Teratogenesis and iv cyclophosphamide.
Explore the source record for details and available documents.
Abnormalities, Drug-Induced↗
Biomedical subjects
J M Friedman
Publications and source records attributed to J M Friedman.
Effect of solvent viscosity on the heme-pocket dynamics of photolyzed (carbonmonoxy)hemoglobin.
The heme-pocket dynamics subsequent to carbon monoxide photolysis from human hemoglobin have been monitored as a function of glycerol-water solvent composition with time-resolved resonance Raman spectroscopy. Prompt (geminate) ligand recombination rates and the transient heme-pocket geometry established within 10 ns after photolysis appear to be largely independent of solvent composition. The rate of relaxation of the transient geometry to an equilibrium deoxy configuration is, however, quite sensitive to solvent composition. These observations suggest that the former processes result from local, internal motions of the protein, while the relaxation dynamics of the proximal heme pocket are predicated upon more global protein motions that are dependent upon solvent viscosity.
Carboxyhemoglobin↗
Genetic and crystallographic studies of the 3',5'-exonucleolytic site of DNA polymerase I.
Site-directed mutagenesis of the large fragment of DNA polymerase I (Klenow fragment) yielded two mutant proteins lacking 3',5'-exonuclease activity but having normal polymerase activity. Crystallographic analysis of the mutant proteins showed that neither had any alteration in protein structure other than the expected changes at the mutation sites. These results confirmed the presumed location of the exonuclease active site on the small domain of Klenow fragment and its physical separation from the polymerase active site. An anomalous scattering difference Fourier of a complex of the wild-type enzyme with divalent manganese ion and deoxythymidine monophosphate showed that the exonuclease active site has binding sites for two divalent metal ions. The properties of the mutant proteins suggest that one metal ion plays a role in substrate binding while the other is involved in catalysis of the exonuclease reaction.
Binding Sites↗
Hepatocellular carcinoma in a child with familial Russell-Silver syndrome.
We describe a 4-year-old boy with Russell-Silver syndrome (RSS) found to have hepatocellular carcinoma. The brother of this child also had manifestations of RSS. This is the third malignancy and the first hepatocellular carcinoma described in a patient with RSS. The coexistence of hepatocellular carcinoma and RSS may be completely fortuitous; however, the known association of liver cancer with growth abnormality and hemihypertrophy, findings also present in RSS, suggest that these disorders may be related.
Abnormalities, Multiple↗
Teratogen update: anesthetic agents.
Although many pregnant women undergo anesthesia and many others are occupationally exposed to anesthetics every year, assessment of the teratogenic risk of anesthetic agents in humans must currently be made on the basis of very limited data. Available studies suggest that administration of an anesthetic to a pregnant woman will usually not have a deleterious effect on embryonic or fetal development. The risk of congenital anomalies does not appear to be substantially increased among children of women who have chronic occupational exposure to anesthetic gases during pregnancy, either, but miscarriages may occur more frequently than expected among such women. There is an urgent need for publication of good human epidemiologic and experimental animal studies on the teratogenicity of anesthetics.
Anesthesia, General↗
The neuroendocrine response to fenfluramine in depressives and normal controls.
Explore the source record for details and available documents.
Adult↗
Biochemical abnormalities in rhizomelic chondrodysplasia punctata.
Biochemical studies with emphasis on peroxisomal functions were conducted in six patients with well-documented rhizomelic chondrodysplasia punctata (RCDP) and compared with findings in patients with Zellweger syndrome and neonatal adrenoleukodystrophy (ALD). Patients with RCDP had three characteristic biochemical abnormalities: (1) profound defect in plasmalogen (ether lipid) synthesis, which is significantly greater than the analogous defect in Zellweger syndrome or neonatal ALD; (2) reduction of phytanic acid oxidation activity to 1% to 5% of control, similar to that observed in Refsum disease, Zellweger syndrome, and neonatal ALD; (3) presence of the unprocessed form of peroxisomal 3-oxoacyl-coenzyme A thiolase in the postmortem liver of two patients. Other peroxisomal functions were normal, including levels of very long chain fatty acids, pipecolic acid, and bile acid intermediates, and immunoblot studies of peroxisomal acyl-CoA oxidase and bifunctional enzyme in postmortem liver. Unlike what is observed in Zellweger syndrome and neonatal ALD, catalase activity in cultured skin fibroblasts was sedimentable, indicating that peroxisome structure is not grossly deficient in RCDP. The biochemical abnormalities in RCDP were consistent and set it apart from all the other known peroxisomal disorders.
