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Biomedical subjects

C Steinberg

Publications and source records attributed to C Steinberg.

At least 19 recordsLinked to original sources
PubMed1998

Mismatch repair co-opted by hypermutation.

Mice homozygous for a disrupted allele of the mismatch repair gene Pms2 have a mutator phenotype. When this allele is crossed into quasi-monoclonal (QM) mice, which have a very limited B cell repertoire, homozygotes have fewer somatic mutations at the immunoglobulin heavy chain and lambda chain loci than do heterozygotes or wild-type QM mice. That is, mismatch repair seems to contribute to somatic hypermutation rather than stifling it. It is suggested that at immunoglobulin loci in hypermutable B cells, mismatched base pairs are "corrected" according to the newly synthesized DNA strand, thereby fixing incipient mutations instead of eliminating them.

Adenosine Triphosphatases↗
PubMed1998

Meiotic synapsis in the absence of recombination.

Although in Saccharomyces cerevisiae the initiation of meiotic recombination, as indicated by double-strand break formation, appears to be functionally linked to the initiation of synapsis, meiotic chromosome synapsis in Drosophila females occurs in the absence of meiotic exchange. Electron microscopy of oocytes from females homozygous for either of two meiotic mutants (mei-W68 and mei-P22), which eliminate both meiotic crossing over and gene conversion, revealed normal synaptonemal complex formation. Thus, synapsis in Drosophila is independent of meiotic recombination, consistent with a model in which synapsis is required for the initiation of meiotic recombination. Furthermore, the basic processes of early meiosis may have different functional or temporal relations, or both, in yeast and Drosophila.

Animals↗
PubMed1998

Molecular mechanisms involved in receptor editing at the Ig heavy chain locus.

In receptor editing, a phenomenon that has recently come to light and into favor, a rearranged VDJ or VJ gene segment encoding a variable region of an Ig chain is replaced by another. In this commentary, the molecular mechanisms involved in the editing process are examined in some detail. Editing is most likely mediated by the same V(D)J recombinase activity responsible for the formation of the original VDJ or VJ segment. An embedded heptamer, which is present near the 3' end of many VH elements, is used as the recombination signal sequence at the Ig heavy chain locus. It has been postulated that the mediation of receptor editing is the evolutionary force maintaining the embedded heptamer. Some of the evidence for and against this hypothesis is discussed.

Animals↗
PubMed1997

Critical test of hot spot motifs for immunoglobulin hypermutation.

In hypermutation at the immunoglobulin loci, some bases are much more mutable than others. The increased mutability of the hot spots has been attributed to their being embedded in short sequence motifs. Among the suggested motifs are palindromes, TAA and RGYW (i.e. A/G G C/T A/T). We have tested these proposed motifs in a transfection system in vitro, which ordinarily uses the hypermutable stop codon TAG. The stop codon TAA is not hypermutable in our system, even when embedded in the pentamer and hexamer palindromes TAATA and ATTAAT; in fact, the revertants isolated were due to deletions. Single or double base changes in an RGYW motif containing a hypermutable stop codon result in a reduction of one order of magnitude or more in point mutation frequency. When the nonamer GACTAGTAT, which includes the same RGYW motif, was moved over hundred base pairs upstream, hypermutability was reduced by an order of magnitude. Thus, while RGYW apparently is a hypermutability motif, it cannot be the sole determinant of mutability.

Animals↗
PubMed1996

Efficacy of buspirone in smoking cessation: a placebo-controlled trial.

Buspirone, a non-sedating anxiolytic, has yielded contradictory results in smoking cessation pilot studies and trials. We tested buspirone (n = 51) versus placebo (n = 49) in a placebo-controlled, double-blind trial of smoking cessation. Survival analyses were performed with use of strict abstinence criteria for efficacy (carbon monoxide levels < or = 8 ppm; no self-reported slips to smoking). No treatment differences were observed between active and placebo groups. There were also no differences among "anxiety" level groups formed post hoc from high versus low, pre-quit anxiety test scores. A number of withdrawal symptoms increased significantly after subjects quit smoking for both the active drug and placebo groups, but these symptoms were not relieved by treatment. There appears to be little evidence that buspirone is effective in smoking cessation or in the relief of withdrawal associated with cessation in a general sample. Selecting for generalized anxiety or anxiety related to cessation is suggested for future testing.

