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M Schultz

Publications and source records attributed to M Schultz.

At least 55 records · Page 3Linked to original sources
PubMed1997

Interleukin-1-induced nuclear factor kappa B activation is inhibited by overexpression of phospholipid hydroperoxide glutathione peroxidase in a human endothelial cell line.

Oxygen radicals are commonly accepted mediators in the tumour necrosis factor-mediated nuclear factor kappa B (NF kappa B) signalling cascade, but evidence for their role during interleukin-1 (IL-1) signalling is lacking. To test the involvement of hydroperoxides we investigated whether IL-1-induced NF kappa B activation could be influenced by glutathione peroxidases (GPx). These enzymes remove hydroperoxides with various specificities for the hydroperoxide substrate. By overexpressing phospholipid hydroperoxide glutathione peroxidase (PHGPx), which characteristically reacts with lipophilic hydroperoxides, the roles of H2O2 and lipid hydroperoxides were assessed. A human umbilical endothelial cell line, ECV 304, was stably transfected with the genes for both PHGPx and selenophosphate synthetase (selD), which provides selenophosphate for selenoprotein biosynthesis. When grown in selenium-deficient culture medium, the double-transfected clone (ECVPHGPx+SelD+) expressed 5-fold higher (P<0.005) PHGPx activity (measured by phosphatidylcholine hydroperoxide removal) than controls. The rate of H2O2 removal was also significantly (P<0.01) higher in this clone. When grown with high levels of extracellular selenium (up to 100 nM selenite), PHGPx activity and H2O2 removal were enhanced substantially in control cells and transfected cells. Under these conditions, PHGPx activity was 1.7-fold (P<0.005) higher in ECVPHGPx+SelD+, but H2O2 removal was the same as in controls. IL-1-induced NF kappa B activation was inhibited by selenium supplementation in control cells. In ECVPHGPx+SelD+ under conditions of selenium restriction, IL-1 induced NF kappa B activation only to a similar extent as under conditions of selenium supplementation in controls, and activation was abolished with 50 nM sodium selenite. These results show that overexpressed PHGPx is sufficient to inhibit NF kappa B activation, and suggests that NF kappa B activation by IL-1 is mediated by a preferential substrate of PHGPx, such as a fatty acid hydroperoxide, rather than by H2O2, the preferred substrate of the more abundant cytosolic GPx.

Cell Line↗
PubMed1997

Inhibitors of glutathione S-transferases as therapeutic agents.

Glutathione S-transferases (GST) are a family of phase II detoxification enzymes with broad substrate specificities. They catalyze the conjugation of glutathione with many different types of xenobiotics, rendering the compound more water soluble and thus more easily eliminated. Resistance to cancer chemotherapeutic drugs, such as the alkylating agents, has been directly correlated with the overexpression of GSTs. Subsequently, a rationale has been established to utilize agents that inhibit GST in combination with alkylating agents to circumvent this resistance. Two such agents, ethacrynic acid (EA) and Terrapin 199 (TER 199), have been examined for this purpose. EA, an inhibitor of all classes of GST isozymes, has been used clinically in combination with thiotepa. More recently, TER 199, a glutathione analog-based GST inhibitor, has been modeled specifically to inhibit GST pi, an enzyme which is commonly found at high levels in human tumor biopsies. Furthermore, a therapeutic strategy has been designed to take advantage of GST pi activation of a prodrug, TER 286. Recent studies have investigated the molecular mechanisms involved in the cellular response to GST inhibitors and have employed techniques such as differential display to examine altered gene expression as well as to identify novel genes induced by these agents. Overall, this strategy may provide further insight into the action of these agents in the cell as well as prove useful in endeavors to modulate anticancer drug resistance.

Journal Article↗
PubMed1997

Significance of p53 overexpression in urinary bladder transitional cell carcinoma in situ before and after bacillus Calmette-Guérin treatment.

