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Biomedical subjects

J Hammer

Publications and source records attributed to J Hammer.

At least 19 recordsLinked to original sources
PubMed2000

[Polyethylene glycol (Macrogol)--an overview of its use in diagnosis and therapy of gastrointestinal diseases].

The pharmacological rationale for the use of polyethylene glycol (PEG) in gastroenterology is its inverse relation between molecular mass and intestinal absorbability, with practically no intestinal absorption at molecular masses exceeding 3000, its lack of intestinal enzymatic degradation or bacterial metabolism, and its water binding capacity. PEG is used as a nonabsorbable marker in the evaluation of small intestinal and colonic absorption and secretion, as a marker for intestinal permeability studies, as an essential component of colonic lavage solutions used for the preparation of the colon for diagnostic and therapeutic interventions, and for the treatment of fecal impaction or chronic constipation. Since PEG has been used for decades, there is extensive data documenting its safety in short term use. Although animal experiments have also proved the safety of chronic PEG administration, the increasing use of PEG for the treatment of chronic constipation in the long term requires further surveillance to establish its safety.

Constipation↗
PubMed2000

Increased levels of platelet-derived growth factor in vitreous fluid of patients with proliferative diabetic retinopathy.

UNLABELLED: It is generally accepted that growth factors play an important role in the pathogenesis of proliferative diabetic retinopathy. Since platelet-derived growth factor AB (PDGF AB) is known to be involved in many angiogenetic and proliferative processes, it was the aim of our study to elucidate the role of PDGF AB in the angiogenetic process in proliferative diabetic retinopathy. We measured PDGF AB concentrations in the vitreous of 23 patients with proliferative diabetic retinopathy, 4 of them with additional rubeosis iridis as an indicator of very high vasoproliferative activity. Control measurements were done in 19 patients without diabetic or ischemic eye diseases and also in 4 non-diabetic patients with ischemic proliferative retinopathy with rubeosis iridis. To exclude PDGF remnants in the vitreous due to vitreous bleeding we additionally measured platelet factor 4 concentrations as a stable marker of activated thrombocytes in the vitreous. RESULTS: Significantly elevated concentrations of PDGF AB were found in the vitreous of patients with proliferative diabetic retinopathy, with higher levels in individuals with additional rubeosis iridis compared to controls. However, concentrations of PDGF AB were also elevated in ischemic non-diabetic retinopathy, supporting the concept that ischemia might be a strong stimulator of growth factor production in the retina. Platelet factor 4 was not detectable in any of the vitreous samples included in the study. In summary, our results indicate that the growth factor PDGF plays an important role in the pathogenesis of proliferative diabetic retinopathy, probably in synergistic action with other growth factors like IGF I, IGF II, VEGF and TNF alpha.

Body Fluids↗
PubMed2000

The motif for peptide binding to the insulin-dependent diabetes mellitus-associated class II MHC molecule I-Ag7 validated by phage display library.

The MHC class II molecule I-Ag7 is essential for the development of insulin-dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse but the requirements for peptide binding to I-Ag7 are still controversial. We have now isolated I-Ag7-binding phage from a large phage display library encoding random nonamer peptides. Ninety peptide-encoding regions of phage eluted from I-Ag7 were sequenced and >75% of the corresponding synthetic peptides bound to I-Ag7. Peptide alignment led to the identification of position-specific anchor residues. Hydrophobic (V and P) and positively charged (K) residues were highly enriched at P6 and positively charged (R and K), aromatic (Y) or hydrophobic (L) residues at P9. In addition, small amino acid residues (G and A) were enriched at P7 and G at P8. The primary anchors at P6 and P9 defining the phage-derived motif were present in most high-affinity I-Ag7-binding peptides from IDDM candidate antigens but only in < or =25% of peptides that were low-affinity binders or failed to bind to I-Ag7. A comparison of these results with the proposed motifs for peptide binding to I-Ag7 validates the one we have previously described.

Amino Acid Motifs↗
PubMed2000

Advanced distal colonic lesions as predictors of advanced lesions in the proximal colon.

