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Biomedical subjects

M J Wilson

Publications and source records attributed to M J Wilson.

232 records · Page 13Linked to original sources
PubMedDate not supplied

Binaural interaction in auditory brain stem responses: parametric studies.

The effects of click stimulus presentation rate, spectrum, and polarity on binaural interaction in auditory brain stem responses (BI/ABR) were observed in guinea pigs and in normal-hearing human adults. The effects of repetition rate on the BI/ABR in both species were similar to those seen in ABRs. Six of 16 human subjects showed an unusual "early BI" only at high click intensity and high repetition rates; this is probably due to acoustic reflex effects. Animal data from stimulus spectrum experiments suggest a mid-to-high frequency dependence of the BI/ABR, while human data are less clear. Results are discussed relative to suggested recording strategies for the BI/ABR.

Acoustic Stimulation↗
PubMedDate not supplied

Coherence analysis of scalp responses to amplitude-modulated tones.

Magnitude squared coherence is a method of auditory evoked potential (AEP) frequency-domain analysis, measuring the degree to which the AEP is determined by the stimulus as a function of frequency. In 10 normal-hearing human subjects, scalp responses to an amplitude-modulated (AM) tone (500 Hz carrier modulated with a 40 Hz envelope) were recorded. Critical value criteria were utilized in the statistical analysis of coherence-intensity functions for determination of threshold responses. When compared with subjective determination of AEP threshold from time-domain waveforms, coherence analysis provided a significantly (p less than 0.001) more sensitive threshold measure. Coherence analysis provides information on the spectral content of the response, and allows for the objective determination of threshold which may potentially be utilized in a more expeditious threshold measurement scheme.

Acoustic Stimulation↗
PubMedDate not supplied

Effect of castration on metalloprotease activities in the lateral, dorsal, and anterior lobes of the rat prostate.

Several proteolytic enzymes are involved in mediating the regression of the prostate gland following castration. A previous study showed that plasminogen activator activities are elevated only in the ventral lobe by castration in the rat. Since matrix metalloproteases represent a different class of protease that degrade extracellular matrix, this study examined their activities in the lateral, dorsal, and anterior lobes of the rat in response to androgen deprivation. The results indicate that, in contrast to plasminogen activators, metalloprotease activities are increased in the lateral, dorsal, and anterior lobes following orchiectomy. This suggests that differences in regulation of certain proteases by androgens may occur in individual prostatic lobes.

Animals↗
PubMedDate not supplied

Intravenous injection of an immunoconjugate (anti-PSA-IgG conjugated to 5-fluoro-2'-deoxyuridine) selectively inhibits cell proliferation and induces cell death in human prostate cancer cell tumors grown in nude mice.

Current chemotherapeutic and/or endocrine treatments for adenocarcinoma of the prostate are not delivered selectively to prostate cancer cells, therefore, they are used in very high doses that induce many unpleasant side effects in patients. New approaches are, therefore, needed to deliver drugs directly to prostate cancer cells to improve treatment effects. We hypothesized that antibody immunoglobulin G (IgG) against human prostate specific antigen (PSA) (anti-PSA-IgG) could function as a carrier protein for conjugated chemotherapeutic drugs (such as 5-fluoro-2'-deoxyuridine, doxorubicin, etc.) and that the immunoconjugate could be delivered selectively to PSA-producing neoplastic prostate. Immunoconjugate would then preferentially inhibit cell proliferation and induce cell death in PSA-producing tumor cells, but not in non-PSA-producing prostate cancer cells or other solid organs of the host. The short-term treatment effect could be assessed by measuring cell death and cell proliferation in tumor-bearing animals. We tested our hypothesis by intravenously injecting an immunoconjugate (anti-PSA-IgG-5-fu-2'-d) into nude mice with subcutaneous PSA-producing LNCaP or non-PSA-producing Du-145 prostate tumors. During 5 days of treatment, we observed that immunoconjugate was retained preferentially in PSA-producing LNCaP tumors where it produced cytotoxic effects in neoplastic prostate cells as revealed by decreased cell proliferation and increased cell death, but similar effects were not observed in non-PSA-producing Du-145 tumor cells or mouse organs. Analysis of untreated control mouse with LNCaP tumor, anti-PSA-IgG alone, anti-irrelevant-IgG-drug complex, and drug alone treatments indicated that there was little or no cytotoxic effects of these treatments on LNCaP and Du-145 tumors, and host organs. Our analysis of control and experimental data showed that the immunoconjugate was highly specific in imparting cytotoxic effects on LNCaP prostate tumors, but not on Du-145 tumors and mouse organs. Thus, we have shown that the immunoconjugate selectively delivered a chemotherapeutic drug to PSA-producing prostate tumor cells where it produced measurable cytotoxic effects on cell proliferation and cell death. This is the first report to show a successful delivery of a chemotherapeutic drug in the immunoconjugate to PSA-producing LNCaP prostate tumors in nude mice and without inducing cytotoxic effects on mouse organs.

