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Biomedical subjects

J M Schmidt

Publications and source records attributed to J M Schmidt.

108 records · Page 6Linked to original sources
PubMed1966

The development of cellular stalks in bacteria.

Extensive stalk elongation in Caulobacter and Asticcacaulis can be obtained in a defined medium by limiting the concentration of phosphate. Caulobacter cells which were initiating stalk formation were labeled with tritiated glucose. After removal of exogenous tritiated material, the cells were subjected to phosphate limitation while stalk elongation occurred. The location of tritiated material in the elongated stalks as detected by radioautographic techniques allowed identification of the site of stalk development. The labeling pattern obtained was consistent with the hypothesis that the materials of the stalk are synthesized at the juncture of the stalk with the cell. Complementary labeling experiments with Caulobacter and Asticcacaulis confirmed this result. In spheroplasts of C. crescentus prepared by treatment with lysozyme, the stalks lost their normal rigid outline after several minutes of exposure to the enzyme, indicating that the rigid layer of the cell wall attacked by lysozyme is present in the stalk. In spheroplasts of growing cells induced with penicillin, the stalks did not appear to be affected, indicating that the stalk wall is a relatively inert, nongrowing structure. The morphogenetic implications of these findings are discussed.

Autoradiography↗
PubMedDate not supplied

Metric and multidimensional scaling: efficient tools for clustering molecular conformations.

The application of metric and multidimensional scaling to conformer ensembles was demonstrated in this work. An automated process was devised to cluster and assign group memberships and cluster representatives. The method allows rapid clustering, leading to intuitive results that can be visually inspected. Multidimensional scaling was found to be superior to metric scaling for clustering conformers. The performance of different hierarchical clustering algorithms was compared using multidimensional plots, and the group average method was found to perform best.

Amino Acid Sequence↗
PubMedDate not supplied

Multiple flexible alignment with SEAL: a study of molecules acting on the colchicine binding site.

An extension of the steric and electrostatic alignment alignment (SEAL) method (MultiSEAL) is described that allows the overlay of multiple molecules and conformations. The method is well-suited for the systematic study of possible alignments, also revealing information about the conformational energies associated with a given overlay. It has been tested on three examples: angiotensin II antagonists, 5-HT3 antagonists, and dopaminergic compounds. The utility of the method is further demonstrated in an analysis of molecules that putatively bind to the colchicine site of tubulin. On the basis of its overlay with colchicine, allocolchicine, 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone, and combretastatin A-4, it appears that 2-methoxyestradiol (2-ME) is unlikely to fit the colchine site properly. The weak antimitotic activity of 2-ME may be explained by its partial fit in the site.

2-Methoxyestradiol↗
PubMedDate not supplied

Marine animal biosynthetic constituents for cancer chemotherapy.

A fifteen year investigation of marine animal components as sources for new and potentially useful cancer chemotherapeutic drugs has led to our discovery of a number of such valuable substance. The especially productive Indian Ocean sea hare Dolabella auricularia has yielded (100 kg leads to or approximately 1 mg each) a series of very potent cell growth inhibitory substances designated dolastatins 1-9. The first member of this new series, dolastatin 1, may represent the most potent anticancer agent so far uncovered with, e.g., a curative response (33%) using a dose of 11 microgram/kg (T/C 240, to T/C 139 at 1.37 microgram/kg) in the National Cancer Institute's murine B16 melanoma. Structural elucidation of the new antineoplastic agents is underway, and recent progress is illustrated with peptide dolastatin 3 (P388 ED 50 2.7 x 10(-7) microgram/ml).

Animals↗
PubMedDate not supplied

Isolation and characterization of palystatins A-D.

Four new and relatively low molecular weight (approximately 3,000-5,000), cell growth (PS) inhibitory peptides designated palystatins A-D have been isolated from the Indian Ocean Palythao liscia Haddon and Duerden. The Isolation utilized chromatographic procedures (Amberlite XAD-7 to Sephadex G-100) guided by bioassay with the P388 murine lymphocytic leukemia (PS system). Palystatins A-D exhibited PS cytotoxicity in the range ED50 0.02-0.0023 microgram/ml.

Amino Acids↗
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Evaluation of limonoids against the murine P388 lymphocytic leukemia cell line.

A structure/activity study of selected limonoids from two plant families (Meliaceae and Rutaceae) of the Rutales order against the murine P-388 lymphocytic leukemia system was undertaken. The presence of both a 19 leads to 28 lactol and a 14,15 beta-epoxide group was found especially important for pronounced inhibition of the PS in vitro cell line. Substitution of an A-ring alpha,beta-unsaturated ketone (3-oxo-1-ene) for the lactol led to diminished activity, while reduction of the olefin caused complete loss of activity. At the dose levels employed, even very good PS in vitro inhibition was not translated into PS in vivo antineoplastic effects.

