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Biomedical subjects

M Kellner

Publications and source records attributed to M Kellner.

At least 19 recordsLinked to original sources
PubMed2005

Efficient and fast targeted production of murine models based on ENU mutagenesis.

Mice with targeted genetic alterations are the most effective tools for deciphering organismal gene function. We generated an ENU-based parallel C3HeB/FeJ sperm and DNA archive characterized by a high probability to identify allelic variants of target genes as well as high efficiencies in allele retrieval and model revitalization. Our archive size of over 17,000 samples contains approximately 340,000 independent alleles (20 functional mutations per individual sample). Based on an estimated number of approximately 30,000 mouse genes, the parallel sperm/DNA archive should permit the identification and recovery of ten or more alleles per average target gene which translates to a calculated 99% success rate in the discovery of five allelic variants for any given average gene. The low rate of unrelated ENU-induced passenger mutations has no practical impact on the analysis of the allele-specific phenotype at the G3 generation because of dilution and free segregation of such unrelated passenger mutations. To date 39 mouse models representing 33 different genes have been recovered from our archive using in vitro fertilization techniques. The generation time for a murine model heterozygous for a mutation in a gene of interest is less than 2 months, i.e., three to four times faster compared with current embryonic stem-cell-based technologies. We conclude that ENU-based targeted mutagenesis is a powerful tool for the fast and high-throughput production of murine gene-specific models for biomedical research.

Alleles↗
PubMed2001

Anxiolyticlike effects of atrial natriuretic peptide on cholecystokinin tetrapeptide-induced panic attacks: preliminary findings.

BACKGROUND: Panic attacks induced by administration of cholecystokinin tetrapeptide (CCK-4) have been evaluated as a valuable tool to investigate the neurobiological mechanisms involved in panic anxiety. The rationale to study the effects of natriuretic peptides on the CCK-4 response is derived from observations that atrial natriuretic peptide (ANP) is released during panic attacks in humans and has anxiolyticlike actions in various animal models. METHODS: A double-blind, placebo-controlled design was conducted in 9 patients with panic disorder and 9 similar healthy control subjects. After pretreatment with an infusion of 150 microg of ANP or placebo in random order, each subject received 50 microg of CCK-4. Psychopathological parameters as well as physiological measures were sampled before and after CCK-4 administration. RESULTS: After pretreatment with ANP, the number of CCK-4-induced panic attacks decreased from 8 to 6 in patients and from 5 to 2 in controls. Acute Panic Inventory ratings were significantly reduced in patients after ANP vs placebo pretreatment. Infusion of ANP significantly curtailed the CCK-4-induced release of corticotropin in patients. Heart rate variability analysis indicated a sympathetic stimulation by CCK-4 that was inhibited by ANP in patients and controls. CONCLUSIONS: The present study indicates that ANP exerts anxiolyticlike effects on CCK-4-stimulated anxiety attacks in patients with panic disorder. In addition, ANP produced an inhibition of the hypothalamopituitary-adrenocortical system and sympatholytic effects.

Adrenocorticotropic Hormone↗
PubMed2001

Anxiolytic activity of atrial natriuretic peptide in patients with panic disorder.

OBJECTIVE: Preclinical evidence exists for the anxiolytic activity of atrial natriuretic peptide, which is released during lactate-induced panic attacks. Atrial natriuretic peptide receptor modulation may have antipanic activity in patients with panic disorder. METHOD: The effects of 150 microg of atrial natriuretic peptide and placebo on panic attacks induced by cholecystokinin tetrapeptide (CCK-4) (25 microg) were studied in 10 panic disorder patients. The panicogenic activity of CCK-4 was measured with the Acute Panic Inventory. RESULTS: Panic attacks occurred in seven patients in the placebo condition and in two patients in the atrial natriuretic peptide condition. CCK-4 administration was accompanied by a significant increase in Acute Panic Inventory scores. Pretreatment with atrial natriuretic peptide resulted in significantly lower Acute Panic Inventory scores than pretreatment with placebo. CONCLUSIONS: The results support the antipanic activity of atrial natriuretic peptide. Nonpeptidergic atrial natriuretic peptide receptor ligands may be ultimately used to treat anxiety disorders.

Adult↗
PubMed2001

Neuroendocrine effects of a short-term osmotic stimulus in patients with chronic schizophrenia.