Acetyl-CoA C-Acyltransferase↗
An unusual case of condylar dislocation.
A 28-year-old woman involved in a motor vehicle accident sustained bilateral mandibular condyle dislocation into the infratemporal fossae. Conventional manipulations were unsuccessful in relocating the condyles. By simulating the dislocations on a dried skull, it was evident that the coronoid processes were trapped anteriorly and superiorly to zygomatic arches. An open surgical approach was required to relocate the condyles.
Accidents, Traffic↗
Cocrystal structure of an editing complex of Klenow fragment with DNA.
High-resolution crystal structures of editing complexes of both duplex and single-stranded DNA bound to Escherichia coli DNA polymerase I large fragment (Klenow fragment) show four nucleotides of single-stranded DNA bound to the 3'-5' exonuclease active site and extending toward the polymerase active site. Melting of the duplex DNA by the protein is stabilized by hydrophobic interactions between Phe-473, Leu-361, and His-666 and the last three bases at the 3' terminus. Two divalent metal ions interacting with the phosphodiester to be hydrolyzed are proposed to catalyze the exonuclease reaction by a mechanism that may be related to mechanisms of other enzymes that catalyze phospho-group transfer including RNA enzymes. We suggest that the editing active site competes with the polymerase active site some 30 A away for the newly formed 3' terminus. Since a 3' terminal mismatched base pair favors the melting of duplex DNA, its binding and excision at the editing exonuclease site that binds single-stranded DNA is enhanced.
Computer Simulation↗
Knowledge of the diagnostic criteria for major depression. A survey of mental health professionals.
Major depression, a mental disorder responsive to specific treatments, may be misdiagnosed by psychiatrists and other mental health personnel. Many patients referred to a depression clinic with other, generally less severe diagnoses were reevaluated by clinic staff and shown to meet DSM-III criteria for a major depressive episode. Discussions with referring therapists about these diagnostic discrepancies revealed frequent misconceptions about the diagnosis of major depression. In response to these observations, a questionnaire was devised to assess clinicians' knowledge about the DSM-III criteria for major depression. One hundred thirteen questionnaires were distributed to clinicians of varied disciplines and levels of experience, and 54 of these questionnaires were returned. Misconceptions about the DSM-III criteria for a major depressive episode were frequent among responders. The most common errors involved the incorrect assumption that vegetative signs and a distinct quality of mood are required for the diagnosis of major depression and that the diagnosis should not be made if chronic. Other major areas of confusion and potential causes of diagnostic error are discussed. Significantly, there were no differences in kind and number of errors when trainees and nontrainees were compared.
Adult↗
Clinical, genetic, and epidemiological factors in neural tube defects.
We examined clinical, genetic, and epidemiologic factors among 512 probands with nonsyndromal neural tube defects (NTDs). Data were analyzed after grouping the probands in four different ways with respect to pathological features and putative pathogenic mechanisms. Apparently unrelated congenital anomalies occurred more frequently among probands with craniorachischisis (62%), encephalocele (30%), or multiple NTDs (25%) than among probands with anencephaly (14.7%) or spina bifida (10.1%) (P much less than .0001). Unrelated congenital anomalies occurred less often among probands with low spina bifida (6.7%) than among probands with high spina bifida (19.5%). NTDs were seen in 7.8% of the siblings of probands with high spina bifida but in only 0.7% of the siblings of probands with low spina bifida, in 2.2% of the siblings of anencephalic probands, and in none of the siblings of probands with craniorachischisis, encephalocele, or multiple NTDS (P less than .001). In all 16 families in which two siblings had NTDs, both had either defects of the type associated with abnormal primary neurulation or defects of the type associated with abnormal canalization. High spina bifida and multiple NTDs were found more frequently than expected among the Sikh probands (P less than .02). The frequency of non-NTD congenital anomalies was higher among siblings of Sikh probands (8.8%) than among siblings of other probands (2.4%) (P less than .05). This excess was due to the occurrence of hydrocephalus without spina bifida in four of 68 siblings of Sikh probands.