Adult↗
PubMed1996

Affinity maturation and class switching.

Affinity maturation and class switching of antibodies are temporally, but not mechanistically, related processes. The basis of affinity maturation is the selection, in the germinal centers, of antibodies that bind the antigen better. Early in an immune response, the selection is from the primary repertoire; later, it is from mutants generated by hypermutation at the immunoglobulin loci. Recently, the door has been opened for the study of the molecular mechanism of hypermutation, which is expected to make a major contribution to general biology. Class switching has been studied in the past for its obvious clinical importance, but also at the basic level of DNA recombination. Progress in understanding class switching has been trailing the progress made in V(D)J recombination, but new in vitro systems and gene-targeted mice are closing the gap.

Animals↗
PubMed1996

Hemodynamic effects of carcinine in the anesthetized, instrumented, open-chest rat.

OBJECTIVE: To determine the pharmacologic effect of carcinine (beta-alanyl histamine), a compound that has been shown to be a positive inotrope in the isolated perfused guinea pig heart, on hemodynamics in an intact, anesthetized rat model. DESIGN: Prospective dose-response study. SETTING: Animal research laboratory of a university medical center. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Eight male Sprague-Dawley rats were anesthetized with ketamine and midazolam. A tracheostomy tube, and central venous and arterial catheters were inserted. An electromagnetic flow probe was placed around the ascending aorta through a right thoracotomy for measurement of cardiac output. Dosages of carcinine from 0 to 10 mg/kg were infused intravenously over 30 secs, and hemodynamic parameters were measured at baseline and at peak effect. MEASUREMENTS AND MAIN RESULTS: At dosages of 3 mg/kg and 10 mg/kg, carcinine significantly reduced mean arterial blood pressure, systemic vascular resistance index, and left ventricular stroke work index. There was no carcinine-induced effect on heart rate, central venous pressure, cardiac index, or stroke index. Lower doses of carcinine had no effect on the measured variables. CONCLUSIONS: In this open-chest rat model, the primary pharmacologic effect of carcinine is systemic arterial vasodilation. A negative inotropic effect is suggested. Hypotension is secondary to these carcinine-induced actions. These results differ from results previously published using an isolated guinea pig heart preparation. Our model suggests that efforts to develop a clinical role for carcinine should exploit vascular rather than cardiac effects. Species differences may also play a role.

Anesthesia↗
PubMed1996

Role of bronchoalveolar lavage in hospitalized pediatric patients.

Bronchoalveolar lavage (BAL) has been shown to be a rapid, relatively safe, and relatively noninvasive diagnostic procedure. Theoretically, BAL can be performed on all children hospitalized for pneumonia resistant to oral antibiotics, though practically and economically, this is not feasible. A 1-year retrospective review was conducted to define a cost-effective role for BAL in the management of hospitalized children with resistant pneumonia. The data revealed identification of at least one pathogen in 87% of sputum samples and in 95% of BAL specimens. Sputum samples provided the same information as the more invasive BAL technique in 60% of patients who had both sputum and BAL obtained for culture. Recommendations are made for the use of BAL as a diagnostic tool in the hospitalized child with resistant pneumonia.

Adolescent↗
PubMed1995

Efficacy of a nicotine nasal spray in smoking cessation: a placebo-controlled, double-blind trial.

