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Biomedical subjects

R Hoffmann

Publications and source records attributed to R Hoffmann.

At least 163 records · Page 9Linked to original sources
PubMed1999

Successful treatment of alopecia areata-like hair loss with the contact sensitizer squaric acid dibutylester (SADBE) in C3H/HeJ mice.

A type of hair loss closely resembling human alopecia areata has been described in C3H/HeJ mice. In order to test the assumed analogy with human alopecia areata, we investigated the efficacy of treatment with the contact allergen squaric acid dibutylester. In 12 C3H/HeJ mice with alopecia areata an allergic contact dermatitis was induced and elicited weekly on one side of the back by topical applications of squaric acid dibutylester. Overt hair regrowth was observed only on the treated side of the back in nine of 12 mice. Histopathologic examination revealed a change in the distribution of the inflammatory infiltrate from a dense perifollicular lymphocytic infiltrate around the mid and lower regions of hair follicles in untreated skin to a uniform presence in the upper dermis in treated skin. Immunohistomorphometric studies revealed that treatment with squaric acid dibutylester increased the CD4+/CD8+ ratio from approximately 1:2 in untreated alopecia areata to 1:1 in treated alopecia areata. Additional immunohistochemical investigations showed an aberrant expression of major histocompatibility complex class I, major histocompatibility complex class II and intercellular adhesion molecule 1 on keratinocytes of the mid and lower parts of hair follicles in untreated alopecia areata. In successfully treated skin ectopic major histocompatibility complex class I and II expression was clearly reduced, whereas intercellular adhesion molecule 1 expression showed only minor changes. In conclusion, alopecia areata-like hair loss in C3H/HeJ mice responded to treatment with the contact sensitizer squaric acid dibutylester analogous to human alopecia areata. Moreover, successful treatment changes the aberrant expression of major histocompatibility complex class I and II in a way similar to that observed in human alopecia areata. These observations support the concept that alopecia areata-like hair loss in C3H/HeJ mice can be utilized as an appropriate model for the study of human alopecia areata.

Allergens↗
PubMed1999

Extent and severity of test positivity during dobutamine stress echocardiography. Influence on the predictive value for coronary artery disease.

AIMS: Recent studies have evaluated the diagnostic accuracy and predictive value of dobutamine echocardiography without considering the additional information implied by the magnitude of induced wall motion abnormalities. We sought to evaluate the positive predictive value of dobutamine echocardiography for coronary artery disease from the extent and severity of the induced wall motion abnormality. In addition, we intended to determine factors associated with false-negative dobutamine echocardiography. METHODS AND RESULTS: Two hundred and eighty-three consecutive patients with suspected coronary artery disease underwent dobutamine echocardiography (up to 40 microg x kg(-1) x min(-1)+atropine up to 1 mg) and coronary angiography. The number of segments and the degree of deterioration were used to describe the extent and severity of induced wall motion abnormality. Analysis of clinical, procedural and echocardiographic variables was performed to determine factors associated with false-negative results. The positive predictive value of dobutamine echocardiography increased from 85% to 90%, 94% and 94% with deterioration of wall motion by one grade in >/=1, >/=2, >/=3 and >/=4 segments, respectively (P<0.05). Deterioration of wall motion by two grades in one segment had a positive predictive value of 96% as compared to 85% for deterioration by only one grade in one segment (P<0.05). Patients with false-negative test results received atropine more frequently (28% vs 13%, odds ration [OR]=3.87, 95% confidence interval [CI]=1.54-9.75, P=0.028) than patients with a correct positive result. However, angina (15 vs 37%, OR=0.26, 95% CI=0.09-0.71, P=0.010), ECG changes during dobutamine stress (15% vs 35%, OR=0.49, 95% CI 0.19-1.25, P=0.014) and high image quality (OR 1.59, 95% CI 1.07-2.37, P=0.015) were less frequent. The sensitivity of dobutamine echocardiography increased from 67% to 71% and 86% (P<0.05) with increasing achieved maximal heart rate (<75%, 75-85% and >85% of maximal heart rate). CONCLUSION: The positive predictive value of dobutamine echocardiography increases significantly as the extent and severity of induced wall motion abnormality increases. Thus, the degree of test positivity should be reported in clinical practice. Despite high pharmacological drug doses, the haemodynamic response may still be insufficient in some patients to induce myocardial ischaemia, resulting in false-negative dobutamine echo tests. To maximize the sensitivity of dobutamine echocardiography, the highest haemodynamic stress level, with a heart rate above 85% of the predicted heart rate, should be reached.

