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M Shlomchik

Publications and source records attributed to M Shlomchik.

8 recordsLinked to original sources
PubMed1991

Structure, map position, and evolution of two newly diverged mouse Ig VH gene families.

We have characterized two novel mouse VH gene families, VH3609N and VHSM7. These VH families have recently diverged from previously defined VH families. The VH3609N family, which may contain only one member in most inbred strains of mice, shares sequence similarity with the VHJ606 family and is located to the 3' side of VHJ606. VHSM7, with at least three members, is related to the VHJ558 family but maps 3' of VHJ558. These findings suggest that physical displacement of VH sequences may facilitate their subsequent divergence. During the early stages of VH gene family evolution that are exemplified by these new families, amino acid replacements have been selected against in frame-work regions and selected for in complementarity-determining regions. This pattern of nucleotide substitution appears to reflect evolutionary pressures to maintain germ-line VH diversity and, possibly, to select for new antibody specificities, as well as to select against mutations resulting in aberrant Ig. The classification of VH sequences with borderline similarity to previously defined VH families is discussed.

Amino Acid Sequence↗
PubMed1991

Making digoxin therapeutic drug monitoring more effective.

Digoxin is an important drug in the treatment of patients with either congestive heart failure or atrial arrhythmia. Because of its narrow therapeutic range, digoxin serum concentrations are commonly monitored in both inpatients and outpatients. However, with the costs of health care skyrocketing, there is debate whether such therapeutic drug monitoring (TDM) is cost-effective. To reduce the number of samples drawn too soon after a previous dose and in an effort to improve digoxin TDM at this teaching hospital, a new dosing and monitoring policy was initiated. This policy involved uniform digoxin dosing at 5 p.m. (1700 h) for all inpatients and serum drug measurements at 7 a.m. (0700 h) the next day. By coordinating the time of dosing to be greater than 12 h prior to serum digoxin analysis, the number of inappropriate digoxin serum determinations have been reduced. This new protocol has increased the effectiveness of the toxicology laboratory and enhanced the efficiency of the house staff. Other issues concerning digoxin TDM are also addressed. These findings can be generalized to all drugs that are monitored at any hospital and can result in a significant cost savings and decrease the time spent analyzing inappropriate data.

Adult↗
PubMed1990

Heavy-chain class switch does not terminate somatic mutation.

We studied the H-chain class switch rearrangement in four groups of clonally related B cell hybridomas, to test the hypothesis that class switch terminates somatic mutation in a B cell. Using switch region-specific probes in Southern blot analysis individual mu-gamma switch rearrangement events can be distinguished. We show that clonally related IgG-producing hybridomas that differ by mutations often share a common switch rearrangement. This indicates that class switch in these cells did not terminate somatic mutation.

Animals↗
PubMed1990

Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation.

The proximate cause of autoantibodies characteristic of systemic autoimmune diseases has been controversial. One hypothesis is that autoantibodies are the result of polyclonal nonspecific B cell activation. Alternatively, autoantibodies could be the result of antigen-driven B cell activation, as observed in secondary immune responses. We have approached this question by studying monoclonal anti-DNA autoantibodies derived from unmanipulated spleen cells of the autoimmune MRL/lpr mouse strain. This analysis shows that anti-DNAs, like rheumatoid factors (19), are the result of specific antigen-driven stimulation. In addition, correlation of sequences with fine specificity shows that: (a) somatic mutations can cause specificity for dsDNA and that such mutations are selected for; (b) arginine residues play an important role in determining specificity; and (c) anti-idiotypes that recognize the majority of anti-DNA are probably not specific for any one family of V regions.

Amino Acid Sequence↗
PubMed1987

Variable region sequences of murine IgM anti-IgG monoclonal autoantibodies (rheumatoid factors). II. Comparison of hybridomas derived by lipopolysaccharide stimulation and secondary protein immunization.

We have obtained the complete variable region mRNA sequences of 11 LPS-derived and 14 secondary immunization-derived monoclonal IgM anti-IgG antibodies (rheumatoid factors, RFs). A comparative analysis of these sequences showed that monoclonal RFs derived after polyclonal activation are structurally very similar to RFs derived after secondary protein immunization. This study was undertaken to evaluate the potential relationship between two previously described phenomena: (a) during a secondary response to a protein antigen, RF is produced in quantities that equal or exceed the immunogen-specific antibody; and (b) the frequency of B cells that make RF after polyclonal activation is quite high; 3-10%. It has been unclear whether LPS-stimulated cells that produce IgM anti-IgG that is detected by an in vitro assay are related to the cells that produce RF after in vivo stimulation. The similarity of the antigen receptors found in the two types of RF, however, suggests that most or all of the RF-producing B cells detected after LPS stimulation would also be stimulated during the secondary immune response. Thus, the presence of relatively large number of B cells that can make RF after nonspecific stimulation provides an explanation for the magnitude of RF production accompanying the secondary immune response.

Amino Acid Sequence↗