Laboratory trials have demonstrated the efficacy of nicotine replacement in smoking cessation but absolute success rates are low. For many, nicotine gum is hard to use and transdermal nicotine is slow-acting and passive. A new, faster-acting nicotine nasal spray (NNS) can provide easily self-administered relief from cigarette withdrawal. The NNS was tested for safety and efficacy in smoking cessation. Two hundred and fifty-five smokers were randomized to NNS or a piperine placebo. Drug use was limited to 8-32 doses/day for 6 months. Subjects were tested while smoking and at post-cessation daily (week 1) with follow-up at weeks 2, 3, 6 and at 3 months, 6 months and 1 year. Continuous abstinence analyses (CO < or = 8 ppm; no slips) showed that NNS significantly enhanced success rates over placebo overall (p < 0.001) and at all test intervals. Differences at key intervals between active and placebo were: 63% vs. 40% (day 5), 51% vs. 30% (week 3), 43% vs. 20% (6 weeks), 34% vs. 13% (3 months), 25% vs. 10% (6 months) and 18% vs. 8% (1 year). Side effects were common but tolerable. Cotinine measures showed that replacement of nicotine approximated 30% of smoking levels. Hazard functions revealed relapse risks peaked at day 1, day 5 and 3 weeks for strict abstinence. It is concluded NNS is safe, efficacious and a viable alternative treatment for smoking cessation.

Administration, Intranasal↗
PubMed1994

Pharmacokinetics of cardiovascular drugs in children. Inotropes and vasopressors.

Infants and children with congenital or acquired heart disease and children with systemic disease often require pharmacological support of their failing circulation. Catecholamines may serve as inotropic (enhance myocardial contractility) or vasopressor (elevate systemic vascular resistance) agents. Noncatecholamine inotropic agents, such as the cardiac glycosides or the bipyridines, may be used in place of, or in addition to, catecholamines. Developmental changes in neonates, infants and children will affect the response to inotropic or pressor therapy. Maturation of the gastrointestinal tract, liver and kidneys alters absorption, metabolism and elimination of drugs, although there are few clear examples of this among the vasoactive drugs considered in this review. Changes in body composition affect the volume of distribution (Vd) and clearance (CL) of drugs. Developmentally based pharmacodynamic differences also affect the responses to both therapeutic and toxic effects of inotropes. These pharmacodynamic differences are based in part upon developmental changes in myocardial structure, cardiac innervation and adrenergic receptor function. For example, the immature myocardium has fewer contractile elements and therefore a decreased ability to increase contractility; it also responds poorly to standard techniques of manipulating preload. Available data suggest that dopamine and dobutamine pharmacokinetics are similar to those in adults. Wide interindividual variability has been noted. A consistent relationship between CL and age has not been demonstrated, although one investigator demonstrated an almost 2-fold increase in the CL of dopamine in children under the age of 2 years. The CL of dopamine appears to be reduced in children with renal and hepatic failure. Fewer data are available regarding the pharmacokinetics of epinephrine (adrenaline), norepinephrine (noradrenaline) and isoprenaline (isoproterenol). Digoxin pharmacokinetics have been extensively evaluated in infants and children. The Vd for digoxin is increased in infants and children. Children beyond the neonatal period display increased CL of digoxin, approaching adult values during puberty. Although it was previously thought that children both needed and tolerated higher serum concentrations of digoxin than adults, more recent studies indicate that adequate clinical response can be achieved with serum concentrations similar to those aimed for in adults, with decreased toxicity. Evaluation of studies of digoxin pharmacokinetics is complicated by the presence of an endogenous substance with digoxin-like activity on radioimmunoassay. Limited studies of amrinone pharmacokinetics in infants and children indicate a dramatically larger Vd, and a decreased elimination half-life in older infants and children, compared with values observed in adults.