Adult↗
PubMed1999

Pharyngeal pH monitoring in patients with posterior laryngitis.

OBJECTIVE: To evaluate the diagnostic value of 3-site 24-hour ambulatory pH monitoring in patients with posterior laryngitis (PL) and the prevalence of esophageal abnormalities in this patient group. METHODS: Twenty patients with PL and 17 healthy volunteers were studied as controls. Control subjects had transnasal esophagogastroduodenoscopy (T-EGD) and ambulatory pH monitoring. Patients underwent T-EGD, ambulatory pH monitoring, and barium esophagram. RESULTS: T-EGD documented no abnormality in controls. Esophagitis was present in 2 PL patients, and hiatal hernia in 3. Ambulatory pH monitoring showed that 15 PL patients and 2 controls exhibited pharyngeal acid reflux. Barium esophagram documented gastroesophageal reflux in 5 PL patients. However, none of these barium reflux events reached the pharynx. All PL patients with barium esophagram evidence of gastroesophageal reflux also showed pharyngeal acid reflux by pH monitoring. CONCLUSION: Pharyngeal acid reflux is more prevalent in patients with PL than in healthy controls. Patients with PL infrequently have esophageal sequelae of reflux disease. Ambulatory 24-hour simultaneous 3-site pharyngoesophageal pH monitoring detects gastroesophagopharyngeal acid reflux events in most patients with PL.

Adolescent↗
PubMed1999

[Fibrodysplasia ossificans progressiva. Case report].

A case of a nine-year-old boy with a rare connective tissue disorder is presented. Fibrodysplasia ossificans progressiva is a chronic progressive hereditary disease of unknown etiology and unfavourable prognosis. Any injury to tissue must be avoided as it induces further progression of the disease.

Bone and Bones↗
PubMed1999

Pronounced perifollicular lymphocytic infiltrates in alopecia areata are associated with poor treatment response to diphencyprone.

Some authors have reported that severe destruction of follicular structures and even scarring patterns occur in those patients with alopecia areata (AA) who fail to respond to topical immunotherapy with contact sensitizers, such as diphencyprone (DCP). Other studies, however, gave contradictory results. Therefore, we re-examined histopathological changes in scalp samples obtained from 85 patients with severe alopecia areata before initiation of DCP treatment (40 responders and 45 non-responders in terms of hair regrowth after DCP treatment). The following parameters were evaluated: i) perifollicular lymphocytic infiltration; ii) perifollicular fibrosis, and iii) miniaturized hair follicles. No difference between responders and non-responders could be observed in the degree of miniaturization of hair follicles and proliferation of perifollicular fibrous tissue. In neither group was there any evidence of scarring or severe follicular destruction. 18 non-responders but only 6 responders showed a very dense perifollicular lymphocytic infiltration. In contrast, a particularly scarce infiltrate was seen in 9 non-responders and in 19 responders. We conclude that non-responders to topical sensitizers tend to have rather pronounced inflammatory reactions with dense perifollicular lymphocytic infiltrates.

Administration, Topical↗
PubMed1999

Linear porokeratosis superimposed on disseminated superficial actinic porokeratosis: report of two cases exemplifying the concept of type 2 segmental manifestation of autosomal dominant skin disorders.

A concept of dichotomous types of segmental involvement of autosomal dominant skin disorders has recently been proposed. Among the different types of porokeratosis, disseminated superficial actinic porokeratosis is known to be an autosomal dominant skin disorder, and linear porokeratosis represents the segmental form of the disease. We intended to exemplify the type 2 segmental manifestation within this concept. Clinical and histopathologic aspects of porokeratotic lesions of 2 patients were investigated. The family history was studied in both cases. Linear porokeratosis superimposed on disseminated superficial actinic porokeratosis was observed in both patients. These 2 cases of linear porokeratosis associated with disseminated superficial actinic porokeratosis can be taken as further examples of a type 2 segmental involvement occurring in an autosomal dominant skin disorder.

