Therapeutic touch: can we trust the data?
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Complementary Therapies↗
Biomedical subjects
S Fish
Publications and source records attributed to S Fish.
Radical axillary dissection in the staging and treatment of breast cancer.
The results of 237 radical axillary dissections undertaken by one surgeon in patients with breast cancer were reviewed to evaluate the role of this procedure in staging and treatment. The accuracy of physical examination in detecting axillary metastases was 68%. With a policy of enforced shoulder immobilisation for 10 days postoperatively, the incidence of postoperative wound complications was 8%. There have been three axillary recurrences during a median follow-up period of 44 months (range 6-97 months). Late complications were assessed in 50 patients followed up for greater than 12 months. While eight patients complained of constant swelling of the arm, only three had a difference in arm circumference of greater than 3 cm and only one had persistent limitation of shoulder abduction. Radical axillary dissection ensures accurate clinical staging and provides excellent local control with few complications and without the need for axillary irradiation.
Axilla↗
Regulation of the immune response to peptide antigens: differential induction of immediate-type hypersensitivity and T cell proliferation due to changes in either peptide structure or major histocompatibility complex haplotype.
The immunodominant CD4 T cell epitope of the bacteriophage lambda cI repressor protein in several inbred mouse strains can be represented by a peptide encompassing amino acids 12-26. Here, we show that this peptide, and a variety of its sequence variants, can induce immediate-type hypersensitivity in mice. 12-26 variants that differ by as little as single amino acid residues deviate greatly in their ability to induce hypersensitivity. Further, differences in major histocompatibility complex class II alleles appear to be as influential as changes in peptide structure in determining whether hypersensitivity is developed. The ability of a given peptide-class II combination to induce hypersensitivity correlates with production of peptide-specific antibody, but not with ability or inability to induce a T cell proliferative response. Administration of anti-interleukin 4 (IL-4) mAb prevents the development of hypersensitivity, and analysis of cytokine production by T cell hybridomas derived from peptide-immunized mice suggests that whether a given peptide-class II combination can induce hypersensitivity depends on its ability to induce IL-4 production. The data demonstrate that changes in the nature of the epitope(s) recognized by the CD4 T cell population can result in qualitative differences in the response elicited in this population, ultimately leading to dramatic quantitative and qualitative variations in the effector phase of the immune response.
Amino Acid Sequence↗
Different epitope structures select distinct mutant forms of an antibody variable region for expression during the immune response.
Antibody variable (V) regions that initially differ from one another by only single amino acid residues at VH-D and D-JH segment junctions (termed canonical V regions) can be elicited in strain A/J mice by three different haptens. Among such V regions an amino acid substitution due to somatic mutation is recurrently observed at VH CDR2 position 58, regardless of which of these haptens is used for immunization. This substitution confers upon a canonical V region a generic increase in affinity for all the haptens. Conversely, the type of amino acid substitution at VH position 59 resulting from somatic mutation that is recurrently observed among such V regions changes with the eliciting hapten, in a manner that correlates directly with the cognate affinity increases (or decreases) for hapten conferred by the observed substitutions. This small subregion of VH CDR2 therefore plays a major role in determining both affinity and specificity for antigen. The data confirm that affinity for antigen is of pivotal importance in determining the degree of selection of different mutant forms of a V region. Moreover, during an immune response a sufficiently diverse mutant repertoire can be generated from a single canonical V region to allow adaptation to increase affinity for three different epitopes.
Amino Acid Sequence↗
Alzheimer's: finding hope in despair.
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Adult↗
Hydroxyamphetamine mydriasis in normal subjects and hydroxyamphetamine mydriasis in Horner's syndrome.
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Horner Syndrome↗
Serious poisonings among older adults: a study of hospitalization and mortality rates in Massachusetts 1983-85.
We analyzed poisoning-related hospitalization and mortality rates among older adults living in Massachusetts during 1983-85. While poisoning-related hospitalization rates of individuals greater than or equal to 60 years were near the state average, death rates for men greater than or equal to 70 years and for women over 60 were higher than those of younger individuals. Medications and carbon monoxide were commonly implicated agents in these poisoning deaths. Older adults are more vulnerable to death from a poisoning than are younger age groups.
Aged↗
Molecular analysis of original antigenic sin. I. Clonal selection, somatic mutation, and isotype switching during a memory B cell response.
