elevated by antisense targeting of the brain prolactin receptors (p < 0.01). This provides evidence for a receptor-mediated attenuation of the responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis by prolactin. The antisense ODN sequence was selected on the basis of secondary structure molecular modeling of the target mRNA to improve antisense ODN-mRNA hybridization. Receptor autoradiography confirmed the expected improvement in the efficacy of downregulation of prolactin receptor expression [empirically designed antisense, 30%; p > 0.05, not significant; adjustment of target position after mRNA modeling, 72%; p < 0.05). Taken together, prolactin acting at brain level has to be considered as a novel regulator of both emotionality and HPA axis reactivity.

Adrenocorticotropic Hormone↗
PubMed2001

Three-dimensional cluster analysis identifies interfaces and functional residue clusters in proteins.

Three-dimensional cluster analysis offers a method for the prediction of functional residue clusters in proteins. This method requires a representative structure and a multiple sequence alignment as input data. Individual residues are represented in terms of regional alignments that reflect both their structural environment and their evolutionary variation, as defined by the alignment of homologous sequences. From the overall (global) and the residue-specific (regional) alignments, we calculate the global and regional similarity matrices, containing scores for all pairwise sequence comparisons in the respective alignments. Comparing the matrices yields two scores for each residue. The regional conservation score (C(R)(x)) defines the conservation of each residue x and its neighbors in 3D space relative to the protein as a whole. The similarity deviation score (S(x)) detects residue clusters with sequence similarities that deviate from the similarities suggested by the full-length sequences. We evaluated 3D cluster analysis on a set of 35 families of proteins with available cocrystal structures, showing small ligand interfaces, nucleic acid interfaces and two types of protein-protein interfaces (transient and stable). We present two examples in detail: fructose-1,6-bisphosphate aldolase and the mitogen-activated protein kinase ERK2. We found that the regional conservation score (C(R)(x)) identifies functional residue clusters better than a scoring scheme that does not take 3D information into account. C(R)(x) is particularly useful for the prediction of poorly conserved, transient protein-protein interfaces. Many of the proteins studied contained residue clusters with elevated similarity deviation scores. These residue clusters correlate with specificity-conferring regions: 3D cluster analysis therefore represents an easily applied method for the prediction of functionally relevant spatial clusters of residues in proteins.

Adenosine Triphosphate↗