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Biomedical subjects

H Kessler

Publications and source records attributed to H Kessler.

At least 19 recordsLinked to original sources

[Pharmacological treatment options in frontotemporal dementia].

In contrast to Alzheimer's disease, there are only few systematic trials for drug therapy of frontotemporal dementia (FTD). Neurochemically, a strong serotonergic deficit is supposed in FTD. This is the rationale for treatment, especially of behavioral abnormalities, with serotonergic antidepressants. However, only paroxetine and trazodone have been studied in trials with class I and II evidence so far. The results of paroxetine are inconsistent; and for trazodone a number of potential side-effects must be considered. Moreover, there is class II evidence for rivastigmine in FTD, even though a cholinergic deficit in this type of dementia is questionable. There are no published data from controlled trials for the use of memantine in FTD so far.

Aged↗

Cerebrospinal fluid diagnostic markers correlate with lower plasma copper and ceruloplasmin in patients with Alzheimer's disease.

Increasing evidence links Alzheimer's disease (AD) with misbalanced Cu homeostasis. Recently, we have shown that dietary Cu supplementation in a transgenic mouse model for AD increases bioavailable brain Cu levels, restores Cu, Zn-super oxide-1 activity, prevents premature death, and lowers A beta levels. In the present report we investigated AD patients with normal levels of A beta 42, Tau and Phospho-Tau in the cerebrospinal fluid (CSF) in comparison with AD patients exhibiting aberrant levels in these CSF biomarkers. The influence of these cerebrospinal fluid (CSF) diagnostic markers with primary dependent variables blood Cu, Zn and ceruloplasmin (CB) and secondary with CSF profiles of Cu, Zn and neurotransmitters was determined. Multivariate tests revealed a significant effect of factor diagnostic group (no AD diagnosis in CSF or AD diagnosis in CSF) for variables plasma Cu and CB (F=4.80; df=2, 23; p=0.018). Subsequent univariate tests revealed significantly reduced plasma Cu (-12.7%; F=7.05; df=1, 25; p=0.014) and CB (-14.1%; F=9.44; df=1, 24; p=0.005) levels in patients with aberrant CSF biomarker concentrations. Although only AD patients were included, the reduced plasma Cu and CB levels in patients with a CSF diagnosis of advanced AD supports previous observations that a mild Cu deficiency might contribute to AD progression.

Aged↗

Targeting RGD recognizing integrins: drug development, biomaterial research, tumor imaging and targeting.

Integrins constitute an important class of cell adhesion receptors responsible not only for cell-matrix adhesion but also for signaling bidirectionally across the membrane. Integrins are involved in many biological processes such as angiogenesis, thrombosis, inflammation, osteoporosis and cancer. Integrins thus play a key role in many severe human diseases. In this review we will describe recent research and development of RGD-containing integrin ligands for medical applications including drug design, radiolabeling, drug targeting, as well as biomaterial research. Many ligands have been developed for targeting the avb3 integrin in order to block angiogenesis or osteoporosis, but there are also other integrins like avb5 and a5b1 which become more and more interesting for similar purposes. aIIbb3 constitutes a potent target in thrombosis therapy; but the search for suitable ligands is still ongoing. We will reconstruct the drug development process for these integrin subtypes considering selected examples with focus on structure based design. Different structural requirements are pointed out concerning integrin activity and particularly the selectivity towards the distinct integrin types. Furthermore, we will show recent progress in tumor and thrombosis imaging based on radiolabeled RGD-containing ligands binding avb3 or aIIbb3, respectively. Additionally further advances in biomaterial research are presented. We describe the coating of different implant materials with various avb3 recognizing ligands for the purpose of increasing cell attachment and biocompatibility.

Animals↗

Multimedia article. Laparoscopic restorative proctocolectomy for ulcerative colitis.

