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At least 1,135 records · Page 63Linked to original sources
PubMed1988

Transformation of C3H/10T1/2 mouse embryo cells to focus formation and anchorage independence by insoluble lead chromate but not soluble calcium chromate: relationship to mutagenesis and internalization of lead chromate particles.

The genotoxicity of soluble and insoluble hexavalent chromium compounds was studied in mammalian cell assays which detect base substitution, deletion, addition, and frameshift mutations [6-thioguanine resistance in Chinese hamster ovary cells], primarily base substitution mutations [ouabain resistance in Chinese hamster ovary and C3H/10T1/2 Cl 8 mouse embryo fibroblasts (10T1/2)] and morphological transformation [focus formation] in 10T1/2 cells. Soluble hexavalent CaCrO4, administered in either acute (5-h) or subacute (24-h) dosing regimens, induced dose-dependent cytotoxicity and mutation to 6-thioguanine resistance in Chinese hamster ovary cells but no mutation to ouabain resistance or focus formation in transformation assays, although the acute treatment induced a high frequency of conversion of 10T1/2 cells to adipocytes. Cell lines established from cloned adipocytic cells were not morphologically transformed and did not grow in soft agarose. PbCrO4 did not induce mutation to either 6-thioguanine or ouabain resistance but did induce a reproducible dose-dependent, low frequency of focus formation in 10T1/2 cells. Cell lines established from PbCrO4-induced foci stably formed foci when coseeded with 10T1/2 cells, had 3-5-fold increased saturation densities relative to nontransformed 10T1/2 cells, and formed colonies in soft agarose, indicating their likelihood to be neoplastic. Long term exposure of 10T1/2 cells to either CaCrO4 or PbCl2, even at 85% cytotoxic concentrations, or pretreatment of cells with either CaCrO4 or PbCl2 followed by treatment with the alternate compound, did not induce morphological transformation. Treatment of cells with insoluble hexavalent PbCrO4 resulted in progressive and extensive vacuolization of cells in contact with the particles. Progressive cytoplasmic engulfment of PbCrO4 particles was observed using scanning electron microscopy, although PbCrO4 particles were not observed inside vacuoles. These results indicate that the soluble clastogens K2Cr2O7 and CaCrO4 were probably mutagenic by a non-base substitution mechanism but could not transform 10T1/2 cells. In contrast, PbCrO4 was not detectably mutagenic but induced transformation, which could not be explained solely by acute or chronic exposure to dissolution products of either lead or chromate alone. Since PbCrO4 particles were found to be intracytoplasmic in extensively vacuolated cells, we suggest that the unique physiochemical properties of PbCrO4 particles, leading to their internalization and the resultant associated cellular stress response, may be related to the transformation induced by this compound.

Adipose Tissue↗
PubMed1986

Triethyl and trimethyl lead: effects on behavior, CNS morphology and concentrations of lead in blood and brain of rat.

The dose-related behavioral effects produced by triethyl (TEL) (2.6 to 7.9 mg/kg) and trimethyl lead (TML) (8.8 to 26.2 mg/kg) were assessed 2, 7, 14, 21 and 28 days following injection. TEL, but not TML, produced dose- and time-related decreases in body weight. Both agents decreased vertical and horizontal components of motor activity 2 days postdosing; increased activity was seen consistently in TEL-exposed rats 7 to 21 days after dosing. TML increased fore- and hindlimb strength for up to 28 days postdosing. TEL had no consistent effect on this measure. Both TEL and TML decreased responsiveness to an acoustic stimulus during the first two weeks postdosing. Latency to respond to a thermal stimulus was increased 2 to 14 days after TEL with the peak change occurring from 2 to 7 days. The peak of effect following TML was two weeks postdosing. In general, there was a significant correlation between both TEL and TML-induced changes in blood and brain lead levels and decreased sensitivity to a thermal stimulus. The apparent delayed onset of TML-induced neurobehavioral effects may be related to a longer time to obtain peak blood or brain levels. Histopathological assessment of rats 7 or 28 days after TEL and TML indicated that TEL caused structural abnormalities in the hippocampus and dorsal root ganglion, while TML produced changes primarily in the spinal cord and brain stem.

Animals↗
PubMed1994

Lack of relationship between hair lead levels and some usual markers (blood lead levels, ZPP, urinary ALA-D) in occupationally exposed workers.