Animals↗
PubMedDate not supplied

The relationship of cathepsin B and stefin A mRNA localization identifies a potentially aggressive variant of human prostate cancer within a Gleason histologic score.

Cathepsin B (CB) is involved in degradation of extracellular matrix proteins during tumor progression in human solid organ tumors (such as colorectal, bladder, and breast cancers), including human prostate cancer. Its activities are regulated by endogenous inhibitors (such as stefins or cystatins). Increased expression of cathepsin B message, protein, and membrane association have been linked to malignancy, but there are very few studies of their mRNA expression in prostate cancer using in situ hybridization techniques. Our objective was to determine the relationship of CB and stefin A (cystatin A) mRNA localization to the Gleason grading system for histologic scores in the hope of distinguishing aggressive and less aggressive variants of prostate cancer. We used a 25-base biotinylated oligonucleotide CB cDNA antisense probe to localize CB message and a 27-base biotinylated oligonucleotide stefin A cDNA antisense probe to localize stefin A message. Prostate samples from 41 prostatectomy patients were collected along with their pre-surgery serum PSA levels and clinical stage of the disease. Sections prepared from frozen prostate tissue samples were hybridized with the CB and stefin A and control pBR 322 probes using techniques reported by Sinha et al. [1] and their distribution quantitated by an image analysis system. Prostate sections treated with RNAse before hybridization or incubated with the pBR 322 control probe showed little or no reaction products, confirming that localization of CB and stefin A probes was specific. In prostate cancer, the reaction products were found in neoplastic and invasive cells and occasionally in stromal cells. The ratios of CB to stefin A were similar in normal prostate and benign prostatic hyperplasia (BPH) whereas they varied consistently within and between Gleason histologic scores for prostate cancer. These variations showed three localization patterns; namely, prostate cancers with higher levels of CB than stefin A, lower levels of CB than stefin A, and similar levels of CB and stefin A. All three patterns and ratios for CB and stefin A were found in prostate samples (22/41) represented by the Gleason histologic score 6 tumors. In these tumors, serum PSA levels ranged from 1 to 78 ng/ml and prostate cancers showed B, C, and D clinical stages. There was no correlation of CB/stefin A ratio and serum PSA values or clinical stage in a limited number of prostate cancer cases. Our data showed that there were prostate cancer cases within Gleason histologic scores which expressed high, similar, and low levels of CB when compared to stefin A. We postulate that prostate cancer cases showing higher levels of CB compared to stefin A probably represent an aggressive variant of this cancer within any one Gleason histologic score. If this is the case, aggressive variants of prostate cancer would occur within Gleason scores 3 to 10 even though higher scores are usually considered more aggressive forms of prostate cancers. Since our study is based upon a very limited number of frozen prostate samples, we emphasize that a larger series of archival prostate cancer samples along with their survival data should be analyzed to establish any relationship of CB/stefin A ratio and aggressive variants of this cancer. Therefore, our conclusion is tentative. Our study provides a partial explanation for differences in the clinical course of prostate cancer in patients. This is the first study to show that determination of CB and stefin A mRNA ratios may lead to identification of aggressive and less aggressive variants of prostate cancer within a Gleason histologic score.

Adenocarcinoma↗
PubMedDate not supplied

Dipeptidylpeptidase IV activities are elevated in prostate cancers and adjacent benign hyperplastic glands.