Adult↗
Ligand binding channels reflected in the resonance Raman spectra of cryogenically trapped species of myoglobin.
Variations in the v2 region of the Raman spectra of cryogenically trapped photoproducts of different liganded myoglobins as a function of ligand (CO, O2, and n-butyl isocyanide) and species (whale, tuna, elephant) are reported. These variations are attributed to differences in the population of "open" (ligand accessible) and "closed" (ligand inaccessible) conformations of the distal heme pocket. Based on these findings and those derived from other spectroscopies including x-ray crystallography, NMR, IR spectra, and ESR, a working model is presented which accounts for how the conformation of the distal heme pocket, the geometry of the bound ligand, the identity of the ligand, and the dynamics of the dissociated ligand are all interconnected.
Animals↗
Linkage of functional and structural heterogeneity in proteins: dynamic hole burning in carboxymyoglobin.
Inhomogeneous broadening of the 760-nanometer photoproduct band of carboxymyoglobin at cryogenic temperatures has been demonstrated with a dynamic hole burning technique. Line-shape changes and frequency shifts in this spectral band are generated by ligand recombination and are shown not to be the result of structural relaxation below 60 K. The observation of dynamic hole burning exposes the relation between the structural disorder responsible for the inhomogeneous broadening and the well-known distributed ligand rebinding kinetics. The findings provide direct evidence for the functional relevance of conformational substrates in myoglobin rebinding. In addition, a general protocol for evaluating the relative contributions of structural relaxation and hole burning to the spectral changes accompanying rebinding in hemeproteins is presented.
Animals↗
Myoglobin recombination at low temperature. Two phases revealed by Fourier transform infrared spectroscopy.
The low-temperature recombination of CO with myoglobin was studied using Fourier transform infrared spectroscopy. The bound state of carbon monoxide myoglobin has two distinct conformers observed at 1926 and 1945 cm-1 with an intensity ratio of 1 to 8. The recombination of these bands after complete photolysis at 10 K followed by a temperature jump shows distinct kinetics for the two bands. Although both bands apparently follow the nonexponential kinetics originally described by Frauenfelder and co-workers (Austin, R., Beeson, K., Eisenstein, L., Frauenfelder, H., and Gunsalus, I. (1975) Biochemistry 14, 5355-5373), the 1926 cm-1 band does not appear appreciably below 70 K. In fact, after 20 min of recombination at 70 K the 1945 cm-1 band is fully recovered, while no detectable amount of the 1926 cm-1 band is present. This is the first association of a spectroscopic marker of protein substructure with reaction kinetics.
Carbon Monoxide↗
Interspecies variations in the transient heme species generated subsequent to CO photolysis from hemoglobins.
The structure, ligand binding kinetics, and thermodynamics of hemoglobin have been the subject of a great deal of investigation. However, the exact pathway(s) by which cooperative energetics are communicated within the protein remain undefined. The effects of interspecies variations in quaternary and tertiary structure, oxygen affinity, cooperativity, and ligand binding kinetics upon the overall ligand binding process are, therefore, of great importance in understanding and solving these problems. The demonstrated sensitivity of resonance Raman spectroscopy to heme structure and environment make it an ideal probe of ligand binding dynamics. It is possible to examine how specific vibrational modes change with time and correlate this with solution conditions and protein structural and conformational differences. Those modes which exhibit the greatest change with ligand photolysis are also indicative of possible paths of cooperative energy dissipation within the protein. The changes which occur in the vibrational modes of the heme within 10 ns of CO photolysis have been determined for a wide variety of mammalian and reptilian hemoglobins. The modes most affected by this process are, without exception, nu(Fe-His), nu4, and the substituent bending modes, delta(cb - s) and delta(cb - c alpha - c beta). Furthermore, a direct correlation exists between the shift in porphyrin pi electron density upon CO photolysis (as indicated by the transient changes in nu 4) and the Hill coefficient of cooperativity. The implications of those results concerning ligand binding cooperativity in hemoglobins are discussed.
