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PubMed1984

Frameshift mutagenesis by acridines in wild-type, uvrB and polA strains of Salmonella typhimurium with and without plasmid pKM101.

A large range of acridines, including several anilinoacridines which are active as antitumour agents, have been studied for their ability to revert derivatives of Salmonella typhimurium strains carrying the frameshift marker hisC3076. The strains used all carried deep-rough (rfa) mutations, and were either wild-type with respect to DNA-repair capacity or carried uvrB, polA1 or polA3 (amber) mutations. Derivatives with and without the mutation-enhancing N group plasmid pKM101 were also used. 9-Aminoacridine and other acridines appeared similar to the anilinoacridines for the most part, in that frameshift mutagenesis and toxicity appeared to be unaffected by the uvrB mutation or by the presence of plasmid pKM101. Exceptions were ICR191, 3-NO2-acridine and 1- or 3-NO2-anilinoacridine derivatives in which mutagenesis was increased in uvrB strains and also when pKM101 was present. These compounds were slightly more toxic in the uvrB background, but less toxic when pKM101 was present in either the uvrB or wild-type backgrounds. Mutagenesis by most compounds was reduced by the polA1 mutation and virtually eliminated (except in the case of ICR191) by the polA3 mutation. Plasmid pKM101 occasionally enhanced mutagenesis in the polA1 strain, whereas in the polA3 it appeared to have no effect whatsoever. Again, there were no obvious differences in toxicity between Pol+ and Pol- strains.

Acridines↗
PubMed1980

Interaction of Herpesvirus ateles and Hepesvirus saimiri with primate lymphocytes. I. Selective adsorption of virus by lymphoid cells.

A semiquantitative infectious bioassay, described by Sairenji and Hinuma for the measurement of Epstein-Barr virus (EBV) receptors, was adapted to study the adsorption of the lymphotropic New World herpesvirus ateles (HVA) to established lymphoid lines and lymphocytes of human versus marmoset origin. All marmoset T-cell lines [HVA- or HVS (herpesvirus saimiri)-carrying] had a high adsorbing capacity. EBV-carrying marmoset or human B-cell lines, one EBV-negative human B-lymphoma line, and one human myeloid leukemia-derived line failed to adsorb detectable virus. Two human T-cell derived cell lines of acute lymphatic leukemia origin showed moderate but significant adsorption, and the same was true for unfractionated marmoset lymphocytes. Human peripheral blood did not adsorb, before or after fractionation, whereas normal human thymocytes showed moderate but significant adsorption. It is concluded that HVA receptors are present on human T cells, probably belonging to certain subclasses.

Adsorption↗
PubMed1983

Pharmacokinetics of benzodiazepines and psychostimulants in children.

The pharmacokinetics of benzodiazepines and psychostimulants are reviewed and an overview of the kinetic principles relevant to the utilization of these drugs in infancy and childhood is provided. Newborns and premature infants can metabolize and eliminate diazepam, although the parent drug has a longer half-life and decreased rate of biotransformation to its primary metabolites than in older children and adults. The newborn's capacity to carry on metabolic processes involved in the biotransformation of diazepam, including hydroxylation, demethylation, and glucuronide conjugation, is also limited before 5 months of age; after this time hepatic enzymes develop to adult capacity. Kinetic studies of psychostimulants in childhood indicate that methylphenidate is metabolized in the child as it is in the adult. The drug appears to be rapidly metabolized to ritalinic acid and the half-life seems to be relatively short. Volumes of distribution appear to be relatively large, suggesting extensive distribution of the drug to body tissues. Neither diazepam nor methylphenidate is without the potential for toxicity, which increases with dosage. The authors conclude that advancements in the technical capacity for obtaining and analyzing microsamples of blood as well as the use of noninvasive urinary studies will make future research in children possible.

Adolescent↗
PubMed2005

Hydrogen sulfide and ammonia removal on activated carbon fiber cloth-supported metal oxides.

The present investigation attempts to provide mechanisms for the influence of metal catalysts on carbon supports in odorous gas removal. For this purpose, an activated carbon fiber cloth (ACFC) was subjected to successive metal impregnation to modify its surface properties and so increase its treatment capacity. The carbon fiber cloth adsorbent was prepared by classical incipient wetness impregnation followed by calcination in order to obtain metal oxide phases. Different impregnation parameters (type of metal, level of impregnation, calcination temperature) in the removal of hydrogen sulfide and ammonia were studied. Adsorption kinetics and capacities were carried out in a batch reactor at room temperature. It was found that removal activity depended on metal loading as well as on the order of the metal addition and calcination phase. The capacity of ACFC-supported metal oxides to adsorb both pollutants showed great improvement compared to the virgin adsorbent.