OBJECTIVES: Overexpression of p53, normally secondary to gene mutation, in invasive uroepithelial neoplasms (transitional cell carcinoma) and a high percentage of transitional cell carcinoma in situ (CIS) has been described; however, the role of p53 before and after bacillus Calmette-Guérin (BCG) treatment of CIS needs to be defined. METHODS: Immunohistochemical reaction for p53 overexpression was performed on 12 patients with CIS before and after BCG treatment. Thirty cystectomy specimens with invasive TCC were also evaluated for the presence of CIS, hyperplasia, and dysplasia. RESULTS: Twenty-three cases of CIS were identified. Approximately 90% of CIS cases (21 of 23) were positive for p53 overexpression, whereas transitional cell hyperplasia was uniformly negative. Less than 5% of the cells in morphologically dysplastic lesions were positively stained. Ten of 12 CIS patients displayed p53 overexpression before BCG treatment. After BCG treatment, 4 patients displayed residual CIS with p53 overexpression, and 8 patients showed no residual CIS or p53 overexpression. Three of the 4 patients with residual CIS and overexpression rapidly developed invasive transitional cell carcinoma requiring cystectomy. The 1 remaining patient was treated with a second course of BCG; further biopsies displayed the development of grade 1 papillary transitional cell carcinoma without invasion, and the patient is currently being followed CONCLUSIONS: Our data suggest that follow-up biopsy procedures are essential in all patients with CIS treated with BCG. The biopsy specimens should be evaluated for p53 overexpression, because our data indicate that persistent p53 overexpression in uroepithelial lesions after BCG treatment is an ominous finding for probable tumor progression.

Adjuvants, Immunologic↗
PubMed1997

A sequencing strategy for the localization of O-glycosylation sites of MUC1 tandem repeats by PSD-MALDI mass spectrometry.

It is demonstrated with glycopeptides of the polymorphic epithelial mucin (MUC1) that post-source decay matrix-assisted laser desorption ionization (PSD-MALDI) is a fast, highly sensitive, and reproducible method for the localization of O-glycosylation sites by reflectron time-of-flight (TOF) mass spectrometry. We have analyzed GalNAc-carrying peptides of up to 25 amino acids, and could distinguish even neighboring glycosylation sites. This method was also able to localize and characterize disaccharides (e.g., the Thomsen-Friedenreich disaccharide) on MUC1 derived peptides. PSD-MALDI-MS fragment ion patterns were recorded in the positive ion mode from the synthetic peptide TAP25 [(T1aAPPAHGVT9S10APDT14RPAPGS20) T1bAPPA], an overlapping sequence of MUC1 tandem repeats, which was glycosylated with GaINAc in vitro. The glycosylation sites found were either Thr9 or Thr1b in the monoglycosylated, Thr9 and Thr1b in the diglycosylated, and Thr9, Thr1b, and Ser20 in the triglycosylated peptide. A single PSD-MALDI-MS spectrum of the underivatized and uncleaved di- or triglycosylated TAP25 peptide was sufficient to identify the glycosylation sites, thereby distinguishing six potential, partly adjacent, glycosylation sites. The monoglycosylated fraction was found to consist of a mixture of two glycosylated species with the same molecular weight. This was shown by the analysis of proteolytic digests. PSD-MALDI-MS of the resulting peptides right out of the digestion probe was sufficient to identify the Gal-NAc-glycosylation sites as either Thr9 or Thr1b, respectively. Beyond the methodical aspects the results revealed that in vitro glycosylation of the TAP25 peptide with a transferase system from human milk differs from that obtained with a breast cancer cell transferase system.

Amino Acid Sequence↗
PubMed1997

Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection after antibiotic treatment.