The characteristics of adenomas found during sigmoidoscopy have been suggested to predict synchronous adenomas in the proximal colon. Our aim was to examine whether the presence and characteristics of distal colonic lesions are associated with the presence and characteristics of lesions in the proximal colon. We performed a university hospital based case-control study with 3,268 consecutive subjects who received colonoscopy between January 1992 and December 1995. Subjects who had a history of colonic polyps, inflammatory bowel disease, intestinal resection, or had a contraindication against biopsies were excluded. Number size, and histologic characteristics of polyps in the distal and proximal colon were recorded. Advanced lesions were defined as neoplastic lesions with 1 or more of the following features: 1) > or = 1 cm diameter, and/or 2) villous histology, and/or 3) severe dysplasia or carcinoma, and/or 4) > or = 3 lesions. We found that 439 patients had neoplastic lesions in the distal colon only (61.3% with advanced lesions), 198 patients had lesions in the proximal colon only (55.1% advanced), and 197 had lesions in both the distal colon (74.6% advanced) and the proximal colon (55.8% advanced). Distal lesions were significantly more often advanced in patients with synchronous proximal lesions compared with patients with lesions in the distal colon only (odds ratio: 1.9; 95% confidence interval [CI]: 1.3-2.8; p < 0.001). The odds ratios for finding any neoplastic lesion in the proximal colon and an advanced proximal lesion, respectively, were 3.7 (2.6-5.3) (p < 0.001) and 2.2 (1.3-3.7) (p < 0.01) when a nonadvanced lesion was found in the distal colon, and 6.8 (5.3-8.7) (p < 0.001) and 6.7 (4.9-9.0) (p < 0.001) when an advanced lesion was found in the distal colon. Logistic regression analysis revealed number of distal polyps and villous histology as independent predictors of advanced lesions in the proximal colon; size and severe dysplasia were not independent predictors. In conclusion, characteristics of neoplastic lesions in the distal colon predict the presence and characteristics of lesions in the proximal colon.

Adenoma↗
PubMed1999

Diagnostic criteria for the irritable bowel syndrome.

The Rome criteria represent a consensus viewpoint based on currently available data, but their development certainly does not establish that the content is truly indicative of a specific disease process. There is a limit to the repertoire of gastrointestinal symptoms; because of the low specificity of symptoms, it is understandable that symptoms alone are unlikely to be accurate enough. However, in the absence of a reproducible and accepted biological marker, symptoms currently remain the primary means of identifying and recruiting patients for research. All diagnostic criteria will continue to be controversial until the pathophysiology of irritable bowel syndrome (IBS) is better understood and treatment more appropriately targeted to relevant disturbances. The aim of this review is to present the current Rome criteria and critically evaluate the arguments for and against the individual components being included as part of the criteria.

Colonic Diseases, Functional↗
PubMed1999

Cutting edge: identification of novel T cell epitopes in Lol p5a by computational prediction.

Although atopic allergy affects </=20% of the total population, the relationship between the protein structure and immunogenic activity of the allergens is still largely unknown. We observed that group 5 grass allergens are characterized by repeated structural motifs. Using a new algorithm, TEPITOPE, we predicted promiscuous HLA-DR ligands within the repeated motifs of the Lol p5a allergen from rye grass. In vitro binding studies confirmed the promiscuous binding characteristics of these peptides. Moreover, most of the predicted ligands were novel T cell epitopes that were able to stimulate T cells from atopic patients. We generated a panel of Lol p5a-specific T cell clones, the majority of which recognized the peptides in a cross-reactive fashion. The computational prediction of DR ligands might thus allow the design of T cell epitopes with potential useful application in novel immunotherapy strategies.

Allergens↗
PubMed1999

A peptide binding motif for I-Eg7, the MHC class II molecule that protects E alpha-transgenic nonobese diabetic mice from autoimmune diabetes.

The nonobese diabetic (NOD) mouse, a model of spontaneous insulin-dependent diabetes mellitus (IDDM), fails to express surface MHC class II I-Eg7 molecules due to a deletion in the E alpha gene promoter. E alpha-transgenic NOD mice express the E alpha E beta g7 dimer and fail to develop either insulitis or IDDM. A number of hypotheses have been proposed to explain the mechanisms of protection, most of which require peptide binding to I-Eg7. To define the requirements for peptide binding to I-Eg7, we first identified an I-Eg7-restricted T cell epitope corresponding to the sequence 4-13 of Mycobacterium tuberculosis 65-kDa heat shock protein (hsp). Single amino acid substitutions at individual positions revealed a motif for peptide binding to I-Eg7 characterized by two primary anchors at relative position (p) 1 and 4, and two secondary anchors at p6 and p9. This motif is present in eight of nine hsp peptides that bind to I-Eg7 with high affinity. The I-Eg7 binding motif displays a unique p4 anchor compared with the other known I-E motifs, and major differences are found between I-Eg7 and I-Ag7 binding motifs. Analysis of peptide binding to I-Eg7 and I-Ag7 molecules as well as proliferative responses of draining lymph node cells from hsp-primed NOD and E alpha-transgenic NOD mice to overlapping hsp peptides revealed that the two MHC molecules bind different peptides. Of 80 hsp peptides tested, none bind with high affinity to both MHC molecules, arguing against some of the mechanisms hypothesized to explain protection from IDDM in E alpha-transgenic NOD mice.