Animals↗
PubMed1993

The relevance of fat content in toxicity of lipophilic chemicals to terrestrial animals with special reference to dieldrin and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Lipophilic chemicals such as chlorinated hydrocarbon insecticides and other persistent chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are fat soluble chemicals and are readily bioconcentrated in animal fat depots. The modifying role of the body fat content in the toxicity of chlorinated cyclodiene insecticides to insects and in the toxicity of TCDD to different mammals was investigated. The single oral acute 30-day LD50 data of TCDD in different mammals are presented and correlated with their total body fat content. A two linear regression equation with log/log values was obtained. It is concluded that the storage of TCDD and other related lipophilic and persistent chemicals in lipids of organisms is, in a sense, a detoxication mechanism by which the compounds are removed from sites of action and/or receptors. Therefore, terrestrial organisms such as insects and mammals with higher total body fat content can accumulate and tolerate higher chlorinated hydrocarbon insecticide and TCDD doses than organisms with lower fat content. The different sensitivity of mammals of various species, strains, body weight, sex, age, etc. to acute toxicity of TCDD and related lipophilic persistent chemicals can mainly be explained by differences in total body fat content.

Adipose Tissue↗
PubMed1992

Measurements of central blood vessels in infants and children: normal values.

In order to provide physicians interpreting vascular radiographic studies with normal data regarding central blood vessel size in children and to facilitate the design and adaptation of intravascular devices for pediatric use, we measured lengths and diameters of central blood vessels in 141 radiographic studies in 136 children. The diameters of the following vessels were determined: right and left internal jugular veins and common carotid arteries; the inferior vena cava and the descending thoracic aorta; right and left iliac veins; and right and left femoral veins and arteries. In addition, the lengths of the inferior vena cava and the descending aorta were also determined. Blood vessel dimensions were highly correlated with age, height, weight, and body surface area. The linear regression equations for each measured dimension against age, weight, height, and surface area are provided, along with a table of predicted vessel size as a function of age.

Adolescent↗
PubMed1992

What limits affinity maturation of antibodies in Xenopus--the rate of somatic mutation or the ability to select mutants?

Although the Xenopus immunoglobulin heavy chain locus is structurally and functionally similar to mammalian IgH loci, Xenopus antibodies are limited in heterogeneity, and they mature only slightly in affinity during immune responses. During the antibody response of isogenic frogs to DNP-KLH, mu and upsilon cDNA sequences using elements of the VH1 family were cloned, sequenced and compared with germline counterparts. There were zero to four mutations per sequence, mostly single base substitutions, in the framework and CDRs 1 and 2 of VH. No mutations were found in JH. Since the point mutation rate was only 4- to 7-fold lower than that calculated for mice, affinity maturation does not seem to be limited by mutant availability. Because of a relatively low ratio of replacement to silent mutations in the CDRs and a very high ratio of GC to AT base pairs altered by mutation, it is suggested that the problem results from the absence of an effective mechanism for selecting mutants, which in turn might be related to the absence of germinal centers in Xenopus.

Amino Acid Sequence↗
PubMed1992

Transient complete heart block following percutaneous balloon pulmonary valvuloplasty: treatment with systemic corticosteroids.

Balloon pulmonary valvuloplasty is a safe and effective treatment for congenital pulmonic valve stenosis. This report describes a child who developed complete atrioventricular (AV) block following balloon pulmonary valvuloplasty. The child was treated with a 10-day course of systemic corticosteroids. The heart block gradually resolved during the first week following the procedure and has not recurred. Heart block is a known complication of right heart catheterization and has been described following balloon pulmonary valvuloplasty. Systemic corticosteroids have been used to treat AV block of various etiologies and may have contributed to the child's recovery in this case.

Catheterization↗
PubMed1991

QSAR for organic chemical bioconcentration in Daphnia, algae, and mussels.

Prediction of the bioconcentration of organic chemicals from water by aquatic organisms has important applications in the management of hazardous chemicals. This study gives a compilation of bioconcentration factors on a wet weight basis (BCFw) of 52 organic chemicals by Daphnia magna from aqueous solution. The bioconcentration factors for the chemicals in Daphnia were successfully correlated with their n-octanol/water partition coefficients (log Kow) using a linear regression analysis. In addition to the ordinary least-square regression technique, the geometric mean regression technique is also used because this takes into account deviations in Kow values. Both results show that the Kow value of a chemical is a good predictor of the BCF in Daphnia. The BCF-Kow relationships between Daphnia, algae (Chlorella), and mussels (Mytilus edulis) are compared with each other.

Animals↗