OBJECTIVES: To compare the diagnostic accuracy of the most widely available tests for diagnosis of Helicobacter pylori infection after antibiotic treatment. METHODS: A total of 59 H. pylori-positive, duodenal ulcer patients (mean age, 40.7 +/- 11.7 yr; 40 male and 19 female) were treated for 2 wk with either amoxicillin-metronidazole (n = 36) or omeprazole-amoxicillin-tinidazole (n = 23), and after 4 wk, were tested for H. pylori infection by [14C]urea breath test (UBT), serum IgG antibody level, and multiple antral biopsies for rapid urease testing, histology, Warthin-Starry stain, and polymerase chain reaction to detect H. pylori DNA. Infection status was established by a concordance of test results. RESULTS: H. pylori was eradicated in 47 patients (80%). UBT and rapid urease testing had the best sensitivity and specificity, although not statistically different to Warthin-Starry stain and polymerase chain reaction. Serology and histology had little diagnostic value in this setting due to high proportion of false-positive results. CONCLUSIONS: Noninvasive UBT is as accurate in predicting H. pylori status after antibiotic treatment as rapid urease testing and Warthin-Starry stain. Especially for duodenal ulcer patients, UBT could be considered the gold standard to confirm eradication of H. pylori.

Adolescent↗
PubMed1996

Tumors of the respiratory tract observed at the German Primate Center, 1978-1994.

Eight spontaneous pulmonary tumors (four bronchiolar tubular adenomas, two bronchiolar adenocarcinomas, two squamous-cell carcinomas) occurred in a total of 54 adult tree shrews (Tupaia belangeri) of the GPC colonies between 1978 and 1994. The adenomas and adenocarcinomas consisted of tubularly or trabecularly arranged cuboidal to cylindrical cells interspersed with some PAS-positive goblet cells, thus resembling the epithelial lining of respiratory bronchioles of tree shrews. The two squamous-cell carcinomas probably originated from the pulmonary alveoles. Three more pulmonary tumors (one small-cell carcinoma, one bronchial adenoma, one squamous-cell carcinoma) developed in 409 adult callitrichids of the GPC colonies during the same period, and one more bronchial adenoma was observed in a common marmoset (Callithrix jacchus) of another colony located in Göttingen. With regard to the adenomas and squamous-cell carcinomas, a similar cellular origin with the three shrews is assumed. The small-cell carcinoma possibly developed from the bronchial epithelium, provided a pathogenesis parallel to that of human small-cell carcinoma is suggested. Four of the tree shrew pulmonary adenomas/adenocarcinomas and the small-cell Ca were macroscopically visible as yellowish-grey nodules of 1 mm x 1 mm to 15 mm x 15 mm diameter, predominantly involving the main lobes (2 x right main lobes, 2 x left main lobes, 1 x all lobes). The pulmonary tumors of the other animals were below macroscopical detectability.

Adenocarcinoma↗
PubMed1996

Pharmacokinetics and safety of multiple-dose valaciclovir in geriatric volunteers with and without concomitant diuretic therapy.

A randomized, double-blind study was conducted to evaluate the safety and pharmacokinetics of acyclovir following multiple-dose oral administration of valaciclovir (three times a day for 8 days) in geriatric volunteers (65 to 83 years of age). Pharmacokinetic evaluation was performed for three groups: normotensive subjects given 500-mg doses of valaciclovir (n = 11), normotensive subjects given, 1,000-mg doses of valaciclovir (n = 9), and thiazide diuretic-treated hypertensive subjects given 500-mg doses of valaciclovir (n = 9). Valaciclovir, the l-valyl ester of acylclovir, was rapidly absorbed and converted to acyclovir, with plasma valaciclovir concentrations generally undetectable or < or = 0.4 microgram/ml. The peak concentration of drug in plasma (Cmax) for acyclovir occurred at 1 to 2 h, and the half-life of acyclovir was 3 to 4 h in all three elderly groups. The Cmax and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) values of acyclovir obtained on days 1 and 8 indicated no unexpected accumulation at steady state. The steady-state acyclovir Cmax (4.30 and 5.98 micrograms/ml) and daily AUC0-infinity (44 and 74 h.micrograms/ml) following dosing of valaciclovir (500 and 1,000 mg) three times a day were two to three times greater than those expected after high-dose oral acyclovir treatment (800 mg, five times daily). There were no valaciclovir-related changes or abnormalities in safety parameters and no reports of serious adverse experiences in these elderly volunteers. The plasma acyclovir concentration-time curves for the hypertensive and normotensive (500-mg valaciclovir treatment) elderly groups were almost superimposable, and acyclovir pharmacokinetic parameters for the two groups were not significantly different, indicating that concomitant thiazide diuretics do not alter acyclovir pharmacokinetics following valaciclovir dosing in the elderly. Compared with historical data for younger volunteers (creatinine clearance [CLCR] > 75 ml/min/1.73 m2), the elderly subjects (CLCR = 40 to 65 ml/min/1.73 m2) showed higher (approximately 15 to 20%) mean Cmaxs and higher (approximately 30 to 50%) mean AUC(0-infinity)s of acyclovir (P < 0.01), which were consistent with age-related decreases in CLCR. The increased acyclovir exposure from valaciclovir dosing will permit reduced dosing frequency and may result in improved efficacy in the management of herpesvirus diseases.