Amino Acid Sequence↗
PubMed1999

Melanoma cells present a MAGE-3 epitope to CD4(+) cytotoxic T cells in association with histocompatibility leukocyte antigen DR11.

In this study we used TEPITOPE, a new epitope prediction software, to identify sequence segments on the MAGE-3 protein with promiscuous binding to histocompatibility leukocyte antigen (HLA)-DR molecules. Synthetic peptides corresponding to the identified sequences were synthesized and used to propagate CD4(+) T cells from the blood of a healthy donor. CD4(+) T cells strongly recognized MAGE-3281-295 and, to a lesser extent, MAGE-3141-155 and MAGE-3146-160. Moreover, CD4(+) T cells proliferated in the presence of recombinant MAGE-3 after processing and presentation by autologous antigen presenting cells, demonstrating that the MAGE-3 epitopes recognized are naturally processed. CD4(+) T cells, mostly of the T helper 1 type, showed specific lytic activity against HLA-DR11/MAGE-3-positive melanoma cells. Cold target inhibition experiments demonstrated indeed that the CD4(+) T cells recognized MAGE-3281-295 in association with HLA-DR11 on melanoma cells. This is the first evidence that a tumor-specific shared antigen forms CD4(+) T cell epitopes. Furthermore, we validated the use of algorithms for the prediction of promiscuous CD4(+) T cell epitopes, thus opening the possibility of wide application to other tumor-associated antigens. These results have direct implications for cancer immunotherapy in the design of peptide-based vaccines with tumor-specific CD4(+) T cell epitopes.

Amino Acid Sequence↗
PubMed1999

Identification of destabilizing residues in HLA class II-selected bacteriophage display libraries edited by HLA-DM.

HLA-DM (DM) functions as a peptide editor by catalyzing the release of class II-associated invariant chain peptides (CLIP) and other unstable peptides, thus supporting the formation of stable class II-peptide complexes for presentation. To investigate the general features that determine the DM susceptibility of HLA-DR1/peptide complexes, we generated a large DM-sensitive peptide repertoire from an M13 bacteriophage display library using a novel double selection protocol: we selected bacteriophage capable of binding to DR1 molecules and, subsequently, we enriched DR1-bound bacteriophage susceptible to elution by purified DM molecules. Sequence and mutational analyses of the DR1/DM double-selected peptides revealed that the amino acids Gly and Pro play a destabilizing role in the dissociation kinetics of DR1 ligands. This observation was confirmed also in natural peptide sequences such as CLIP 89-101, HA 307-319 and bovine collagen II (CII) 261-273. Our results demonstrate that DM susceptibility does not only depend on the number and nature of anchor residues, or the peptide length. Instead, less obvious sequence characteristics play a major role in the DM editing process and ultimately in the composition of peptide repertoires presented to T cells.

Amino Acid Sequence↗
PubMed1999

Breast boost--why, how, when...?

BACKGROUND: Breast conservation management including tumorectomy or quadrantectomy and external beam radiotherapy with a dose of 45 to 50 Gy in the treatment of small breast carcinomas is generally accepted. The use of a radiation boost--in particular for specific subgroups--has not been clarified. With regard to the boost technique there is some controversy between groups emphasizing the value of electron boost treatment and groups pointing out the value of interstitial boost treatment. This controversy has become even more complicated as there is an increasing number of institutions reporting the use of HDR interstitial brachytherapy for boost treatment. The most critical issue with regard to interstitial HDR brachytherapy is the assumed serious long-term morbidity after a high single radiation dose as used in HDR-treatments. METHODS AND RESULTS: This article gives a perspective and recommendations on some aspects of this issue (indication, timing, target volume, dose and dose rate). CONCLUSION: More information about the indication for a boost is to be expected from the EORTC trial 22881/10882. Careful selection of treatment procedures for specific subgroups of patients and refinement in surgical procedures and radiotherapy techniques may be useful in improving the clinical and cosmetic results in breast conservation therapy. Prospective trials comparing on the one hand different boost techniques and on the other hand particular morphologic criteria in treatments with boost and without boost are needed to give more detailed recommendations for boost indications and for boost techniques.

Brachytherapy↗
PubMed1999

Effect of inhaled nitric oxide on respiratory mechanics in ventilated infants with RSV bronchiolitis.