Female↗
PubMed1999

[Acetabulum surgery. Development, current status and prospects].

The indication for operative treatment of displaced acetabular fractures is widely accepted. The radiologic diagnostics consist of the a.p. pelvic view and the oblique ala and obturator views. With the X-rays and the additional CT images the fracture is classified according to Letournel or to the AO Classification into an A, B or C-type fracture. The appropriate surgical approach is chosen depending on the classification and the site of the main dislocation. Extended or combined approaches are only indicated for complex or older fracture patterns. Osteosynthesis is performed either with small fragment cortical screws in lag screw technique or with reconstruction plates. In about 80% of the cases an anatomical reduction of the joint is possible as prerequisite for good functional results. First clinical trials with computer- and/or CT-assisted procedures are promising. In future computer- and robotics-based procedures will gain increased importance with reduced patient morbidity and improved reconstruction of the joint surface.

Acetabulum↗
PubMed1998

Standardized guidelines for the interpretation of dobutamine echocardiography reduce interinstitutional variance in interpretation.

Subjective interpretation of dobutamine echocardiograms provides only moderate interinstitutional observer agreement if nonunified data acquisition and assessment criteria are applied. The present study was undertaken to evaluate parameters associated with low interinstitutional observer agreement in the interpretation of dobutamine echocardiograms and to analyze whether standardized interpretation criteria improve interinstitutional observer agreement. One hundred fifty dobutamine echocardiograms (dobutamine up to 40 microg/kg/min body weight and atropine up to 1 mg) were evaluated at 5 centers. Clinical, procedural, and echocardiographic parameters were included in the analysis of variables with significant impact on interinstitutional agreement. Standardized interpretative criteria were established, and 90 dobutamine echocardiograms were reanalyzed by 3 observers using a standardized image display. Multivariate analysis demonstrated low image quality (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.08 to 0.45, p=0.0002), low severity of induced wall motion abnormality (OR 0.17, 95% CI 0.07 to 0.40, p <0.0001), and a low peak rate-pressure product (OR 0.93, 95% CI 0.43 to 2.27, p=0.0382) to result in a low interinstitutional agreement. Standardization of image display in cine loop format and of dobutamine stress echo interpretation criteria resulted in improvement in test result categorization as normal or abnormal, with a kappa value of 0.50, compared with 0.39 using the original subjective interpretation. In conclusion, image quality, the severity of induced wall motion abnormalities, and the obtained rate-pressure product have a significant impact on the interpretation homogeneity of dobutamine echocardiograms. Standardization of image display in cine loop format and of reading criteria results in improved interinstitutional agreement in interpretation of stress echocardiograms.

Adult↗
PubMed1998

Intimal hyperplasia thickness at follow-up is independent of stent size: a serial intravascular ultrasound study.

The purpose of this study was to determine whether the thickness of the intimal hyperplasia (IH) layer that accumulates within Palmaz-Schatz stents is dependent on stent size. Intravascular ultrasound (IVUS) and quantitative angiographic (QCA) studies were performed after stent implantation and at follow-up (5.4 +/- 3.8 months) in 161 patients with 177 lesions treated with 221 Palmaz-Schatz stents. Stent and lumen cross-sectional area (CSA) were measured. IH CSA and thickness at follow-up were calculated and compared with stent CSA and circumference. Maximum IH CSA and thickness were measured at the smallest follow-up lumen CSA; mean IH CSA and thickness was averaged over the length of the stent. Maximum IH CSA measured 4.8 +/- 2.4 mm2, and mean IH CSA measured 2.8 +/- 2.2 mm2. Maximum IH thickness (at the smallest follow-up lumen CSA) measured 0.60 +/- 0.36 mm, and mean IH thickness (over the length of the stent) measured 0.30 +/- 0.19 mm. There was a weak, but significant correlation between mean and maximum IH CSA versus stent CSA (r = 0.215, p <0.0001 and r = 0.355, p <0.0001, respectively). However, there was no correlation between mean or maximum IH thickness versus stent CSA (r = 0.018, p = 0.643 and r = 0.056, p = 0.463, respectively) or stent circumference (r = 0.002, p = 0.956 and r = 0.069, p = 0.361, respectively). IH thickness was found to be independent of the stent size. This explains the known higher frequency of restenosis in smaller stents compared with larger stents.