Acyclovir↗
PubMed1996

Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases.

PURPOSE: To determine the clinicopathologic features of lymphoproliferative disorders (LPD) that occur in the setting of methotrexate (MTX) therapy for rheumatic diseases (RD) and to define the relationship between the presence of Epstein-Barr virus (EBV) in tumor cells and the response of LPD to MTX withdrawal. PATIENTS AND METHODS: In addition to nine new cases, we analyzed 28 cases previously reported in the literature of LPD in patients receiving MTX for RD. In addition to MTX, immunosuppressive therapy included corticosteroids in 19 patients, azathioprine in three, and cyclosporine in one. Extranodal disease was identified in 16 patients, but none had CNS involvement. Pathologic findings included five cases of Hodgkin's disease and seven low-grade lymphomas. The remaining patients had intermediate or aggressive lymphomas. In situ hybridization studies (ISHS) for EBV-RNA transcripts were positive in 12 of 27 patients (44%). RESULTS: Among 37 patients, 16 were initially observed after MTX withdrawal without additional antitumor therapy. Six achieved a spontaneous complete remission (CR), three had a partial response (PR), one had a minimal response, and six had no response to MTX withdrawal. Of 10 responding patients, EBV was detected by ISHS (n = 6) or polymerase chain reaction (PCR) (n = 2); one patient had a CR despite the absence of EBV by PCR and one had a CR but did not have viral assays performed. Only one of six patients with negative EBV by ISHS or PCR responded to MTX withdrawal. CONCLUSION: MTX withdrawal and observation for a short period should be considered in the initial management of patients who develop LPD while on MTX therapy. Responses were consistently observed, but not limited to patients in whom EBV was detected by ISHS or PCR. Further studies are required to confirm these findings and to evaluate the role for EBV in LPD that occur in patients receiving MTX.

Adult↗
PubMed1996

[Not Available].

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Amputation, Surgical↗
PubMed1996

[Frequency and histopathologic features of chronic gastritis in 300 patients without endoscopic lesions].

Three gastric mucosal biopsies were obtained from 300 patients showing a normal upper digestive tract endoscopy. Histologically, in 9% of the patients the biopsies were normal: in 87%, showed a common-type chronic gastritis, and in 4% showed a reactive (chemical or reflux-type) gastritis. Helicobacter pylori was present in 25.9% of the patients without gastritis, in 33.3% of the patients with reactive gastritis, and in 87.7% of those with common-type gastritis. In 19.9% of the patients with common-type chronic gastritis there was intestinal metaplasia, consisting of type I metaplasia in 14.1%, type II in 3.1% and type III metaplasia in 2.3%. The association of type III intestinal metaplasia with the other forms of metaplasia, its lower frequency and its tendency to be present in older patients supports the hypothesis that type III incomplete colonic metaplasia represents a more advanced stage than complete and incomplete small bowed metaplasia of the gastric mucosa.