Adsorption↗
PubMed1989

Galactoside-dependent proton transport by mutants of the Escherichia coli lactose carrier: substitution of tyrosine for histidine-322 and of leucine for serine-306.

The lac Y genes from two Escherichia coli mutants, MAB20 and AA22, have been cloned in a multicopy plasmid by a novel 'sucrose marker exchange' method. Characterization showed that the plasmids express a lactose carrier with poor affinity for lactose. Neither mutant carried out concentrative uptake with methyl beta-D-galactopyranoside, lactose, or melibiose as the substrate. Nor did the mutants catalyze counterflow or exchange with methyl beta-D-galactopyranoside. Both mutants did, however, retain the capacity to carry out facilitated diffusion with lactose or melibiose. DNA sequencing revealed that MAB20 (histidine-322 to tyrosine) and AA22 (serine-306 to leucine) have amino acid substitutions within the putative 'charge-relay' domain thought to be responsible for proton transport. Galactoside-dependent H+ transport was readily measured in both mutants. We conclude, therefore, that the presence of a histidine residue at position 322 of the lactose carrier is not obligatory for H+ transport per se.

Binding Sites↗
PubMedDate not supplied

Brain atrophy and neuronal loss in alcoholism: a role for DNA damage?

Chronic alcohol abuse has deleterious effects on several organs in the body including the brain. Neuroradiological studies have demonstrated that the brains of chronic alcoholics undergo loss of both gray and white matter volumes. Neuropathological studies using unbiased stereological methods have provided evidence for loss of neurons in specific parts of the brain in chronic alcoholics. The purpose of this paper is to propose a mechanism for this alcohol related neuronal loss. The hypothesis is based on the neurodegeneration observed in patients with the genetic disorder xeroderma pigmentosum (XP), who lack the capacity to carry out a specific type of DNA repair called nucleotide excision repair (NER). Some XP patients develop a progressive atrophic neurodegeneration, termed XP neurological disease, indicating that endogenous DNA damage that is normally repaired by NER has the capacity to cause neuronal death. Accumulating evidence indicates that the neurodegenerative DNA damage that is responsible for neuronal loss in XP patients results from reactive oxygen species (ROS) and lipid peroxidation products, and has the capacity to inhibit gene expression by RNA polymerase II. Therefore, the following model is proposed: chronic alcohol abuse results in increased levels of ROS and lipid peroxidation products in neurons, which results in an overwhelming burden on the NER pathway, and increased steady state levels of DNA lesions that inhibit gene expression. This results in neuronal death either by reduction in the levels of essential gene products or by apoptosis. The implications of this model for future studies are discussed.

Alcoholism↗
PubMed1999

Encoding of visual information by LGN bursts.

Encoding of visual information by LGN bursts. Thalamic relay cells respond to visual stimuli either in burst mode, as a result of activation of a low-threshold Ca2+ conductance, or in tonic mode, when this conductance is inactive. We investigated the role of these two response modes for the encoding of the time course of dynamic visual stimuli, based on extracellular recordings of 35 relay cells from the lateral geniculate nucleus of anesthetized cats. We presented a spatially optimized visual stimulus whose contrast fluctuated randomly in time with frequencies of up to 32 Hz. We estimated the visual information in the neural responses using a linear stimulus reconstruction method. Both burst and tonic spikes carried information about stimulus contrast, exceeding one bit per action potential for the highest variance stimuli. The "meaning" of an action potential, i.e., the optimal estimate of the stimulus at times preceding a spike, was similar for burst and tonic spikes. In within-trial comparisons, tonic spikes carried about twice as much information per action potential as bursts, but bursts as unitary events encoded about three times more information per event than tonic spikes. The coding efficiency of a neuron for a particular stimulus is defined as the fraction of the neural coding capacity that carries stimulus information. Based on a lower bound estimate of coding efficiency, bursts had approximately 1.5-fold higher efficiency than tonic spikes, or 3-fold if bursts were considered unitary events. Our main conclusion is that both bursts and tonic spikes encode stimulus information efficiently, which rules out the hypothesis that bursts are nonvisual responses.

Action Potentials↗
PubMed2006

Mutations of the Hepatitis C virus protein NS4B on either side of the ER membrane affect the efficiency of subgenomic replicons.