We studied the effects of a short-term hypertonic stimulus on plasma levels of the stress hormones adrenocorticotropin (ACTH), cortisol, prolactin, and the blood volume- and electrolyte-controlling hormones arginine vasopressin (AVP) and atrial natriuretic peptide (ANP). Seven patients suffering from chronic schizophrenia with negative symptoms and ten healthy control subjects were investigated by a 20-minute infusion of 10 ml/kg body weight of hypertonic (2.5%) versus isotonic (0.9%) saline. All patients, who were medication-free for at least one week prior to the study, and all control subjects participated in two investigations in randomized order according to a single-blind cross-over design. During hypertonic infusion, plasma osmolarity and sodium levels were increased similarly in both groups and significantly more than during isotonic saline. Hypertonic saline caused a significant increase of plasma ACTH, cortisol and prolactin in patients in contrast to controls. AVP and ANP plasma concentrations were elevated after infusion of hypertonic saline, however, only patients showed a significant rise in plasma ANP. These results show that a dysregulation of the hypothalamic-pituitary-adrenal (HPA) system in a subset of patients with chronic schizophrenia may become overt during an osmotic stimulation, indicating an increased sensitivity of patients with schizophrenia to osmotic stress.

Adrenocorticotropic Hormone↗
PubMed2000

Behavioral and endocrine response to cholecystokinin tetrapeptide in patients with posttraumatic stress disorder.

BACKGROUND: Given the relationship between posttraumatic stress disorder (PTSD) and panic, it was of interest to examine whether panic provoking agents affect PTSD symptoms. We therefore investigated the behavioral and endocrine response of PTSD patients to the panicogen cholecystokinin tetrapeptide (CCK-4). METHODS: Eight patients with PTSD (DSM-IV) received 50 micrograms CCK-4 intravenously in a placebo-controlled, double-blind balanced design. Provocation of panic, anxiety, and flashbacks was assessed. Plasma adrenocorticotropin (ACTH) and cortisol levels after CCK-4 were measured and compared to healthy subjects matched for age, gender, and provoked symptoms. RESULTS: Despite significant effects of CCK-4 on anxiety and panic symptoms, no significant provocation of flashbacks emerged. CCK-4-induced panic symptoms showed an inverse correlation to trait dissociation. The ACTH response after CCK-4 was significantly lower in PTSD patients than in controls. Cortisol was similarly increased in both groups after CCK-4, but PTSD patients showed a more rapid decrease of stimulated cortisol concentrations. CONCLUSIONS: Panic symptoms or heightened anxiety are not necessarily conditioned stimuli for the provocation of posttraumatic flashbacks. Further studies in PTSD with different panicogens should be controlled for the potential interference of trait dissociation. Our hormone data show further evidence for a corticotropin-releasing hormone (CRH) overdrive and enhanced negative glucocorticoid feedback in PTSD patients.

Adrenocorticotropic Hormone↗
PubMed2000

Effects of natriuretic peptides upon hypothalamo-pituitary-adrenocortical system activity and anxiety behaviour.

Natriuretic peptides (ANP, BNP and CNP) comprise a family of structurally related peptides, which are derived from three different genes and which share a 17-amino acid internal ring. Besides their peripheral involvement in diuresis and blood pressure regulation these peptides, their bioactive fragments and their corresponding receptors (natriuretic peptide receptors NPR-A, NPR-B and NPR-C) are found throughout the central nervous system (CNS): NPR-A and NPR-C are found on neurons and astrocytes, while NPR-B is located mainly on neurons and partially colocalizes with NPR-A. In the CNS of man and rodents NPR-A is found mainly in cortex and hippocampus, whereas NPR-B is present in the amygdala and several brainstem regulatory sites. NPR-C is found widely within the CNS i.e. in neocortex, limbic cortex, the hippocampal area and the amygdala. These peptides and their receptors represent an important neuromodulatory system within the CNS, which is involved not only in the regulation of fluid homeostasis but also directly influences emotional behaviour, such as anxiety and arousal, and the sequelae of stress hormone release and autonomic nervous system activation. Natriuretic peptides are specifically involved in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) system: in man and rodents ANP inhibits the HPA system at all regulatory levels, while CNP stimulates the release of cortisol. Complementarily, the anatomic structure of natriuretic peptide systems within the CNS supports an important role for these in normal and pathologic emotional behaviour (e.g. anxiety and panic): in rodents ANP was found to reduce anxiety levels, whereas CNP induced the opposite effect. In patients with panic disorder basal ANP plasma levels are lower in comparison to healthy volunteers, but ANP secretion is faster and more pronounced during experimentally induced panic attacks. The inhibitory potency of ANP could explain the unexpected and so far unresolved failure of autonomic and HPA system activation during panic attacks. Moreover, panic anxiety and concomitant ACTH and cortisol secretion elicited by stimulation with the panicogen cholecystokinin-tetrapeptide were also attenuated by ANP infusions in patients as well as in healthy volunteers. Hence, it may be surmised that in man and rodents ANP reduces anxiety and terminates panic attacks and their neuroendocrine sequelae.