BACKGROUND: With increasing experience, laparoscopic techniques have been applied even to extended colorectal operations as restorative proctocolectomy for ulcerative colitis and familial adenomatous polyposis. METHODS: A 36-year-old woman with a 7-year history of ulcerative colitis was transferred for elective surgery 6 weeks after an episode of toxic megacolon treated conservatively. The procedure was performed in modified lithotomy position using six trocars. After initial medial transection of the three main vascular pedicles of the ileocolic and middle colic vessels and the inferior mesenteric artery and vein, the colon was dissected free laterally, from the sigmoid orally toward the ileum. Special consideration was necessary for dissection of the omentum. The rectum was mobilized down to the pelvic floor in two steps, starting at the level of the promontory and the upper rectal stalks. It was transected at the level of the dentate line. Through a Pfannenstiel incision, the bowel was extracted. After transection of the ileum and removal of the specimen, a J-pouch was created. The anastomosis was completed laparoscopically using a double-stapling technique. Finally, a diverting loop ileostomy was created. RESULTS: A total of 13 patients underwent surgery. The medium age of these patients was 25.5 years (range, 19-57 years). There was no conversion to an open procedure. The median length of hospital stay was 11.5 days (range, 7-107 days). Four patients experienced major complications, including one case each of pouch failure after arterial occlusion, pouch-vaginal fistula, infected hematoma, and intraabdominal abscess formation. There was no postoperative mortality. CONCLUSIONS: For restorative proctocolectomy, laparoscopic techniques proved to be safe and feasible. With further experience, they may have the potential to become an appealing alternative to open surgery.

Adult↗

Emotion recognition in stroke patients with left and right hemispheric lesion: results with a new instrument-the FEEL Test.

The aim of this study was to investigate the effect of a stroke event on people's ability to recognize basic emotions. In particular, the hypothesis that right brain-damaged (RBD) patients would show less of emotion recognition ability compared with left brain-damaged (LBD) patients and healthy controls, was tested. To investigate this the FEEL Test (Facially Expressed Emotion Labeling) was used, a computer based psychometric test that assesses one's ability to recognize facially displayed basic emotions via a forced-choice paradigm. We examined 24 patients after a stroke event (13 RBD, 11 LBD) and compared them with a matched group of healthy controls (HC, n=29). Results showed that the stroke patients performed significantly worse in the FEEL Test than did HC (p<.001). This deficit was especially evident for negative emotions (fear, anger, sadness, and disgust). In contrast to other studies we did not find any significant differences between RBD and LBD patients in their ability to recognize emotions. These results indicate that a stroke event has a negative effect on the recognition of facially displayed emotions but suggest that this effect is apparently not dependent on the side of the brain damage.

Adult↗

[The role of copper in the pathophysiology of Alzheimer's disease].

Alzheimer's dementia (AD) is a chronically progressive neurodegenerative disease. The key protein in the pathophysiology of AD is the amyloid precursor protein (APP) which releases the amyloid-beta peptide (Abeta) by proteolytic cleavage. APP is probably involved in the homeostasis of cellular copper (Cu) metabolism, because significantly changed Cu levels in the brain were found in AD patients as well as in mouse models. In vivo studies with transgenic mice showed that oral Cu supplements can restore lowered Cu levels in the brain to normal, can reduce Abeta production, and can reduce mortality of the animals. Currently, the influence of oral Cu supplementation (in addition to an established acetylcholinesterase inhibitor) on the progression of the disease is being studied in a prospective, double-blind, randomized and placebo-controlled longitudinal clinical trial in patients with mild AD.

Alzheimer Disease↗

Mediating specific cell adhesion to low-adhesive diblock copolymers by instant modification with cyclic RGD peptides.

One promising strategy to control the interactions between biomaterial surfaces and attaching cells involves the covalent grafting of adhesion peptides to polymers on which protein adsorption, which mediates unspecific cell adhesion, is essentially suppressed. This study demonstrates a surface modification concept for the covalent anchoring of RGD peptides to reactive diblock copolymers based on monoamine poly(ethylene glycol)-block-poly(D,L-lactic acid) (H(2)N-PEG-PLA). Films of both the amine-reactive (ST-NH-PEG(2)PLA(20)) and the thiol-reactive derivative (MP-NH-PEG(2)PLA(40)) were modified with cyclic alphavbeta3/alphavbeta5 integrin subtype specific RGD peptides simply by incubation of the films with buffered solutions of the peptides. Human osteoblasts known to express these integrins were used to determine cell-polymer interactions. The adhesion experiments revealed significantly increased cell numbers and cell spreading on the RGD-modified surfaces mediated by RGD-integrin-interactions.

Adhesiveness↗

Dementia of frontal lobe type in Kennedy's disease.

The pathomorphological correlate of Kennedy's disease (KD) is a degeneration of spinal and bulbar alpha-motor neurons. The disease is caused by a CAG repeat expansion in the first exon of the X-chromosomal androgene receptor gene. Contrary to the common belief that cognitive disorders in motor neuron diseases (MND) are either rare or only mild, there is now an increasing number of case reports on dementia in amyotrophic lateral sclerosis (ALS). In ALS, dementia of the frontal lobe type (frontotemporal dementia, FTD) seems to be the characteristic pattern. However, in KD cognitive dysfunction has not been studied systematically. Here we present a case with clinical characteristics of FTD in a patient with genetically confirmed KD. It remains speculative whether there is an association between KD and FTD comparable to a genetic linkage between ALS and FTD, which has been proposed in recent years. However, we suggest that cognitive dysfunction may be more common in KD than reported until today.