To determine how the memory B cell population elicited to one epitope might be used in immune responses to other, structurally related epitopes, we explored the phenomenon of original antigenic sin. Strain A/J mice reproducibly respond to immunization with p-azophenylarsonate (Ars) by production of anti-Ars antibodies encoded predominantly by a single VH gene segment (VHIdCR). The structural analogue of Ars p-azophenylsulfonate (Sulf) fails alone to elicit such V regions, but can do so in A/J mice previously immunized with Ars, providing a means to specifically examine B cells capable of responding secondarily to a crossreactive antigen (i.e., memory cells). VHIdCR-expressing hybridomas were derived from the Ars-primed, Sulf-boosted original antigenic sin response of A/J mice at various times after Ars priming, and the properties of the antibodies they express and the structure of the genes encoding these antibodies were characterized. The data obtained support the following conclusions: (a) The Ars-induced memory B cell population capable of being crossreactively stimulated by Sulf is largely formed from a small fraction of all B cells participating in the anti-Ars primary response that express somatically mutated V regions; (b) the antibody repertoire and clonal composition of this population are stable over long periods of time; (c) memory B cells are capable of clonal expansion in the absence of a high rate of V gene somatic mutation; (d) the activation requirements for clonal selection of memory, versus naive B cells appear to differ; and (e) a major fraction of Ars-induced memory B cells express either IgM or IgG3 prior to and during the initial stages of the sin response.
Animals↗
An endogenous peptide that induces long-term blood pressure elevation.
A peptide was recently isolated from the blood of spontaneously hypertensive (SH) rats that stimulated an increase of calcium uptake by vascular tissue in vitro. In the present study normotensive rats were given nanomolar amounts of this peptide by intravenous or picomolar amounts by intracerebral injection and the effect on blood pressure was recorded. Injection of the peptide into the circulation had no significant effect on the elevation of blood pressure. By comparison, the injection of the compound into the third ventricle of the brain resulted in the elevation of blood pressure to hypertensive levels. The blood pressure response was characterized by a prolonged period of onset with maximal elevation observed several days after the beginning of treatment. Subsequently, the increase in blood pressure was well maintained with significant elevation noted days following the cessation of treatment.
Animals↗
Influence of the macromolecular form of a B cell epitope on the expression of antibody variable and constant region structure.
We investigated the influence of the macromolecular form of an epitope on the structure of antibody variable and constant regions expressed by the B cell population participating in an immune response to that epitope. Hybridomas were constructed from strain A/J mice undergoing either primary or secondary immune responses to p-azophenylarsonate conjugated to Brucella abortus (Ars-Bruc). We determined the sequences of the V genes expressed by hybridomas selected on the basis of expression of a single VH gene segment known to encode a large family of anti-Ars antibodies. These sequences were compared with the sequences of V genes expressed by a previously characterized panel of hybridomas isolated in the same way during the primary and secondary responses of A/J mice to Ars-KLH. The repertoire of Ars-specific V domains expressed among primary and secondary hybridomas elicited with these two forms of Ars were similar, as were the differences between primary and secondary V region somatic mutational alteration and affinity for Ars. In contrast, predominant expression of IgG2 anti-Ars antibodies was elicited in the secondary Ars-Bruc response, whereas secondary anti-Ars antibodies elicited with Ars-KLH are predominantly IgG1. Thus, differences in the macromolecular form of Ars clearly influence the isotypic profile of the anti-Ars response, but the expression, diversification, and selection of V domains elicited with this hapten are not greatly affected by such differences. Our results suggest that while isotype regulation is highly perceptive of the macromolecular form of a B cell epitope, V region regulation is primarily influenced by the molecular structure of that epitope.
Animals↗
Binding and processing of fibrinogen by rabbit hepatocytes.
We describe a specific fibrinogen-hepatocyte interaction. Rabbit 125I-labeled fibrinogen (125I-FGN) was incubated at 4 degrees C with suspensions of rabbit hepatocytes (approximately 1 X 10(6) cells/ml). Bound ligand was separated from free by centrifugation of cells through oil and quantitated by gamma-scintillation counting. Specific binding, determined by subtraction of nonspecific binding in the presence of 8 mM EDTA from total binding in the presence of 2 mM CaCl2, required 3 h to plateau and represented approximately 70% of total binding. Specific binding was calcium-dependent and was negligible in buffer containing 2 mM MgCl2. Half-maximal saturation occurred at approximately 30 nM 125I-FGN with approximately 480,000 molecules/cell at saturation. Dilution experiments revealed comparable affinities for labeled and unlabeled fibrinogen. Total binding was irreversible as determined by addition of excess unlabeled fibrinogen or EDTA. Specific binding of 25 nM 125I-FGN was inhibited, in a concentration-dependent fashion, by unlabeled fibrinogen or fibrinogen fragment D95 (Mr = 95,000), but not by fibrinogen fragment E or Arg-Gly-Asp-containing peptides. Unlabeled fibrinogen (3.1 microM) completely abolished specific binding, whereas greater than 80% inhibition was achieved with 10 microM fragment D95. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography of 125I-FGN bound in the presence of calcium demonstrated disappearance of A alpha chains with formation of products of Mr greater than 200,000; EDTA or unlabeled fibrinogen prevented fibrinogen processing. These data describe a unique fibrinogen-hepatocyte interaction which differs considerably from the platelet-fibrinogen interaction, especially with regard to the processing of the fibrinogen molecule.