Adrenal Cortex↗
PubMed2000

[Arthrography, ultrasound and MRI in rotator cuff lesions: a comparison of methods in partial lesions and small complete ruptures].

PURPOSE: To evaluate the accuracy of arthrography, ultrasound and MR imaging in rotator cuff disease. METHODS: 40 patients suffering from subacromial impingement syndrome for at least three months and who were selected for surgery, underwent ultrasound, double-contrast arthrography and MR imaging. Patient preselection focused on partial and small complete tears. RESULTS: 13/26 surgically confirmed tears were partial tears (articular surface: 10, bursal surface: 2, intra-substance tearing: 1). Arthrography, ultrasound and MR imaging yield a sensitivity for complete tears of 91%, 69% and 92% with a specificity of 100%, 93% and 93%. For partial tears sensitivity was 50%, 69% and 69% with a specificity of 100%, 79% and 86%. Concerning evaluation of localisation, extent and correct classification ultrasound was correct in 17/26 cases, MR in 21/26 cases. CONCLUSION: Arthrography is not helpful in detecting partial tears. Ultrasound and MR imaging yield comparable accuracy. MR imaging has advantages concerning better evaluation of extent, location and classification as well as for the detection of associated pathologies.

Arthrography↗
PubMed2000

Comparison of the effects of endothelin-1 and -3 on secretion of pituitary hormones in healthy male volunteers.

The investigation was conducted to study the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on adrenocorticotropin (ACTH), cortisol and prolactin release in man. The design was a prospective placebo controlled double-blind study, including 7 healthy males studied on three occasions. After infusion of either 20 ng/min x kg ET-1, ET-3 or normal saline, venous blood samples were drawn 12 times for determination of ACTH, cortisol and prolactin during the pre- within- and postinfusion period. ET-1 infusion induced a significant increase of plasma ACTH (p< 0.009) and prolactin (p<0.0001) whereas cortisol levels increased without reaching significance (p<0.074). Infusion of ET-3 induced no changes in plasma levels of ACTH, cortisol or prolactin. The parallel increase of ACTH and prolactin induced by infusion of ET-1 could indicate an involvement of corticotropin-releasing hormone (CRH) in mediating the ET-1 effect on the HPA-axis in man. Whether this supports a possible role of ET-1 as a modulator of the hypothalamo-pituitary-adrenal (HPA) axis remains to be clarified.

Adrenocorticotropic Hormone↗
PubMed1999

Behavioral, neuroendocrine, and cardiovascular response to flumazenil: no evidence for an altered benzodiazepine receptor sensitivity in panic disorder.

BACKGROUND: Flumazenil is a benzodiazepine receptor antagonist thought to be panicogenic in patients with panic disorder but not in control subjects. The present study was undertaken to compare the effects of flumazenil in patients with panic disorder and those in healthy control subjects, and also to determine whether panic disorder is characterized by a hypothesized shift in the benzodiazepine receptor "set-point" and a differential response to flumazenil. METHODS: Eight patients with panic disorder and 8 matched control subjects were given infusions of saline and flumazenil in randomized order. Psychopathological changes, cardiovascular parameters, together with adrenocorticotropic hormone (ACTH) and cortisol secretion were recorded. RESULTS: Patient and control subjects responded to flumazenil uniformly; there was no evidence for an anxiogenic activity of flumazenil in control subjects or panic disorder patients. ACTH and cortisol levels were also not differentially influenced by flumazenil or panic disorder diagnosis. Heart rate and systolic blood pressure in both groups were slightly but significantly reduced by flumazenil compared to saline. CONCLUSIONS: These findings do not support the view that panic disorder patients and control subjects respond differentially to flumazenil or that the suggested shift in the benzodiazepine receptor "set-point," which leads to an inverse agonistic activity of flumazenil, characterizes panic disorder.