Adult↗

3-Azido-aspartic acid derivatives - orthogonally protected precursors for the stereoselective incorporation of 2,3-diaminosuccinic acid into peptide structures.

The stereoselective synthesis of orthogonally protected 3-azido aspartic acid derivatives is described. The convenience of their application as 2,3-diaminosuccinic acid in peptide chemistry was demonstrated by the incorporation of the nonproteinogenic diamino diacid as a cystine-substitute into the core structure of somatostatin.

Amino Acids, Diamino↗

Synthesis and biological evaluation of a (99m)Tc-labelled cyclic RGD peptide for imaging the alphavbeta3 expression.

AIM: The alphavbeta3 integrin is involved in tumour induced angiogenesis and tumour metastasis. We describe the synthesis and evaluation of a (99m)Tc-labelled RGD analogue for the visualisation of alphavbeta3 integrin expression. METHODS: The linear peptides were assembled on a solid support. Cyclisation was performed under high dilution conditions. For conjugation with the chelator peptide, a water soluble carbodiimide was used. Radiolabelling was carried out due to standard procedures with high radiochemical yield and radiochemical purity. For in vivo evaluation, nude mice bearing alphavbeta3-positive human melanoma M21 and alphav-negative human melanoma M21-L or Balb/c mice bearing alphav-positive murine osteosarcoma were used. RESULTS: Activity accumulation of (99m)Tc-DKCK-RGD 240 min p. i. was 1.1% ID/g in the alphavbeta3-positive melanoma and 0.3% ID/g in the negative control tumour. In the osteosarcoma model 2.2% ID/g was found 240 min p. i. Planar gamma camera images allowed contrasting visualisation of alphavbeta3-positive tumours 240 min p. i. Blocking of the tumour using the alphavbeta3-selective pentapeptide cyclo(-Arg-Gly-Asp-D-Phe-Val-) reduces activity accumulation in the tumour to background level. However, 240 min p. i. highest activity concentration was found in kidneys resulting in low tumour/kidney ratios. Metabolite analysis 240 min p. i. showed approximately 60% intact tracer in kidneys and 80% in the tumour. Only 24% intact tracer was found in blood 30 min p. i. CONCLUSION: (99m)Tc-DKCK-RGD allows imaging of alphavbeta3-positive tumours in mice. However, pharmacokinetics as well as metabolic stability of the tracer have to be improved for potential clinical application.

Amino Acid Sequence↗

[White matter alterations in neurodegenerative and vascular dementia].

Due to a significant overlap of the two syndromes, differentiation of degenerative dementia of the Alzheimer-type from vascular dementia may be difficult even when imaging studies are available. White matter changes occur in many patients suffering from Alzheimer's disease. Little is known about the impact of white matter changes on the course and clinical presentation of Alzheimer's disease. High sensitivity of MRI in the detection of white matter alterations may account for over-diagnosing vascular dementia. The clinical significance of white matter alterations in dementia is still a matter of debate. The article reviews current concepts about the role of white matter alterations in dementia.

Age Factors↗

A cyclo peptide activates signaling events and promotes growth and the production of the bone matrix.

The interaction of bone cells and their underlying extracellular matrix impacts biological processes such as maintenance of tissue integrity. The biological recognition of the extracellular matrix by attached cells is mediated by the activity of integrins that recognize adhesive-specific domains. The most widely recognized adhesive motif is the RGD sequence, common to many of the adhesive matrix molecules. Here, we show that cyclo DFKRG which was previously selected to increase cell adhesion of human bone marrow stromal cells (HBMSC), increases both cell differentiation and mineralization through activation of tyrosine kinases, focal adhesion kinase (p(125)FAK) and Mitogen Activated Protein (MAP) kinases.

Bone Matrix↗

Early viral kinetics on treatment with pegylated interferon-alpha-2a in chronic hepatitis C virus genotype 1 infection.