The non-structural protein NS4B of the Hepatitis C virus (HCV) is an integral membrane protein located in the endoplasmic reticulum (ER). Although the function of the NS4B in the viral life cycle is unknown a critical role in replication has been indicated. In order to investigate which components are involved we initially introduced restriction sites near the extremities of the NS4B in a subgenomic replicon that resulted in the alterations of six amino acid residues. This totally abolished replication. We subsequently introduced 14 single point mutations into different regions of NS4B based on the current topology model. One mutation abolished replication, while most conferred reduced replicon establishment and one mutation resulted in improved efficiency. Neither the protein processing nor the membrane altering capacity of NS4B was affected. Surprisingly, mutations situated in the ER lumen also conferred strong effects, despite the fact that replication occurs on the cytosolic side of the ER membrane. We conclude that the molecular integrity of NS4B is vital for HCV replication. Our results suggest that NS4B interacts with itself and with other viral and cellular factors, and may carry intrinsic capacities in order to allow replication.

Cell Line, Tumor↗
PubMed1986

Mutagenic and cytotoxic effects of oxygen free radicals generated by methylviologen (paraquat) on Escherichia coli with different DNA-repair capacities.

Investigations were carried out to examine the mutagenic and cytotoxic effects of oxygen free radicals on E. coli. E. coli B strains with different DNA-repair capacities were exposed to methyl viologen, commonly called paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride, MV), which has been shown to act as an intracellular generator of superoxide radicals. The results obtained were as follows: The cytotoxicity of MV in E. coli was dioxygen-dependent and due to the extent of intracellular generation of superoxide radicals. Cells containing higher levels of superoxide dismutase were more resistant to the toxic effect of MV. The cytotoxicity of MV was greater in DNA repair-deficient E. coli, Bs-1(exrA uvrB), NG30(recA) and R15(polA), than in DNA-repair-proficient strains (B/r and H/r30) and Hs30 (uvrB). MV was found to be mutagenic to E. coli H/r30 and Hs30 under aerobic conditions. The mutation frequencies to streptomycin resistance and to arginine prototrophy increased with the dose of MV in both strains. However, E. coli NG30 was unmutable by MV. The mutation induction did not occur under anaerobic conditions. The expression of the umu operon in E. coli was induced by MV under aerobic conditions. From these results, it was concluded that superoxide radicals intracellularly generated by MV include DNA damage, which causes cytotoxicity and mutation induction in E. coli, and that DNA damage induced by oxygen radicals is repairable by at least recA, polA and exrA(lexA) gene-controlled mechanisms.

DNA Repair↗
PubMedDate not supplied

[Gangrene of the newborn. Report of a case].

A case of gangrene of the right lower limb is reported in a 6 hours of age newborn with satisfactory course following management based on the prevention of possible infections and on maintaining good general conditions. World literature is reviewed finding only 50 cases reported of gangrene of the newborn. Guidelines are established to determine an integral diagnosis of the disease and to carry out a correct differential diagnosis. It is concluded that the etiology of this entity is unknown, although a number of factors are invoked. However, most of these factors imply thromboembolic disturbances that may be either of maternal origin, of the product or mixed. Stress in placed on the necessity that the pediatrician becomes not only thoroughly acquainted with these processes, but also, that he develops the capacity to carry out an early diagnosis and management since these may be guidelines for a satisfactory evolution of the problem.

Diagnosis, Differential↗
PubMed2006

Viral gene therapy.

Cancer is a multigenic disorder involving mutations of both tumor suppressor genes and oncogenes. A large body of preclinical data, however, has suggested that cancer growth can be arrested or reversed by treatment with gene transfer vectors that carry a single growth inhibitory or pro-apoptotic gene or a gene that can recruit immune responses against the tumor. Many of these gene transfer vectors are modified viruses. The ability for the delivery of therapeutic genes, made them desirable for engineering virus vector systems. The viral vectors recently in laboratory and clinical use are based on RNA and DNA viruses processing very different genomic structures and host ranges. Particular viruses have been selected as gene delivery vehicles because of their capacities to carry foreign genes and their ability to efficiently deliver these genes associated with efficient gene expression. These are the major reasons why viral vectors derived from retroviruses, adenovirus, adeno-associated virus, herpesvirus and poxvirus are employed in more than 70% of clinical gene therapy trials worldwide. Because these vector systems have unique advantages and limitations, each has applications for which it is best suited. Retroviral vectors can permanently integrate into the genome of the infected cell, but require mitotic cell division for transduction. Adenoviral vectors can efficiently deliver genes to a wide variety of dividing and nondividing cell types, but immune elimination of infected cells often limits gene expression in vivo. Herpes simplex virus can deliver large amounts of exogenous DNA; however, cytotoxicity and maintenance of transgene expression remain as obstacles. AAV also infects many non-dividing and dividing cell types, but has a limited DNA capacity. This review discusses current and emerging virusbased genetic engineering strategies for the delivery of therapeutic molecules or several approaches for cancer treatment.