Adolescent↗
PubMed1996

[Semiquantitative histopathologic analysis of chronic gastritis: extension and grading score].

Three endoscopic systematic biopsies were obtained from 261 patients showing chronic gastritis. Histopathologic features of chronic gastritis were graded from 0 to 3 points according to the Sydney System. In addition, an extension and grading histopathologic score was applied. This score was obtained from the sum of qualified grades for each feature in all three samples. Inflammation, activity, atrophy, and intestinal metaplasia were predominantly grade 1 and H pylori density was predominantly grade 2. Only 2.6% of the sections without atrophy showed intestinal metaplasia, while 79.3% of the sections depicting grade 2-3 intestinal metaplasia showed moderate to severe atrophy. Inflammation was more severe in the antral lesser curvature and the more severe atrophy was present in the antrum than in the corpus mucosa. Sydney System and extension and grading histopathologic score showed more extensive activity in patients older than 45 years. A lower histopathologic score of H pylori was seen in these patients. The presence of H pylori was directly correlated with inflammation severity and inversely with atrophy. These results, in accordance with data shown in the literature, suggest that the Sydney System and the extension and grading histopathologic score can be applied to compare chronic gastritis features in different groups of patients.

Chronic Disease↗
PubMed1995

Duchenne muscular dystrophy and myotonic dystrophy in the same patient.

We report on the first patient identified with myotonic dystrophy and Duchenne muscular dystrophy (DMD). The family of the propositus had a strong history of myotonic dystrophy, and there was an intrafamilial pathological expansion of the responsible CTG repeat between the mildly affected mother (160 repeats; normal 27 repeats) and her more severely affected son (650 repeats), and his sister (650 repeats). The propositus was an isolated case of Duchenne muscular dystrophy with marked dystrophin deficiency in muscle biopsy. The patient was still ambulatory post age 16. Myotonic dystrophy could interfere to some extent with the progression of Duchenne dystrophy. However, other interpretations are possible. Twelve percent of dystrophin revertant fibers as observed by immunohistochemistry could be sufficient to ameliorate typical DMD clinical severity, or the patient may present a somatic mosaic. The pathophysiological interactions of these two unlinked disorders are discussed at the clinical and histopathological levels.

Child↗
PubMed1995

Chemical and enzymatic synthesis of glycopeptides.

Progress recently made in the synthesis of biologically relevant N- and O-glycopeptides is illustrated by examples. In this context, developments in the preparation of complex saccharide side chains and in the subsequent coupling to peptide portions is described. Special emphasis is given to the synthesis of Lewis antigen-type structures. Furthermore, modern methods in solid phase peptide syntheses utilizing glycosylated building blocks are presented. Recent advances in glycopeptide syntheses employing enzymatic methods in deprotection steps as well as in peptide/saccharide chain elongation are reported.

Amino Acid Sequence↗
PubMed1995

Simulated exposure of hospital emergency personnel to solvent vapors and respirable dust during decontamination of chemically exposed patients.

STUDY OBJECTIVE: To ascertain the breathing-zone level of organic solvents and respirable particulates in a simulated hospital patient decontamination. DESIGN: An adult-sized, clothed plastic mannequin was contaminated with a solvent or particulate, then decontaminated. Rescuers were exposed to acetone, p-xylene, iron oxide, or zinc oxide during decontamination. We performed breathing-zone air sampling on the two rescuers. Five trials were run with each chemical. PARTICIPANTS: Two physicians performed the decontamination. RESULTS: Measured breathing-zone concentrations for the chemicals tested were significantly lower than their respective short-term breathing-zone limits (P = .042, .043, .001, and .001 for acetone, p-xylene, iron, and zinc oxide, respectively). CONCLUSION: The chemicals tested during simulated hospital decontamination did not pose a respiratory health risk to rescuers. This model may be useful in the extrapolation of breathing-zone exposure to more toxic chemicals. Because ours are preliminary data, the use of respiratory protective equipment during decontamination must be recommended.

Decontamination↗