Blood and hair samples collected from 54 male workers occupationally exposed to lead were assayed for this metal by graphite furnace atomic absorption spectrophotometry. Blood ZPP and urinary ALA-D were also determined for most subjects tested. Blood and hair lead concentrations (PbB and PbH) ranged from 100 to 770 ng/ml (10 to 77 micrograms/100 ml) (mean +/- SD: 384.6 +/- 143.4 ng/ml (38.46 +/- 14.34 micrograms/100 ml)), and from 3 to 243 ng/mg (mean +/- SD: 102.4 +/- 72.6 ng/mg), respectively. No correlation was observed between the PbH and PbB values, nor between PbH and ZPP or ALA-D values. Neither hair coloration nor subjects' age were related to PbH levels. Results are discussed in the light of the existing literature.

Adult↗
PubMedDate not supplied

Lead concentrations in semen of healthy men without occupational exposure to lead.

Lead analyses were performed by atomic absorption spectrometry of semen and blood specimens from 21 medical students and technicians (ages 19 to 41 years) who had no occupational or avocational exposure to lead (Pb). Seminal Pb concentrations averaged 5.9 (S.D. +/- 2.7) microgram per dl (range = 1.0 to 11), and blood Pb concentrations averaged 13.1 (S.D. +/- 3.5) microgram per dl (range = 7.0 to 19). Sperm counts averaged 54 X 10(6) (S.D. +/- 29 X 10(6)) sperm per ml (range = 13 X 10(6) to 120 X 10(6)). Seminal protein concentrations averaged 2.9 (S.D. +/- 0.5) g per dl (range = 2.0 to 4.0). No significant correlations were found between seminal Pb concentrations and blood Pb concentrations or between seminal Pb concentrations and sperm counts. In each subject, the concentration of seminal Pb was less than or equal to the concentration of blood Pb. These measurements are the first published data on seminal Pb concentrations in healthy men, and they serve as reference values for measurements of Pb in semen from Pb-poisoned men.

Adult↗
PubMed1977

"De novo" trisomy 1q32 leads to 1qter and monosomy 3p25 leads to 3pter.

Minor abnormalities are described in an 11-month-old female in which a "de novo" trisomy 1q32 leads to lqter and a monosomy 3p25 leads to ter has been produced. The amount of the exceeding material in this case is less than that found in previous reports of partial trisomy 1q and in cases of parental 1q balanced translocations which has originated recurrent abortions.

Aneuploidy↗
PubMed1997

Comparison of electrocardiograms recorded with standard leads and derived from the vectorcardiographic frank leads in high risk patients.

Dynamic vectorcardiography (VCG) is increasingly employed for ischaemia monitoring with the use of a computerized method for recording and on-line analysis by the calculation of trend parameters. To elucidate how well the derived electrocardiogram (dECG), calculated from the VCG, compares with the simultaneously registered standard ECG (sECG), dECGs from 17 postoperative cardiac-risk patients and 36 subjects with acute myocardial infarction (AMI) were compared to sECGs, both quantitatively in leads II, III, V2 and V5 and qualitatively. Despite small, but some significant differences, mainly in the amplitudes of precordial leads, the qualitative interpretation by two independent cardiologists showed good agreement between the methods (kappa = 0.72 and 0.67, respectively) for the diagnosis of AMI/ischaemia. The dECG seems to be reliable and can be used clinically in these groups of patients during VCG recordings.

Aged↗
PubMed1976

Preparation and properties of carp muscle parvalbumin fragments A (residues 1 leads to 75) and B (residues 76 leads to 108).

The calcium-binding protein (parvalbumin), isolated from carp (Cyprinus carpio) muscle, has been specifically fragmented into two polypeptides by tryptic hydrolysis at the single arginine residue at position 75. Fragment A contains residues 1 leads to 75 and fragment B is composed of residues 76 leads to 108. The fragments have been characterized according to size, amino acid composition, carboxyl- and aminoterminal analysis. Both fragments appear to be homogeneous by these criteria. The intact protein is known to bind 2 mol of calcium per mol of parvalbumin, and although each fragment alone contains all of the essential ligands for the coordination of one Ca2+, neither fragment displays calcium binding activity. Attempts to reconstitute the two fragments, under a variety of conditions, into a functional complex which can bind calcium have been unsuccessful. The side chain of Arg-75 is known to occupy an internal position in the crystalline structure of parvalbumin (Kretsinger, R.H. and Nockolds, C.E. (1973) J. Biol. Chem. 248, 3313), where it is stabilized by an intricate network of hydrogen bonding involving the side chain of Glu-81. Although this internal salt bridge is approx. 20 A from either calcium binding site, it has been suggested that this structural feature of the molecule plays an essential role in the reversible binding of Ca2+. That the side chain of Arg-75 likewise occupies an internal position in the solution structure is indicated by its unavailability for reaction with 1,2-cyclohexanedione under conditions of physiological pH and temperature. However, in the presence of EDTA and at pH 8, it is readily modified by cyclohexanedione. This modification is accompanied by a concomitant loss in calcium binding activity. Reversal of the modification by treatment with hydroxylamine is accompanied by restoration of calcium binding activity. The serum of these data support the hypothesis that Arg-75 plays a critical role in the structural organization and calcium binding activity of the molecule, and in addition, suggests that the integrity of the peptide bond between Arg-75 and Ala-76 may be necessary for establishing the proper micro-environment required for formation of the internal salt bridge between Arg-75 and Glu-81.