Animals↗
Catabolic properties of aglycofibrinogen synthesized by tunicamycin-treated human hepatoma (HepG2) cells and rabbit hepatocytes.
Human hepatoma cell (HepG2) or rabbit hepatocyte monolayers were incubated with [35S]methionine in presence or absence of tunicamycin, a potent inhibitor of asparagine-linked glycosylation. The 35S-labeled nonglycosylated and control fibrinogens purified from the media were used to evaluate the influence of the oligosaccharide on the catabolic properties of this glycoprotein. Plasmin, pronase, cathepsin D or cathepsin B each degraded the nonglycosylated and control fibrinogens similarly, as evidenced by the release of trichloroacetic acid-soluble radioactivity and by SDS-polyacrylamide gel electrophoresis and autoradiography of plasmic digests. Nonglycosylated and control fibrin clots also showed no differences in susceptibility to plasmic digestion. The two forms of fibrinogen demonstrated the same plasma half-life in rabbits. These data indicate that the oligosaccharide does not influence the proteolytic stability or the in vivo plasma survival of fibrinogen, and suggest that other biochemical determinants may influence the catabolic properties of this molecule.
Animals↗
Neplanocin A. Actions on S-adenosylhomocysteine hydrolase and on hormone synthesis by GH4C1 cells.
We have investigated the biochemical actions of Neplanocin A (Nepl A), a carbocyclic adenosine analog, on purified calf liver S-adenosylhomocysteine hydrolase and in the GH4C1 strain of functional rat pituitary cells. Addition of 1 mol of Nepl A/2 mol of S-adenosylhomocysteine hydrolase subunit led to rapid and complete inactivation. Concomitant with inactivation, half of the enzyme-bound NAD was reduced and adenine was released stoichiometrically from Nepl A. In GH4C1 cells Nepl A caused a dose-dependent rapid (within 5 min) and irreversible inactivation of S-adenosylhomocysteine hydrolase and concomitant increase in intracellular S-adenosylhomocysteine. In cells treated with Nepl A for 4-5 days, methylation of DNA cytosine was depressed approximately 50%, and the level of cytoplasmic prolactin mRNA was elevated 2-fold. While acute (30 min) release of prolactin from intracellular stores was unaffected, Nepl A acted in a dose- and time-dependent manner to increase the production of both prolactin and growth hormone, the two hormones synthesized and secreted by GH4C1 cells. The lowest effective dose was 0.12 microM, the concentration required to decrease S-adenosylhomocysteine hydrolase activity by 50%. By 4-7 days the production of both hormones in Nepl A-treated cells was increased 2-3 times above control. The action on hormone production persisted for at least 7 days after removal of Nepl A from the culture medium. We conclude that Nepl A inhibits S-adenosylhomocysteine hydrolase, raises cellular S-adenosylhomocysteine, decreases bulk DNA methylation, and increases hormone synthesis in GH4C1 cells.
Adenosine↗
Nursing Mirror clinical forum 7. Hormone replacement therapy.
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Adult↗
Sympathetic nervous system and adrenal medullary responses to ischemic injury in mice.
Acute, severe injury is frequently attended by hypotension, hypothermia, and decreased metabolic rate despite elevated urine and plasma catecholamine levels. Because the combination of sympathetic nervous system (SNS) suppression and adrenal medullary stimulation documented in several other situations could account for these observations, SNS and adrenal medullary function were examined independently in mice in the hindlimb ischemia model of acute injury. SNS activity was assessed by the measurement of [3H]norepinephrine (NE) turnover in heart and adrenal medullary secretion by depletion of adrenal catecholamine content. In nine separate experiments during the first 10 h after termination of a 2.5-h period of hindlimb ischemia, cardiac NE turnover was reduced an average of 23% (P less than 0.05) in injured mice. At the same time, adrenal catecholamine content fell 37% (P less than 0.05) in injured animals but not in controls. In contrast to the acute reaction, SNS activity in mice surviving 3 days was 59% greater than in controls. Thus, the reduction in NE turnover and depletion of adrenal catecholamine content suggest that SNS suppression and adrenal medullary stimulation constitute the acute sympathoadrenal response in this model of severe injury. Because survival within the first 24 h after injury was decreased in adrenalectomized mice despite glucocorticoid treatment, adrenal medullary catecholamines may contribute to survival in severely injured animals. Furthermore, because the SNS plays an important role in the regulation of blood pressure and heat production, the diminution in SNS activity in the hours after injury may contribute to posttraumatic hypotension and hypometabolism.