OBJECTIVE: To evaluate the bronchodilator effect of inhaled nitric oxide (NO) in infants with respiratory failure caused by respiratory syncytial virus (RSV) bronchiolitis and to compare the effect with the one obtained by salbutamol. DESIGN: Prospective study. SETTING: Pediatric intensive care unit of a university children's hospital. PATIENTS: Twelve acutely ill, intubated infants (mean age 4.5 months, mean weight 4.9 kg) with respiratory failure due to documented RSV bronchiolitis. INTERVENTIONS: Total respiratory system resistance (Rrs) was measured by single breath occlusion at the baseline and after inhaling NO at 20, 40 and 60 ppm for 1 h, and after inhalation of a standard beta2-agonist, salbutamol. Arterial blood gas analysis was performed at each study level on 6 of the 12 patients. RESULTS: The baseline mean Rrs (SE) was 0.29 (0.04) cm H2O/ml per s. At each dose of NO, the mean Rrs (SE) was 0.28 (0.04) cm H2O/ml per s. With salbutamol, the mean Rrs (SE) was 0.21 (0.03) cm H20/ml per s. These values were not significantly different from each other (by ANOVA). Inhaled NO produced a significant decrease in Rrs of greater than 4 times the coefficient of variation of the baseline measurement in 3 of 12 patients. Seven of 12 patients had no significant change while two patients had a significant increase in Rrs. Inhaled salbutamol produced a significant decrease in Rrs in 5 of 11 patients, while 6 showed no change in Rrs. CONCLUSION: Inhaled NO has no apparent bronchodilator effect in the majority of acutely ill infants with RSV bronchiolitis and does not appear to provide any additional benefit over the use of salbutamol. The clinical benefit of inhaled NO as a bronchodilator is questionable under these conditions.

Administration, Inhalation↗
PubMed1999

Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices.

Most pockets in the human leukocyte antigen-group DR (HLA-DR) groove are shaped by clusters of polymorphic residues and, thus, have distinct chemical and size characteristics in different HLA-DR alleles. Each HLA-DR pocket can be characterized by "pocket profiles," a quantitative representation of the interaction of all natural amino acid residues with a given pocket. In this report we demonstrate that pocket profiles are nearly independent of the remaining HLA-DR cleft. A small database of profiles was sufficient to generate a large number of HLA-DR matrices, representing the majority of human HLA-DR peptide-binding specificity. These virtual matrices were incorporated in software (TEPITOPE) capable of predicting promiscuous HLA class II ligands. This software, in combination with DNA microarray technology, has provided a new tool for the generation of comprehensive databases of candidate promiscuous T-cell epitopes in human disease tissues. First, DNA microarrays are used to reveal genes that are specifically expressed or upregulated in disease tissues. Second, the prediction software enables the scanning of these genes for promiscuous HLA-DR binding sites. In an example, we demonstrate that starting from nearly 20,000 genes, a database of candidate colon cancer-specific and promiscuous T-cell epitopes could be fully populated within a matter of days. Our approach has implications for the development of epitope-based vaccines.

Alleles↗
PubMed1999

Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules.

We have identified a heptapeptide with high affinity to rheumatoid arthritis-associated class II major histocompatibility (MHC) molecules. Using a model of its interaction with the class II binding site, a variety of mimetic substitutions were introduced into the peptide. Several unnatural amino acids and dipeptide mimetics were found to be appropriate substituents and could be combined into compounds with binding affinities comparable to that of the original peptide. Compounds were designed that were several hundred-fold to more than a thousand-fold more potent than the original peptide in inhibiting T-cell responses to processed protein antigens presented by the target MHC molecules. Peptidomimetic compounds of this type could find therapeutic use as MHC-selective antagonists of antigen presentation in the treatment of autoimmune diseases.

Amino Acid Sequence↗
PubMed1999

Fibreoptic bronchoscopy in sedated infants facilitated by an airway endoscopy mask.

Fibreoptic bronchoscopy (FB) is frequently associated with a decline in PaO2, whose degree and duration can be substantial especially in infants. The effect of a face mask, which allows the administration of 100% oxygen and continuous positive airway pressure during FB, on the incidence and severity of hypoxaemia was studied in thirty-one consecutive infants. Sedation was provided by intravenous propofol titrated to allow patient comfort. A transient fall in SpO2 <95% was recorded in 6/31 patients during endoscopy of the upper airway (lasting 1.6+/-1.1 min) and in 11/31 patients during endoscopy of the lower airways (lasting 1.4+/-1.1 min). Capillary blood gas analysis before and after endoscopy of the lower airways demonstrated an increase in the PCO2 6.4+/-1.3 to 7.3+/-1.4 kPa (49+/-10 to 56+/-11 mmHg). The risk of hypoxaemia in sedated infants breathing spontaneously is low when 100% oxygen and continuous positive airway pressure are administered during FB

Blood Pressure↗