Dipeptidylpeptidase IV (DPP IV) is a serine exopeptidase that has been implicated in cell-extracellular matrix interactions and bioactive peptide/cytokine/growth factor metabolism. The objective of this study was to determine if DPP IV activities were changed with development of cancer in the prostate. DPP IV activity was measured in human prostate cancer and benign prostatic hyperplasia (BPH) tissues by biochemical assays with glycylprolyl-p-nitroanalide as substrate in tissue extracts (BPH, n = 8: cancer, n = 7; 2 with Gleason score 5 and 5 with Gleason score 7) and quantitative morphometry of histochemical activities with glycylproline-4-methoxy-beta-naphthylamide as substrate (BPH, n = 9: cancer, n = 13, 1 with Gleason score 4, 10 with Gleason score 6, 2 with Gleason score 8) in frozen-tissue sections. Data were analyzed by analysis of variance. The peptidase activity was detected in epithelial but not stromal cells of BPH and cancer tissues, and it was present as a single band of activity of approximately 160 kDa in electrophoretically separated activity blots of the extracts. DPP IV activity was increased approximately twofold in cancer versus BPH tissues as determined by biochemical and quantitative histochemical methods. In addition, DPP IV activity was increased to a similar extent in BPH glands associated with the cancers. These data indicate that DPP IV activity is increased not only in primary prostatic cancers but also in associated BPH glands, suggesting that there may be some local factors produced by cancer cells that influence adjacent BPH epithelial cells to positively affect the immediate growth environment of the cancer.

Aged↗
PubMedDate not supplied

Pharmacokinetics and metabolism of a 4'-methylthio derivative of propranolol in the dog.

The purpose of this study was to examine the effect of a methylthio substituent in the metabolically most active position of propranolol, i.e. the 4'-position, on the pharmacokinetics and metabolism of this drug in the dog. The kinetics of 4'-methylthiopropranolol (MTP) were compared to those of propranolol following simultaneous iv doses of labeled drug and oral doses of unlabeled drug. MTP had a significantly larger volume of distribution and a longer half-life, and demonstrated a greater accumulation by red blood cells and cardiac conductile tissue than propranolol, effects which presumably are due to a higher lipophilicity of MTP. The greatest effect was on the oral clearance, which was substantially lower for MTP (1.6 vs. 5.5 liters/min) with an associated higher bioavailability (23.1 vs. 10.9%). Studies of MTP metabolism using radiolabeled drug showed that MTP, like propranolol, was eliminated entirely by metabolism. About 70% of the urinary radioactivity was extractable into ethyl acetate at pH 9.8 and pH 2.0. The extractable metabolites were separated by HPLC and identified by GC/MS, direct probe MS, and comparison with authentic compounds. Eleven metabolites were identified as sulfoxides and, in particular, sulfones of MTP and its N-dealkylated and subsequently deaminated glycollic and lactic acid metabolites. The nonextractable urinary radioactivity (30%) was isolated by DEAE-Sephadex chromatography and identified by HPLC/MS as four glucuronic acid conjugates. In contrast to propranolol, there was no evidence of aromatic carbon oxidation for MTP. These observations suggest that the markedly decreased oral clearance of MTP compared to propranolol is due to qualitatively altered metabolism from a highly efficient aromatic carbon oxidation for propranolol to a less efficient sulfur oxidation for MTP.

Animals↗
PubMedDate not supplied

Stereochemical composition of propranolol metabolites in the dog using stable isotope-labeled pseudoracemates.

Previous studies have demonstrated a larger oral bioavailability of (+)- as compared to (-)-propranolol in the dog. The objective of the present study was to examine how this difference is reflected in the metabolism in the drug. The stereochemical composition of propranolol and its metabolites was, therefore, determined in the urine of four dogs after single 160-mg oral doses of stable isotope-labeled pseudoracemates of propranolol. All major metabolites, accounting for 84% of the dose excreted in urine, were isolated by solvent extraction or HPLC, glucuronic acid conjugates after enzymatic hydrolysis, and analyzed by GC/MS after chemical derivatization. Of the three primary metabolic pathways, glucuronidation of the parent drug, about 16% of the dose recovered in urine, was highly selective for (-)-propranolol, (-)/(+)-enantiomer ratio 3.5. In contrast, all of the side-chain oxidation metabolites, about 30% of the dose, were mainly derived from (+)-propranolol, (-)/(+)-enantiomer ratio ranging from 0.35 to 0.74. Ring oxidation, involved in the metabolism of the remainder of the dose studied, about 38%, was, however, also found to be selective for (-)-propranolol, with the greatest selectivity observed in 4'-hydroxypropranolol, (-/(+)-enantiomer ratio 1.49. There was an excellent mass balance for the enantiomers of the metabolites studied, i.e. the total (-)/(+)-enantiomer ratio was close to unity. The higher oral bioavailability of (+)-propranolol in the dog, well reflected in the stereochemical composition of unchanged propranolol in urine, is suggested to be due to stereoselective presystemic hepatic removal of (-)-propranolol by glucuronidation and ring oxidation.