Adrenal Medulla↗
S-Adenosylhomocysteinase: mechanism of inactivation by 2'-deoxyadenosine and interaction with other nucleosides.
S-Adenosylhomocysteinase (SAHase), a tetrameric enzyme, is inactivated by 2'-deoxyadenosine (2'dAdo) in a time-dependent process [Hirshfield, M. S. (1979) J. Biol. Chem. 254, 22-25]. It has been proposed that inactivation involves oxidation of 2'dAdo at C-3' by enzyme-bound nicotinamide adenine dinucleotide (NAD), subsequent proton abstraction at C-2', and elimination of adenine. This results in irreversible formation of enzyme-bound NADH and of adenine (Ade) and inactivation [Abeles, R. H., TAshjian, A. H., Jr., & Fish, S (1980) Biochem. Biophys. Res. Commun. 95, 612-617]. It has now been established that upon inactivation of SAHase with deoxy[2'(R)-3H]adenosine, 3H2O is formed. This is consistent with the proposed mechanism and of 3H2O release shows that maximally two of the four subunits participate in the reaction that results in 3H2O release. Reaction of SAHase with 2'dAdo results in reduction of two of the enzyme-bound NAD molecules. However, all four NAD molecules can be reduced by NaBH4, but only two are reduced to C-4 NADH. When the enzyme is inactivated with adenine-labeled 2'dAdo, radioactivity corresponding to 0.5-1.0 mumol of 2'dAdo binds tightly per micromole of subunit. This radioactive material is not removed from the enzyme by extensive dialysis but can be displaced by unlabeled 2'dAdo or Ade. After denaturation of the complex, radioactive material is released. Of this material 80-90% is adenine and less than 1% 2'dAdo. 2'dAdo also binds tightly to the enzyme reduced with NaBH4. Upon denaturation mostly adenine (80-90%) is released. Reaction of [2'-3H]2'dAdo with enzyme reduced with NaBH4 does not result in 3H2O formation. We conclude that the enzyme catalyzes the release of adenine from 2'dAdo by two mechanisms: One involves formation of 3'keto-2'dAdo and subsequent elimination of adenine. The other does not involve oxidation of 2'dAdo and probably is a hydrolytic process. It is proposed that the ability of the enzyme to carry out the hydrolytic process is a direct consequence of the manner in which 2'dAdo as well as the normal substrate binds to the enzyme, i.e., hydrogen-bond interaction of the protein with the adenine moiety and distortion of the ribose ring. When adenine-labeled adenosine is added to the enzyme, radioactivity corresponding to 0.5 mumol/mumol of subunit is associated with the protein after gel filtration. Of the radioactive material bound to the protein, 20% is adenine, 15% is adenosine, and the remaining radioactivity is present in unidentified compounds. The adenine bound to the enzyme does not participate in the catalytic process, and we conclude that it is bound to two of the subunits that do not participate in catalysis. Possible, these two subunits have a regulatory function. SAHase probably consists of two nonequivalent pairs of subunits. Only one pair participates in catalysis, but all four subunits probably bind Ado and 2'dAdo. We have confirmed the fact that the carbocyclic analogue of adenosine inactivates SAHase [Guranowski, A., Montgomery, J. A., 110-115]...
Adenine↗
Succinylcholine for endotracheal intubation.
In the emergency department at Hennepin County Medical Center, succinylcholine has been used to assist difficult intubations since March 1, 1979. In this report, the first 48 cases are reviewed. In these 48 patients, complete relaxation allowing endotracheal intubation was achieved in 42. Forty of the 42 patients intubated suffered no adverse effects. One patient vomited, delaying intubation, and another developed transient asystole. Six of 48 patients were not successfully intubated after succinylcholine; five of these six subsequently required cricothyrotomy. Inadequate dose, improper technique of administration, foreign material obscuring airway, and idiosyncratic reactions were thought to be reasons for failure. When properly administered, succinylcholine can be used to facilitate difficult intubations in the emergency department with an acceptable incidence of adverse effects or failures.
Adult↗