Amphibians↗
Cellular promoters incorporated into the adenovirus genome. Effect of viral DNA replication on endogenous and exogenous gene transcription.
Cell-specific utilization of the albumin and immunoglobulin promoters within non-replicating adenovirus genomes has been established. With such viruses plus helper viruses we now consider the impact of infection by replicating viruses on liver-specific gene expression in hepatoma cells and of the effect of replication on the previously established limits of cell-specific expression. We find that replication of any adenovirus, whether or not it contains the albumin promoter, decreases albumin and apolipoprotein A transcription in hepatoma cells but does not affect transcription of at least four other genes expressed mainly (or only) in the liver. Thus, it may be that some hepatoma-specific genes and late adenoviral genes require a factor(s) in common, and these factors become limiting during replication. In hepatoma cells, the increased copy number of the exogenous promoters resulting from viral DNA replication did not influence the cell-specific expression noted previously; only albumin and not globin or immunoglobulin promoters in the virus were active. In contrast, replication by the same viruses in HeLa cells resulted in high levels of expression from all the exogenous promoters.
Adenoviridae↗
ReCAP: the Registry of Cytogenetic Abnormalities and Phenylketonuria.
The Registry of Cytogenetic Abnormalities and Phenylketonuria (ReCAP) is a multicenter collaborative registry of information on patients with constitutional cytogenetic abnormalities or hyperphenylalaninemia (HPA). Data are entered by microcomputer at four contributing centers. Records are then electronically transmitted to the coordinating center, where the composite cytogenetic and hyperphenylalaninemia databases are maintained on a mainframe computer. A set of programs, known as the ReCAP ISCN Translator, is used to create additional database records describing in detail the chromosome abnormalities present in each patient. The ReCAP computer system permits rapid and flexible retrieval of cases on the basis of any combination of laboratory, clinical, psychometric, or genetic characteristics contained within the databases. Special procedures protect patient confidentiality and assure that ReCAP data are of consistently high quality. Qualified investigators may use ReCAP as a resource for a variety of scientific studies.
Chromosome Aberrations↗
Hepatoma variants (C2) are defective for transcriptional and post-transcriptional actions from both endogenous and viral genomes.
A series of rat hepatoma cell lines was infected with a recombinant adenovirus bearing the rat albumin promoter. Transcription from this promoter was scored directly and was highest in FAO, the differentiated parent, undetectable in C2, a cell variant that has lost almost all hepatocytic characteristics, and high again in C2-Rev7, a 'revertant' cell line derived from C2 that has regained the ability to produce many proteins characteristic of hepatocytes. The endogenous albumin gene is not transcribed in C2 cells, and at a very low rate in C2-Rev7 cells, which accumulate endogenous albumin mRNA at close to normal amounts. Thus the C2-Rev7 'recovery' of albumin mRNA concentration for the endogenous gene is based mainly on post-transcriptional events while the ability of C2-Rev7 to transcribe the albumin promoter in the viral genome is based on a transcriptional factor(s). We also showed that the C2 phenotype included post-transcriptional effects for other genes: transcription of phenylalanine hydroxylase and phosphoenolpyruvate carboxykinase mRNA sequences continue in C2 at rates equivalent to FAO but these C2 cells have no mRNA for these proteins while FAO does. In addition, C2 cells transcribed certain early adenovirus transcription units (E2 and 4) as well as FAO cells but accumulated E2 mRNAs poorly if at all. The changes that led to the C2-Rev7 cell line produced a return to normal of the ability to accumulate these viral mRNAs. Thus a major event in the C2 to C2-Rev7 transition involves post-transcriptional processes as well as the ability to transcribe the albumin promoter positioned in the virus genome.
Adenoviridae↗