Animals↗
PubMedDate not supplied

Immunocytochemical localization of an immunoconjugate (antibody IgG against prostatic acid phosphatase conjugated to 5-fluoro-2'-deoxyuridine) in human prostate tumors.

Current chemotherapeutic and/or endocrine treatments for adenocarcinoma of the prostate (CaP) do not selectively target neoplastic prostate cells. Therefore, new approaches are needed to improve treatment for prostate tumors. We hypothesized that because of the specific binding of antibody immunoglobulin G (IgG) against human prostatic acid phosphatase (PAcP), PAcP-IgG could function as a carrier protein for the conjugated chemotherapeutic drugs and that the immunoconjugate would then selectively localize (bind) to epithelial cells of human prostate tumors, but not to epithelial cells of other solid organs. Our objective was to test this hypothesis using human prostate, colon, and kidney tissue samples and human prostate pieces incubated in short-term organ culture. We used derivatives of 5-fluorouracil labeled with fluorescein isothiocyanate (FITC) and rabbit anti-PAcP-IgG tagged with CY3/rhodamine alone or as an immunoconjugate. Localization of PAcP-IgG alone and the immunoconjugate in prostate produced similar and specific immunostaining in prostate epithelial cells and their tumors, but not in epithelia of colon and kidney tissue sections or in prostate sections-treated with normal rabbit serum. Confocal microscopy showed co-localization of CY3 and FITC of the immunoconjugate in the same group of prostate epithelial cells and their tumors. Organ culture studies showed that human prostate tissue samples incubated with normal rabbit serum did not show any fluorescence whereas those cultured with PAcP-IgG immunoconjugate showed fluorescence in glandular epithelial cells. The later study also showed that in organ culture the immunoconjugate had penetrated and labeled prostate glands internal to the cut surfaces. Drug labeled with FITC did not localize specifically in the prostatic epithelium. Analysis of our data has shown that PAcP-IgG was needed for specific localization of the immunoconjugate in prostate glands. We conclude that PAcP-IgG was essential for delivery and binding of the drug in human prostate. This is the first report to show that PAcP-IgG-5-Fu-2'-d-based immunoconjugate was selective and specific to epithelial cells of human prostate and its tumors, as revealed by organ culture, immunocytochemical, and confocal microscopic techniques.

Acid Phosphatase↗
PubMedDate not supplied

Protein kinase CK2 activities in human prostatic and seminal-vesicle secretions and seminal plasma.

Human prostatic secretion and seminal plasma contain certain protein kinase activities. Protein kinases play important roles in regulating a vast variety of cellular functions. The objective of this study was to determine whether one of these protein kinase activities in human prostatic secretion and seminal plasma is due to CK2, a messenger-independent, serine/threonine protein kinase that has considerable potential as a regulatory enzyme. By employing an anti-CK2 antibody and a CK2-specific peptide substrate, we have established that CK2 is present in these secretions. Approximately 70% of the CK2 activity present in seminal plasma of normozoospermic men (n = 49) is correlated to the number of sperm originally present in the semen. Further, both the prostate gland and the seminal vesicles are sources of CK2 activity in the seminal plasma of vasectomized men (n = 38). Although there was considerable variation between individuals in CK2 activity, the variation in repeat semen samples of the same vasectomized men (n = 6) was within 21%. There was no correlation of CK2 activity in seminal plasma with age for vasectomized (27-48 years, n = 38), oligozoospermic (28-43 years, n = 24), or normozoospermic men (26-48 years, n = 49). These data suggest that the majority of CK2 activity in the seminal plasma of normozoospermic men originates from sperm but that the prostate and seminal vesicles are accessory sex-gland sources of this enzyme.

Adult↗