Plasma exchange in the long-term management of Waldenstr?m's macroglobulinemia.

Two patients with Waldenström''s macroglobulinemia (WM), which had become resistant to cytotoxic drugs, were treated for features of the hyperviscosity syndrome by repeated plasma exchange with the continuous-flow blood-cell separator over periods of 36 and 28 months, respectively. After four initial weekly plasma exchanges the procedure was carried out every 4 to 6 weeks and both patients tolerated it well. Relative viscosity of the serum was maintained within the normal range in one patient, and both patients remained free of symptoms of the hyperviscosity syndrome. The results suggest that treatment of WM by long-term "maintenance" plasma exchange alone should be considered in any patient with complications due to chemotherapy or whose disease fails to respond to chemotherapy.     

Clinical Studies of Neuropathy due to Macroglobulinemia (Waldenstr?m's Syndrome)

A case of severe neuropathy due to macro-globulinemia is reported with clinical, biochemical and electrophysiological studies. The clinical picture was that of a severe, symmetrical polyneuropathy of a sensory-motor type with increased protein in the CSF. Sedimentation rate was increased and a sharp rise was found in the globulin fractions on plasma electrophoresis. Immuno-assays of CSF showed increases of albumin, transferrin and gamma globulin. Blood chromosome studies were normal. EMG showed neuromuscular atrophy. Nerve conduction times were prolonged. These studies are compatible with a neuropathy of an allergic or metabolic nature. Macro-globulinemia of Waldenström should be considered in the differential diagnosis of obscure neuropathies.     

Interaction of human Waldenstr?m's IgM proteins with guinea pig and human complement.

The activity of purified human Waldenstr?m's IgM protein to fix complement of human and guinea pig origins was compared at different temperatures using the polystyrene latex particle-adsorption method. It was shown that the interaction of the IgM proteins with complement differed depending on the source of complement and that a pronounced heterogeneity in complement-fixing activity was observed among the IgM proteins when tested with guinea pig complement. Thus, by the use of guinea pig complement, six human IgM proteins examined were classified roughly into two groups, one having a high and the other a low activity at 3 C as well as at 37 degrees C. With human complement, five proteins showed a rather uniform activity at 37 degrees C. However, there was one protein with no detectable activity, suggesting the presence of non-complement-fixing protein in the IgM class. All the six proteins showed no significant activity with human complement at 3 C. No antigenic difference has been found as yet in the Fc or Cmu2 region among these IgM proteins examined.     

Structural studies of the asparagine-linked sugar chains of two immunoglobulin M's purified from a patient with Waldenstr?m's macroglobulinemia

The structures of the sugar chains present in two human monoclonal IgM molecules purified from the serum of a patient with Waldenstr?m's macroglobulinemia have been determined. The asparagine-linked sugar chains were liberated as oligosaccharides by hydrazinolysis and labeled by reduction with NaB3H4 after N-acetylation. Their structures were studied by serial lectin column chromatography and sequential exoglycosidase digestion in combination with methylation analysis. These two IgM's were shown to contain almost the same sugar chains. The sugar chains were a mixture of a series of high-mannose-type and biantennary complex-type oligosaccharides. The complex-type oligosaccharides contain Man alpha 1----6(+/- GlcNAc beta 1----4)(Man alpha 1----3)Man beta 1----4GlcNAc beta 1----4(Fuc alpha 1----6)GlcNAc as their core and GlcNAc beta 1----, Gal beta 1----4GlcNAc beta 1---- and Neu5Ac alpha 2----6Gal beta 1----4GlcNAc beta 1---- groups in their outer chain moieties.     

A Waldenstr?m's macroglobulin with anti-G3m(b1) antibody activity.

A human monoclonal macroglobulin (IgM, K) from a patient (KI) with Waldenstr?m's macroglobulinemia was shown to have antibody activity against a human IgG (Gm) allotype. In hemagglutination tests, only one anti-D serum with G3m(b0b1) reacted with macroglobulin KI. Antiglobulin specificity of macroglobulin KI was determined to be an anti-G3m(b1) antibody by hemagglutination inhibition tests. Fab fragments from macroglobulin KI could react with human IgG3 protein possessing G3m(b1), but Fc fragments could not react. Gm phenotype in IgG isolated from serum KI was determined to be Gm(a,z,g,b0,s,t,u). This is the first report of a Waldenstr?m's macroglobulin with antiglobulin specificity against a Gm allotype.     