Even with pegylated (PEG) interferons (IFN), therapy of chronic hepatitis C (genotype 1) remains unsatisfactory. The initial viral response to IFN identifies patients infected with IFN resistant viruses not responding to standard IFN/ribavirin therapy. The impact of primary IFN unresponsiveness for PEG-IFN-alpha-2a/ribavirin therapy is unknown. Viral load was measured in 22 chronic hepatitis C (genotype 1) patients before and 24 h after 9 MU IFN-alpha-2a (days 0 and 1), and before and during weekly 180 microg PEG-IFN-alpha-2a (days 7, 8, 11, 14 and 21) administration. Thereafter, ribavirin (800 mg/d) was added for 6 months. Virological responders continued treatment for a further 6 months. Twenty-eight patients treated with standard IFN/ribavirin therapy in a previous study using an analogous protocol served as historic controls. After 6 months 15 (68.2%) patients were (HCV-RNA) negative, eight of whom (36.4%) had a sustained response. The decrease in viral load 24 h after 9 MU IFN-alpha-2a was greater in virological responders (1.05 log [0.25-1.67]) than in nonresponders (NR) (0.34 [0.14-0.65]; P=0.003). In contrast, viral decline was not different between responders and NRs during the first 2 weeks on PEG-IFN-alpha-2a. All patients with an initial decline > 1.4 log became sustained responders. Five of 12 patients with a log change < 0.8 became end of treatment responders, two had a sustained response. Antiviral response to PEG-IFN-alpha-2a is different to that on standard IFN. In spite of a lower initial response PEG-IFN-alpha-2a/ribavirin combination therapy may overcome predicted IFN unresponsiveness.

Adult↗

[Homocysteine and dementia].

Homocysteine is a vascular risk factor including cerebral macroangiopathy and microangiopathy. Furthermore, there might also be an association with cognitive disorders including vascular dementia and Alzheimer's disease. Hyperhomocysteinemia linked with cognitive impairment might be an indirect marker for low concentrations of vitamin B 12, vitamin B 6 or folate, resulting from low intake or from an impaired transport of the vitamins to the brain. Another possibility is a direct harmful effect of homocysteine to cognition via vascular and neurotoxic pathophysiologic mechanisms. Because hyperhomocysteinemia is a potentially reversible risk factor and can be identified early, it should be investigated by prospective intervention studies whether lowering homocysteine levels by vitamin supplementation could reduce incidence and progression of cognitive disorders.

Alzheimer Disease↗

Structure-function analysis of lipopeptide pheromones from the plant pathogen Ustilago maydis.

Mating of two haploid cells is a prerequisite for the successful infection of corn by the pathogenic fungus Ustilago maydis. Cell-cell recognition is mediated by small lipopeptide pheromones. Genes encoding pheromone precursors as well as pheromone receptors are located in the a mating type locus. Two pheromones are known, the tridecapeptide a1 and the nonapeptide a2, both of which contain an S-prenylated cysteine methyl ester at the C-terminus. It has previously been shown that synthetic pheromones are active in a biological test system. Here, we used the same assay to perform a detailed analysis of synthetic a1 and a2 pheromones. Testing of truncated derivatives of a1 and a2 revealed that in both cases the pheromone function is less sensitive to N-terminal than to C-terminal truncations. Replacement of each amino acid in the a1 pheromone by either alanine or the corresponding D-amino acids revealed that four positions are important for function: the two central glycines (positions 5 and 9), proline at position 7 and tyrosine at position 10. By introducing different naturally occurring as well as synthetic amino acids at position 10, we demonstrate that the presence of an aromatic side chain at this position is necessary for function. We propose a model in which a cis peptide bond at proline 7 favours the formation of a type II' beta turn of the a1 pheromone backbone with glycine 9 in position i+1 (where i refers to the first position of the beta turn). As a result, tyrosine 10, at position i+2 of the turn, would be highly exposed and could be inserted into a structurally well-defined binding pocket of the receptor. The latter may represent an important facet of receptor specificity.

Amino Acid Sequence↗

Reproducability and transferability of topological properties; experimental charge density of the hexapeptide cyclo-(D,L-Pro)2-(L-Ala)4 monohydrate.

The charge density of a hexapeptide was determined from high-resolution CCD area-detector experiments at 100 K. Two datasets, one from a rotating anode and a second one from synchrotron radiation, were measured and the results are compared. The data are interpreted in terms of the 'rigid pseudoatom' model. The topology of the experimental density is analyzed and compared with the topology of the constituting amino acids, and shows good agreement. All critical points of the electron density at the covalent and hydrogen bonds, as well as those of the Laplacian, were located. With respect to the transferability of electronic and bond topological properties the six peptide bonds were compared with values given in the literature.

Models, Molecular↗