Animals↗
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Antineoplastic agents, 88. Pimelea prostrata.

The aerial portion of Pimelea prostrata (Thymelaeaceae) collected in New Zealand was evaluated as a source of substances that inhibit growth of the murine P-388 lymphocytic leukemia (PS). Simplexin (1) and Pimelea factor P2 (2) were found to strongly inhibit growth (ED50 5 X 10(-3) and 8 X 10(-4) micrograms/ml, respectively) of the PS in vitro cell line. The cyclic orthoester (2) was also found to inhibit growth (T/C 132 at 20 micrograms/kg) of the PS in vivo system. Detailed 1H-nmr (at 400 MHz) and 13C-nmr studies combined with fast atom bombardment mass spectral evidence were employed to confirm the structural assignments.

Animals↗
PubMedDate not supplied

Antineoplastic agents, 103. The isolation and structure of hypoestestatins 1 and 2 from the East African Hypoëstes verticillaris.

The East African shrub Hypoëstes verticillaris representing a heretofore chemically unexplored. Acanthaceae genus has been found to contain two new cell growth inhibitory (murine P-388 lymphocytic leukemia) phenanthroindolizidine alkaloids termed hypoestestatin 1 (1a) and hypoestestatin 2 (1b). Both substances were found to markedly inhibit growth of the murine P-388 cell line (ED50 = 10(-5) micrograms/ml). The structures of hypoestestatins 1 and 2 were assigned primarily on the basis of results from extensive spectral studies.

Alkaloids↗
PubMedDate not supplied

Antineoplastic agents, 120. Pancratium littorale.

The bulbs of Pancratium littorale collected in Hawaii were found to contain a new phenanthridone biosynthetic product designated pancratistatin (4a) that proved to be effective (38-106% life extension at 0.75-12.5 mg/kg dose levels) against the murine P-388 lymphocytic leukemia. Pancratistatin also markedly inhibited (ED50, 0.01 microgram/ml) growth of the P-388 in vitro cell line and in vivo murine M-5076 ovary sarcoma (53-84% life extension at 0.38-3.0 mg/kg). An X-ray crystal structure determination of pancratistatin monomethyl ether (4c) and a detailed high resolution (400 MHz) nmr study of pancratistatin and its pentaacetate (4b) completed assignment of structure 4a. Companion antineoplastic constituents of P. littorale were found to be narciclasine (2c) and its 7-deoxy derivative (2a). The structure of 7-deoxynarciclasine (2c) was also confirmed by an X-ray crystallographic analysis.

Amaryllidaceae Alkaloids↗
PubMedDate not supplied

Isolation, structure, and synthesis of combretastatins A-1 and B-1, potent new inhibitors of microtubule assembly, derived from Combretum caffrum.

The principal antineoplastic constituent of the South African tree Combretum caffrum has been isolated and designated combretastatin A-1. The structure of this new cis-stilbene was unequivocally established by X-ray crystal structure determination and total synthesis. A Wittig reaction sequence in THF comprised the synthetic key step (92.5% yield) and provided a very favorable 9:1 ratio of the cis:trans [1c:2c, geometrical isomers]. Selective hydrogenation of combretastatin A-1 afforded combretastatin B-1, a companion cell growth inhibitory constituent of C. caffrum. Combretastatin A-1 provided 26-29% life extension at 2.75-11 mg/kg dose levels with ED50 0.99 microgram/ml against the murine P-388 lymphocytic leukemia in vivo and in vitro systems. Both combretastatin A-1 and combretastatin B-1 are potent inhibitors of microtubule assembly in vitro and among the most potent inhibitors of the binding of colchicine to tubulin yet described. The structural simplicity and ready synthesis of combretastatin A-1 and combretastatin B-1 suggest that these new biosynthetic products will become useful in a variety of biological endeavors.

Acetylation↗
PubMedDate not supplied

Isolation, structure, synthesis, and antimitotic properties of combretastatins B-3 and B-4 from Combretum caffrum.

Further investigation of a CH2Cl2 fraction prepared from the South African tree Combretum caffrum for substances inhibitory to the murine P-388 lymphocytic leukemia (PS system) cell line has led to the isolation of two new bibenzyls, designated combretastatins B-3 and B-4, accompanied by the previously known bibenzyls 7, 8, and 9. The structure of each substance was ascertained by results of mass and nmr spectral analyses and confirmed by crystal structure determination (for 7) or synthesis. Combretastatins B-3 and B-4 gave PS ED50 values of 0.4 and 1.7 micrograms/ml, respectively, and bibenzyls 7, 8, and 9 were comparably cell growth inhibitory against the PS cell line with ED50 results of 1.7, 2.5, and 0.25 ug/ml, respectively. All the bibenzyls caused leukemia cells to accumulate in mitosis at cytotoxic drug concentrations; however, a wide range of in vitro activity against the protein tubulin (the major component of the mitotic spindle) was observed.