Antineoplastic Agents↗
PubMed1989

Glyoxylate cycle in the epiphyseal growth plate: isocitrate lyase and malate synthase identified in mammalian cartilage.

Peroxisomes were identified in chondrocytes from all zones of the mammalian epiphyseal growth plate by using light microscopic techniques for the cytochemical demonstration of catalase, the marker enzyme for these organelles. Additional cytochemistry showed the presence of malate-synthase-positive structures within the chondrocytes. The latter enzyme, also associated with peroxisomes, is unique to the glyoxylate shunt, a metabolic pathway thought to be absent in vertebrate tissues. The glyoxylate cycle allows the net conversion of lipid to carbohydrate, i.e., gluconeogenesis. Biochemical studies on growth plate cartilage indicate that this tissue has the capacity to carry out cyanide-insensitive B-oxidation of fatty acids. The latter takes place in a nonmitochondrial compartment, most likely the peroxisomal compartment. Additionally, both of the unique enzymes associated with the glyoxylate cycle, i.e., isocitrate lyase and malate synthase, were also identified in a cell-free homogenate of this cartilage. These studies indicate that cartilage, a poorly vascularized tissue characterized by its low oxygen tension and anaerobic glycolysis, may have the capacity to convert lipid to carbohydrate, i.e., gluconeogenesis via the glyoxylate pathway. In this way, cartilage may be unique among mammalian tissues.

Animals↗
PubMed2000

Physical fitness of young women: carrying simulated patients.

An evaluation of physical fitness prior to employment appears to be mandatory for several occupations in order to protect the employee from overburdening and the employer from placing excess demands on the employee. One such occupation seems to be that of the field medical specialist who needs special physical strength since terrain conditions deny wheel-assisted transport of stretcher patients. The anthropometric and isometric force data of a total of 62 female and 48 male recruits for the medical service of the Bundeswehr were evaluated, together with their ability to carry a patient on a stretcher (weight = 14 kg) within a gymnasium. Initially the 'casualties' were simulated by sandbags weighing 60, 70, 80 and 90 kg each on stretchers; subsequently equivalent-weight water cans were used. The tests were administered at the beginning and at the end of the general Basic Military Training (BMT). While all males were able to carry the simulated 90 kg patient, only 22 out of 62 female recruits were able to do so at the beginning of BMT. At the end, the number had improved to 29 out of 55 women soldiers completing training. At the beginning of BMT 22.5% of the women soldiers were unable to rescue a simulated 70 kg patient; at the end of BMT the number had fallen to 18%. The isometric force values as measured revealed the hand grip strength as the best predictor for the capacity to carry simulated 90 kg patients. It is, therefore, suggested that a hand strength test be administered prior to field medical specialist training in order to channel unsuitable candidates into other training schemes.

Adult↗
PubMed1992

Properties of redox-inactivated bleomycins. In vitro DNA damage and inhibition of Ehrlich cell proliferation.

Blenoxane, bleomycin A2, bleomycin B2, and demethyl bleomycin A2 and products of their reactions with Fe2+ and oxygen were used to explore the relationship between their capacity to carry out in vitro DNA strand scission and their growth inhibitory activity against Ehrlich cells. Reaction of Fe2+, bleomycin and O2 in the absence of DNA decreased the subsequent effectiveness of various bleomycin congeners to degrade DNA in the presence of Fe2+ and oxygen. In comparison with controls, this loss of strand scission activity was not paralleled by equivalent decreases in growth inhibition. Demethyl bleomycin A2 retained full biological activity relative to bleomycin A2, despite being only 30% as effective as bleomycin A2 in its ability to cleave DNA in vitro. Prior reaction of bleomycins with Fe2+ did not alter their capacity to reduce oxygen or affect their ability to generate the activated intermediate which, for native bleomycin structures, is competent to cleave DNA in vitro.

Animals↗
PubMed1991

Population and development within the ecosphere: one view of the literature.

"Contemporary academic economists, unlike those of the nineteenth century, find that although population growth and density can have bad effects on development, these will only be severe with wrong economic policies. Technical advance and substitution in free markets avoid major difficulties, for example shortage of materials. But ecologists see the poor cutting trees for firewood, the rich pouring carbon in to the atmosphere, and doubt the capacity of the environment to absorb the effects of dense and growing populations and their present technologies. On both sides are distinguished scholars, whose writings cannot here be covered exhaustively, but only enough said for background to the question posed to demographers: Should this central population issue not be on our research agendas?"

Conservation of Natural Resources↗