Redefining disease? The nosologic implications of molecular genetic knowledge

How will developments in genetic knowledge affect the classification of disease? Leaders in genetics have suggested that knowledge of the role of genes in disease can determine nosology. Diseases might be defined by genotype, thus avoiding the limitations of more empirical approaches to categorization. Other commentators caution against disease definitions that are detached from the look and feel of disease, and argue for an interplay between genotypic and phenotypic information. Still others attribute nosologic change to social processes. We draw on an analysis of the scientific literature, our conversations with genetics clinicians, and reviews of patient organization Web sites to offer a revised interpretation of the nosologic implications of molecular genetic knowledge. We review the recent histories of three diseases--hemophilia, Rett syndrome, and cystic fibrosis--to argue that nosologic change cannot be explained by either biologic theories of disease etiology or sociologic theories of social tendencies. Although new genetic information challenges disease classifications and is highly influential in their redesign, genetic information can be used in diverse ways to reconstruct disease categories and is not the only influence in these revisions. Ironically, genetic information is likely to play a central role in producing a new, but still empirical, classification scheme.     

The prognosis of latent tuberculosis: can disease be predicted?

In humans, Mycobacterium tuberculosis persists for long periods in a clinically latent state, creating a huge reservoir of 'silent' tuberculosis (TB) (roughly one-third of the global population) from which new cases continually arise. A prognostic marker for active TB would enable targeted treatment of the small fraction of infected individuals who are most at risk of developing contagious TB, contributing greatly to TB control efforts. Here, we propose that TB-specific interferon-gamma release assays might be useful for identifying individuals with progressive infections who are likely to develop the disease. This might provide an unprecedented advantage for TB control, namely targeted preventive therapy for individuals who are most at risk of developing active contagious TB.     

Aberrations of chromosome 3. A marker of T-cell lymphomas?

Aberrations of chromosome occur in different malignancies, but they are more frequent in lymphoproliferative ones than in the others. In this study here four out of five T-zone lymphomas had abnormalities of chromosome 3. This lead to the question of whether aberrations of chromosome 3 might be a marker of T-cell lymphomas. The conclusion which can be drawn from the cases described in the literature, the own unpublished cases, and these four T-zone lymphomas is that abnormalities of chromosome 3 cannot be regarded as a discriminative marker of T-cell derived malignancies. It is suggested that the relationship between chromosome aberrations and type of disease is not necessarily a direct one. One possible model of the genesis of chromosome aberrations in malignant diseases is presented.     

The absence of crossovers on chromosome 4 in Drosophila melanogaster: Imperfection or interesting exception?

Drosophila melanogaster chromosome 4 is an anomaly because of its small size, chromatin structure, and most notably its lack of crossing over during meiosis. Earlier ideas about the absence of crossovers on 4 hypothesize that these unique characteristics function to prevent crossovers. Here, we explore hypotheses about the absence of crossovers on 4, how these have been addressed, and new insights into the mechanism behind this suppression. We review recently published results that indicate that global crossover patterning, in particular the centromere effect, make a major contribution to the prevention of crossovers on 4.     

Alteration of chromosome numbers by generation of minichromosomes -- is there a lower limit of chromosome size for stable segregation?

Practical applications of minichromosomes, generated by de novo composition or by truncation of natural chromosomes, rely on stable transmission of these chromosomes. Functional centromeres, telomeres and replication origins are recognized as prerequisites for minichromosome stability. However, it is not yet clear whether, and if yes, to what degree the chromatin content has a qualitative or quantitative impact on stable chromosome transmission. A small translocation chromosome, which arose after X-irradiation of a reconstructed field bean karyotype, comprised approximately 5% of the haploid metaphase complement and was found to consist of three pieces of duplicated chromatin and a wild-type centromere. This chromosome was stably transmitted through all meristematic and pollen grain mitoses but was frequently lost during meiosis (66% loss in hemizygous and 33% in homozygous condition). This minichromosome was only a little smaller than stably segregating translocation chromosomes (comprising approximately 6% of the genome) of a euploid field bean karyotype. The duplications specific for this minichromosome did not influence meiotic segregation when associated with non-duplicated chromatin of other chromosomes. In comparison with minichromosomes of other species, the possibility of a lower size limit for a stable chromosome transmission must therefore be considered which might be based, for instance, on insufficient lateral support of centromeres or on insufficient bivalent stability due to the incapability of chiasma formation.