Amino Acid Sequence↗
PubMed1976

Two new haemoglobins: haemoglobin Perspolis (alpha 64 (E13) Asp leads to Tyr) and haemoglobin J-Kurosh (alpha 19 (AB) Ala leads to Asp).

Two new haemoglobins are described which were found during a regular survey on voluntary blood donors in Iran. They are haemoglobin Perspolis [alpha 64 (E13) Asp leads to Tyr] and haemoglobin J-Kurosh [alpha 19 (AB) Ala leads to Asp]. The amino acid substitution in these two variants was determined by fingerprinting and amino acid analysis of the tryptic peptides and thermolytic peptides derived from abnormal tryptic peptides. Neither haemoglobin was associated with clinical symptoms.

Adult↗
PubMed2004

Applying data mining techniques to library design, lead generation and lead optimization.

Many data mining techniques have been applied to activity and ADMET datasets and the resulting models are being used to understand quantitative structure-activity relationships and design new libraries. This review summarizes data mining concepts and discuss their application to library design, lead generation (particularly for sequential screening) and lead optimization (specifically for generating and interpreting QSAR models). Also, this review discusses recent comparative studies between data mining techniques and draws some conclusions about the patterns emerging in the drug discovery data mining field.

Algorithms↗
PubMed2005

Can orthogonal lead indicators of propensity to atrial fibrillation be accurately assessed from the 12-lead ECG?

AIMS: When analyzing P-wave morphology, the vectorcardiogram (VCG) has been shown useful to identify indicators of propensity to atrial fibrillation (AF). Since VCG is rarely used in the clinical routine, we wanted to investigate if these indicators could be accurately determined in VCG derived from standard 12-lead ECG (dVCG). METHODS: ECG and VCG recordings from 21 healthy subjects and 20 patients with a history of AF were studied. dVCG was calculated from ECG using the inverse Dower transform. Following signal averaging of P-waves, comparisons were made between VCG and dVCG, where three parameters characterizing signal shape and 15 parameters describing the P-wave morphology were used to assess the compatibility of the two recording techniques. The latter parameters were also used to compare the healthy and the AF groups. RESULTS: After transformation, P-wave shape was convincingly preserved. P-wave morphology parameters were consistent within the respective groups when comparing VCG and dVCG, with better preservation observed in the healthy group. CONCLUSION: VCG derived from routine 12-lead ECG may be a useful alternate method for studying orthogonal P-wave morphology.

Aged↗
PubMed2005

A vector-based, 5-electrode, 12-lead monitoring ECG (EASI) is equivalent to conventional 12-lead ECG for diagnosis of acute coronary syndromes.