Adult↗
PubMed1998

Phosphorylation of the C-terminal sites of human p53 reduces non-sequence-specific DNA binding as modeled with synthetic peptides.

Phosphorylation of the tumor suppressor p53 is generally thought to modify the properties of the protein in four of its five independent domains. We used synthetic peptides to directly study the effects of phosphorylation on the non-sequence-specific DNA binding and conformation of the C-terminal, basic domain. The peptides corresponded to amino acids 361-393 and were either nonphosphorylated or phosphorylated at the protein kinase C (PKC) site, Ser378, or the casein kinase II (CKII) site, Ser392, or bis-phosphorylated on both the PKC and the CKII sites. A fluorescence polarization analysis revealed that either the recombinant p53 protein or the synthetic peptides bound to two unrelated target DNA fragments. Phosphorylation of the peptide at the PKC or the CKII sites clearly decreased DNA binding, and addition of a second phosphate group almost completely abolished binding. Circular dichroism spectroscopy showed that the peptides assumed identical unordered structures in aqueous solutions. The unmodified peptide, unlike the Ser378 phosphorylated peptide, changed conformation in the presence of DNA. The inherent ability of the peptides to form an alpha-helix could be detected when circular dichroism and nuclear magnetic resonance spectra were taken in trifluoroethanol-water mixtures. A single or double phosphorylation destabilized the helix around the phosphorylated Ser378 residue but stabilized the helix downstream in the sequence.

Amino Acid Sequence↗
PubMed1998

A monoclonal antibody to a multiphosphorylated, conformational epitope at the carboxy-terminus of p53.

Mutations of the gene encoding the tumor suppressor protein p53 are the most common molecular alterations of cancer cells found in about half of all human tumors. Mutations which cluster in well-defined hot spots change the structure of the protein thus affecting its ability to bind to DNA. Post-translational modifications, primarily phosphorylation, might also influence how p53 binds to DNA or folds to its active tetrameric form. However, the lack of appropriate biochemical markers to characterize the status of phosphorylation in different cell types and in cells at different stages of tumor progression has prohibited such investigations. To generate a sensitive and phosphorylation-specific monoclonal antibody (mAb), we chemically synthesized the C-terminal 23 amino acid stretch of human p53 in a double-phosphorylated form. The peptide 371-393, carrying phosphate groups on Ser378 and Ser392, was co-synthesized with a turn-inducing spacer and peptide 31D, an immunodominant T-helper cell epitope in mice of the H-2k haplotype. After immunization and fusion of splenocytes with myeloma cells, a number of mAbs were obtained, from which mAb p53-18 emerged as a highly sensitive reagent. By enzyme-linked immunosorbent assay, p53-18, a mAb of the IgM isotype, recognized phosphorylated p53, expressed in insect cells infected with a recombinant baculovirus but not p53 expressed in Escherichia coli. Moreover, murine p53 from insect cells could be immune purified with mAb p53-18. Mass spectrometry following tryptic digestion of the purified protein and liquid chromatography of the fragments verified the presence of phosphate groups at both Ser375 and Ser389. From the corresponding human protein fragments, mAb p53-18 bound to the immunizing peptide phosphorylated on Ser378 and on Ser392, but failed to cross-react with the unphosphorylated peptide, or peptides phosphorylated individually on either Ser378 or Ser392. The binding to the unphosphorylated peptide could be restored, however, if the peptide conformation was stabilized to that of an alpha-helix. The immunogenic nature of the multiphosphorylated C-terminus of p53 is indicated by the finding that human sera, mostly from cancer patients, preferentially recognized the double-phosphorylated peptide over the monophosphorylated or unphosphorylated analogs. Antibody p53-18 appears to be a highly useful biochemical marker to detect low levels of p53 protein in different tissues, and to be a key tool to characterize the phosphorylation status of the C-terminus of p53 protein originated from various sources.

Amino Acid Sequence↗
PubMed1998

Prediction of retention times of peptide nucleic acids during reversed-phase high-performance liquid chromatography.