Adrenocorticotropic Hormone↗
PubMed1998

Atrial natriuretic hormone decreases endocrine response to a combined dexamethasone-corticotropin-releasing hormone test.

BACKGROUND: An escape from the dexamethasone-induced suppression of pituitary-adrenocortical activity can be provoked by corticotropin-releasing hormone (CRH) in depressed patients, but not in healthy controls. One important antagonist of the CRH-stimulated secretion of corticotropin (ACTH) and cortisol is atrial natriuretic hormone (ANH). METHODS: To study a potential role of ANH in the dexamethasone-CRH test, we investigated 7 healthy men who did not suppress cortisol below 40 ng/mL after they had received 0.5 mg dexamethasone the evening before. RESULTS: We found 1) that the CRH-stimulated ACTH and cortisol secretion was significantly reduced by the administration of ANH in comparison to saline; and 2) that there was an increased pituitary-adrenocortical ratio. CONCLUSIONS: Our results support the view that ANH may also be involved in the frequently observed nonsuppression after dexamethasone during depression. Biol Psychiatry.

Adrenocorticotropic Hormone↗
PubMed1998

[SieScape panorama imaging in radiologic diagnosis].

Through high-performance computer processing it has become possible to realize a new ultrasound imaging process: SieScape imaging. This method provides extended field of view images in real time using successive ultrasound images obtained when a standard transducer is scanned over a distance of up to 60 cm without any position sensor. SieScape offers new possibilities to view topographical anatomy. It is especially advantageous for scanning extended and tubular structures as well as large and enlarged organs and big pathologic volumes. Parallel scanning sequences allow documentation comparable to that of computed tomography. In addition, just as in magnetic resonance, variable imaging planes can be realized. The following describes the results obtained with SieScape in a multitude of clinical applications, especially in examinations of throat, thoracic and abdominal walls, breast, and intraabdominal organs as well as the soft tissues and small vessels of the extremities. The experience gathered with SieScape imaging--its advantages as well as its potential limitations, such as the formation of artefacts--is described.

Equipment Design↗
PubMed1998

[In vitro studies to determine the degree of stenosis using spiral CT angiography].

UNLABELLED: Aim of the study was to evaluate the influence of different spiral-CT parameters for the visualisation of vascular stenoses, especially of the renal arteries. MATERIAL AND METHODS: Models with a density equivalent to that of fat, filled with diluted contrast agent, and an inner lumen of 4, 6, 8 mm were scanned in x-, y- and z-direction. Data were acquired in up to 24 second long spiral-CT scans using different spiral-CT parameters (collimation, table speed, reconstruction algorithm, tube current). Detection of the degree of stenosis was achieved by assessment of the axial images and 3D reconstructions. RESULTS: The best correlation between real and measured degree of stenosis was seen by using a small collimation, a low table increment and assessment of the axial images reconstructed in standard algorithm. The stenosis degrees of models directed in x- and y-direction were overestimated and those in z-direction were underestimated depending on the spiral-CT parameters. CONCLUSION: For optimal imaging of renal artery stenoses, collimation of 2 mm (pitch = 1-2 and a reconstruction interval of 1 mm is recommended.

Algorithms↗
PubMed1998

[3-dimensional MR coronary angiography with navigator technique: imaging of the proximal course of a coronary artery anomaly].

Congenital coronary artery anomalies are found in 0.3 to 1.3% of patients and can cause ischemic heart disease or sudden cardiac death, especially if the anomalous coronary artery courses between the aortic root and the pulmonary artery. Identification of the anatomic course of the anomalous vessel is not always feasible by conventional radiographic coronary angiography. With MR coronary angiography not only flowing blood but also the vessel anatomy can be imaged. In previous studies, a two-dimensional gradient-echo sequence during breathhold was used demanding both cooperation of the patient and operator skill. The navigator technique reduces respiratory artifacts by retrospective respiratory gating on the diaphragm's position, obviating the need for breathhold studies. Furthermore, the three-dimensional MR coronary angiography enables post-processing using the Volume Rendering Technique for evaluation of three-dimensional view. We report on the use of this technique for the identification of the course of anomalous coronary arteries in two patient cases.

Artifacts↗