Animals↗
PubMedDate not supplied

Antineoplastic agents, 107. Isolation of acteoside and isoacteoside from Castilleja linariaefolia.

The southwestern Indian paintbrush, Castilleja linariaefolia, yielded extracts that displayed in vivo activity against murine P-388 (PS) lymphocytic leukemia. Separation guided by PS cell line inhibition led to isolation of cytotoxic compounds that were identified as the known glycosides acteoside [1] (ED50 2.6 micrograms/ml) and isoacteoside [2] (ED50 10 micrograms/ml). The identifications were established by spectral measurements and degradation studies. Mannitol was also found in this plant.

Animals↗
PubMedDate not supplied

[Surgical treatment of the snapping hip].

Snapping hip (Coxa saltans) is the abrupt sliding of the iliotibial tract over the greater trochanter. In the case of pain, which cannot be alleviated by a conservative treatment, an operation is advised. The methods of operation applied up to this day showed--especially because of their high recidive-quotas--great disadvantages. In a detailed post-operational check-up over the past 20 years the new method of "diagonal notching" (27 cases) developed at the Orthopedic Hospital München-Harlaching was compared to the old method of fixing the tract according to M. Lange (24 cases). After "diagonal notching" the snapping occurred again seven times less than after fixing the tract. After "diagonal notching" only 4% of the patients had to be re-operated, however, after fixing the tract a re-operation was necessary on 38% of the patients. 91% of the patients were relieved from their pain almost completely after "diagonal notching", compared to only 50% after fixing the tract. Considering that the "diagonal notching" offers simple technics of operation and better results than other methods, the "diagonal notching" should be used as method of choice to eliminate a snapping hip.

Adolescent↗
PubMedDate not supplied

Cochlear neuronal populations in developmental defects of the inner ear. Implications for cochlear implantation.

A histological study was made to determine the cochlear neuronal populations of 20 human ears having hearing loss caused by developmental defects. The neuronal populations ranged from 7677 in an ear with Mondini dysplasia to 30 753 in an ear with DiGeorge's syndrome, the norm for young human subjects being 35 000 neurons. The length of the cochlear (spiral) ganglion varied from 7.3 mm to 14.8 mm, the norm for human subjects being 12 mm. The sensorineural hearing losses in all cases were attributable to malformation or degeneration of the sensorineural structures. The hearing loss was moderate in one case of Alport's syndrome, severe in one case of Usher's syndrome and in one case of severe Mondini dysplasia; it was profound in one case of maternal rubella, one of congenital deafness of unknown cause, another case of severe Mondini dysplasia and one of Down's syndrome (Trisomy 21). One case of mild Mondini dysplasia and one of DiGeorge's syndrome were known to have normal hearing. In 4 other cases hearing status was absent.

Adolescent↗
PubMedDate not supplied

Hearing loss in students at a conservatory.

We tend not to think of music as noise but as a pleasant sound. Yet, played loud enough, music can become a threat to the human ear. The question arises whether professional musicians suffer from hearing losses caused by their playing of music. The hearing of students at the Rotterdam conservatory was studied; medical students served as a reference group. High percentages of audiometric noise dips (16%) and high-frequency losses (20%) were found in students of the conservatory, as well as a high percentage (72%) of extended high-frequency losses relative to the reference curves of Dreschler et al. Surprisingly, an equally large (and in the high-frequency region an even higher) percentage of hearing losses was found in the control group of medical students with the same median age. In sum, the exposure of conservatory students to the practice of music has as yet had no effect on their hearing.

Adolescent↗
PubMedDate not supplied

Antineoplastic agents 460. Synthesis of combretastatin A-2 prodrugs.

The original synthesis of combretastatin A-2 (1a) was modified to provide an efficient scale-up procedure for obtaining this antineoplastic stilbene. Subsequent conversion to a useful prodrug was accomplished by phosphorylation employing in situ formation of dibenzylchlorophosphite followed by cleavage of the benzyl ester protective groups with bromotrimethylsilane to afford the phosphoric acid intermediate 11. The latter was immediately treated with sodium methoxide to complete a practical route to the disodium phosphate prodrug (2a). The phosphoric acid precursor (11) of phosphate 2a was employed in a parallel series of reactions to produce a selection of metal and ammonium cation prodrug candidates. Each of the phosphate salts (2a-q) was evaluated with respect to relative solubility behavior, cancer cell growth inhibition and antimicrobial activity.

Antineoplastic Agents, Phytogenic↗