Peptide nucleic acids (PNAs) are synthetic biopolymers consisting of nucleobase side chains attached to an amino ethyl glycine backbone. At present this family of compounds enjoys a well deserved popularity in biomedical research, due to a number of favorable biological and chemical properties of PNAs compared to conventional oligonucleotides. PNAs are basically peptides, and are synthesized, purified and analyzed by traditional peptide chemistry, chromatography and mass spectrometry techniques. In the current report, we analyzed factors that influence the elution behavior of 29 PNAs on reversed-phase high-performance liquid chromatography using a water-acetonitrile-trifluoroacetic acid gradient elution system on C18 columns. We found that increasing the temperature from 25 degrees C to 55 degrees C resulted in improved peak shape and resolution. The retention times of the PNA analogs were dependent upon the length of the polymers with longer PNAs eluting later. Mixtures of PNAs with length, originating from inefficient monomer coupling during the polymer assembly, could be separated by single chromatographic runs. The retention time also depended upon the cytosine, thymine, adenine and guanine contact of the polymers. These differences in the contribution to the retention times could be explained by simple hydrophobicity features of the monomer side chains at pH 1.8. Based on all data, a linear equation was generated which predicted the retention time of any synthetic PNA based on composition and length. Comparison of the predicted and observed retention times showed a remarkable reliability of the algorithm.

Chromatography, High Pressure Liquid↗
PubMed1998

cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model.

Ser-13 and Ser-54 were shown to provide the sole sites for the protein kinase A (PKA)-mediated phosphorylation of the human cAMP-specific phosphodiesterase isoform HSPDE4D3. The ability of PKA to phosphorylate and activate HSPDE4D3 was mimicked by replacing Ser-54 with either of the negatively charged amino acids, aspartate or glutamate, within the consensus motif of RRES54. The PDE4 selective inhibitor rolipram ¿4-[3-(cyclopentoxy)-4-methoxyphenyl]-2-pyrrolidone¿ inhibited both PKA-phosphorylated HSPDE4D3 and the Ser-54-->Asp mutant, with an IC50 value that was approximately 8-fold lower than that seen for the non-PKA-phosphorylated enzyme. Lower IC50 values for inhibition by rolipram were seen for a wide range of non-activated residue 54 mutants, except for those which had side-chains able to serve as hydrogen-bond donors, namely the Ser-54-->Thr, Ser-54-->Tyr and Ser-54-->Cys mutants. The Glu-53-->Ala mutant exhibited an activity comparable with that of the PKA phosphorylated native enzyme and the Ser-54-->Asp mutant but, in contrast to the native enzyme, was insensitive to activation by PKA, despite being more rapidly phosphorylated by this protein kinase. The activated Glu-53-->Ala mutant exhibited a sensitivity to inhibition by rolipram which was unchanged from that of the native enzyme. The double mutant, Arg-51-->Ala/Arg-52-->Ala, showed no change in either enzyme activity or rolipram inhibition from the native enzyme and was incapable of providing a substrate for PKA phosphorylation at Ser-54. No difference in inhibition by dipyridamole was seen for the native enzyme and the Ser-54-->Asp and Ser-54-->Ala mutants. A model is proposed which envisages that phosphorylation by PKA triggers at least two distinct conformational changes in HSPDE4D3; one of these gives rise to enzyme activation and another enhances sensitivity to inhibition by rolipram. Activation of HSPDE4D3 by PKA-mediated phosphorylation is suggested to involve disruption of an ion-pair interaction involving the negatively charged Glu-53. The increase in susceptibility to inhibition by rolipram upon PKA-mediated phosphorylation is suggested to involve the disruption of a hydrogen-bond involving the side-chain hydroxy group of Ser-54.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

In-stent restenosis: the Washington Hospital Center experience.