AIMS: The conventional 12-lead electrocardiogram (cECG) derived from 10 electrodes using a cardiograph is the gold standard for diagnosing myocardial ischemia. This study tested the hypothesis that a new 5-electrode 12-lead vector-based ECG (EASI; Philips Medical Systems, formerly Hewlett Packard Co, Boeblingen, Germany) patient monitoring system is equivalent to cECG in diagnosing acute coronary syndromes (ACSs). METHODS: Electrocardiograms (EASI and cECG) were obtained in 203 patients with chest pain on admission and 4 to 8 hours later. Both types of ECGs were graded as ST-elevation myocardial infarction if at least 1 of the 2 consecutive recordings showed ST elevation more than 0.2 mV, as ACS if one or both showed ST elevation less than 0.2 mV, T-wave inversion, or ST depression. Otherwise, the ECG was graded negative. RESULTS: Final diagnosis was identical in 177 patients (87%; 95% confidence interval [CI], 82%-91%; kappa = 0.81; SE = 0.035). ST-elevation myocardial infarction was correctly identified or excluded by EASI with a specificity of 94% (95% CI, 89%-97%) and a sensitivity of 93% (95% CI, 86%-97%; using cECG as the gold standard). Of 118 patients with enzyme elevations, an almost identical number (72 [61% by EASI] and 73 [62% by cECG]) had ST elevations. Both techniques were equivalent in predicting subsequent enzyme elevation (identical, 108/143; 75% of ACS and ST-elevation myocardial infarction ECGs by EASI and cECG). Thus, both ECG methods had exactly the same specificity of 59% (95% CI, 48%-69%) and sensitivity of 91% (95% CI, 85%-96%) for detecting myocardial injury. CONCLUSION: EASI is equivalent to cECG for the diagnosis of myocardial ischemia.

Chest Pain↗
PubMed1975

Synthesis of O-beta-D-mannopyranosyl-1 leads to 4)-O-alpha-L-rhamnopyranosyl-(1 leads to 3)-D-galactopyranose, the trisaccharide repeating-unit of the o-specific polysaccharide from Salmonella anatum.

Glycosylation of 1,2:5,6-di-O-idopropylidene-alpha-D-galactofuranose with 2,3-di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-beta-D-mannopyranosyl)-alpha-L-rhamnopyranosyl bromide, followed by removal of the protecting groups, gave O-beta-D-mannopyranosyl-(1 leads to 4)-O-alpha-L-rhamnopyranosyl-(1 leads to 3)-D-galactose, which is the trisaccharide repeating-unit of the O-specific polysaccharide chain of the lipopolysaccharide from Salmonella anatum. The formation of the beta-D-mannopyranosyl linkage was achieved by a glucose-mannose conversion via stereoselective reduction of the corresponding oxo-disaccharide.

Antigens, Bacterial↗
PubMed2005

Fragment-based lead discovery: leads by design.

Fragment-based lead discovery (also referred to as needles, shapes, binding elements, seed templates or scaffolds) is a new lead discovery approach in which much lower molecular weight (120-250 Da) compounds are screened relative to HTS campaigns. Fragment-based hits are typically weak inhibitors (10 microM-mM), and therefore need to be screened at higher concentration using very sensitive biophysical detection techniques such as protein crystallography and NMR as the primary screening techniques, rather than bioassays. Compared with HTS hits, these fragments are simpler, less functionalized compounds with correspondingly lower affinity. However, fragment hits typically possess high 'ligand efficiency' (binding affinity per heavy atom) and so are highly suitable for optimization into clinical candidates with good drug-like properties.

Drug Design↗
PubMed2006

Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits.

Drug-like and lead-like hits derived from HTS campaigns provide good starting points for lead optimization. However, too strong emphasis on potency as hit-selection parameter might hamper the success of such projects. A detailed absorption, distribution, metabolism, excretion and toxicology (ADME-Tox) profiling is needed to help identify hits with a minimum number of (known) liabilities. This is particularly true for drug-like hits. Herein, we describe how to break down large numbers of screening hits and we provide a comprehensive overview of the strengths and weaknesses for each structural class. The overall profile (e.g. ligand efficiency, selectivity and ADME-Tox) is the distinctive feature that will define the priority for follow-up.

Administration, Oral↗
PubMed1978

Structure of a major glycophosphoceramide from tobacco leaves, PSL-I: 2-deoxy-2-acetamido-D-glucopyranosyl(alpha1 leads to 4)-D-glucuronopyranosyl(alpha1 leads to 2)myoinositol-1-O-phosphoceramide.

The chemical structure of a major glycophosphoceramide from tobacco leaves, called PSL-I [K. Kaul and R. L. Lester (1975), Plant Physiol. 55, 120], has now been characterized as 2-deoxy-2-acetamido-D-glucopyranosyl(alpha1 leads to 4)D-glucuronopyranosyl(alpha1 leads to 2)myoinositol-1-O-phosphoceramide. Sites of glycoside linkage were determined by (1) methylation analysis on a trisaccharide isolated by degradation of carboxyl-reduced PSL-I and (2) periodate oxidation experiments on PSL-I. The resulting products were identified with gas chromatography/mass spectrometry. Anomeric configurations were determined by resistance of the sugars in the peracetylated trisaccharide to chromium trioxide treatment.

Glycosphingolipids↗