In-stent restenosis has become a significant clinical problem. In 1997 alone, it is estimated that up to 100,000 patients world-wide with in-stent restenosis were treated. Serial intravascular ultrasound (IVUS) analysis has shown that tubular-slotted stents almost never chronically recoil and that neointimal hyperplasia is responsible for in-stent restenosis. With the rapid recent explosion in stent use, information about in-stent restenosis has lagged behind, especially on the impact of new stent designs. For example, the true prevalence of in-stent restenosis (1) varies with the lesion and patient subset, being much higher in the "real world" than in the selected patients typically enrolled in many studies; and (2) depends on its definition (i.e., clinical vs angiographic, intralesion vs in-stent). "Conventional" catheter-based treatments have included percutaneous transluminal coronary angioplasty (PTCA), rotational atherectomy, excimer laser coronary angioplasty, directional coronary atherectomy, and additional stent implantation. Rates of recurrence with these approaches are not known and vary considerably among series; however, certain lesions seem likely to recur regardless of the treatment modality. Recently, brachytherapy has emerged as the most promising way to treat in-stent restenosis.

Angioplasty, Balloon, Coronary↗
PubMed1998

Comparative early and nine-month results of rotational atherectomy, stents, and the combination of both for calcified lesions in large coronary arteries.

The aim of this study was to determine the preferred treatment modality for calcified lesions in large (> or = 3 mm) coronary arteries, resulting in the largest lumen dimensions and the most favorable late clinical responses. Three hundred six lesions in 306 patients (223 men, mean age 66 +/- 11 years) were treated with either rotational atherectomy plus adjunct balloon angioplasty (n = 147), Palmaz-Schatz stents (n = 103), or a combination of rotational atherectomy plus adjunct Palmaz-Schatz stents (n = 56). The procedural success rate was 98.0% to 98.6% for each treatment modality. Minimal lumen diameter (MLD) before therapy was similar for all therapies. Final MLD after combination of rotational atherectomy plus Palmaz-Schatz stents was larger than after stent therapy or rotational atherectomy plus balloon angioplasty (3.21 +/- 0.49 mm, 2.88 +/- 0.51 mm, and 2.29 +/- 0.55 mm, respectively, p <0.0001). Correspondingly, final percent diameter stenosis was lowest after the combination of rotational atherectomy plus stent therapy, and significantly higher for stents or rotational atherectomy plus balloon angioplasty (4.2 +/- 15.3%, 14.1 +/- 13.3%, and 26.7% +/- 16.9%, respectively, p <0.0001). Event-free survival at 9 months was higher for patients treated with the combination of rotational atherectomy plus stents than either stent therapy or rotational atherectomy alone (85%, 77%, and 67%, respectively, log-rank p = 0.0633). The only significant independent predictor of an event during the 9-month follow-up period was the MLD after intervention (odds ratio 0.495, 95% confidence interval 0.308 to 0.796, p = 0.0037). We conclude that preatheroablation using rotational atherectomy, followed by adjunct stent placement for calcified lesions in large arteries, is associated with infrequent complications, the largest acute angiographic results, and the most favorable late clinical event rates.

Aged↗
PubMed1998

5-HT3 antagonists derived from aminopyridazine-type muscarinic M1 agonists.

A conformational analysis, performed on muscarinic M1 agonists, identified four structural features characteristic of the muscarinic M1 pharmacophore: (i) a protonable basic or quaternary nitrogen acting as a cationic head; (ii) an electronegative dipole usually part of a planar mesomeric ester, amide, or amidine function which can be replaced by an ether (muscarine) or a dioxolane (AF 30); (iii) an intercharge distance of 5 +/- 0.5 A between the cationic head and the electronegative atom of the dipole; (iv) an elevation of 0.5 +/- 0.03 A of the cationic head over the plane containing the electronegative dipole. During a reinvestigation of the conformational behavior of published structures of 5-HT3 antagonists, similar features were observed for the 5-HT3 pharmacophore. However many 5-HT3 antagonists possess additional aromatic planes not present in the muscarinic M1 agonists. These observations brought us to predict the chemical modifications that would change muscarinic M1 agonists into 5-HT3 antagonists. Four of the predicted aminopyridazines were actually synthesized and submitted to testing. The observed IC50 values for 5-HT3 receptor binding ([3H] BRL 43694) ranged from 10 to 425 nM, whereas the affinities for the muscarinic receptor preparations ([3H] pirenzepine) layed over 10,000 nM. In electrophysiological studies the two most active compounds 10 and 13 produced antagonist-like effects on the 5-HT receptor channel complexes responsible for the generation of the rapidly desensitizing ionic currents, and agonist-like effects on those responsible for the slowly desensitizing components.

Animals↗