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PubMed2002

Imbroglios of viral taxonomy: genetic exchange and failings of phenetic approaches.

The practice of classifying organisms into hierarchical groups originated with Aristotle and was codified into nearly immutable biological law by Linnaeus. The heart of taxonomy is the biological species, which forms the foundation for higher levels of classification. Whereas species have long been established among sexual eukaryotes, achieving a meaningful species concept for prokaryotes has been an onerous task and has proven exceedingly difficult for describing viruses and bacteriophages. Moreover, the assembly of viral "species" into higher-order taxonomic groupings has been even more tenuous, since these groupings were based initially on limited numbers of morphological features and more recently on overall genomic similarities. The wealth of nucleotide sequence information that catalyzed a revolution in the taxonomy of free-living organisms necessitates a reevaluation of the concept of viral species, genera, families, and higher levels of classification. Just as microbiologists discarded dubious morphological traits in favor of more accurate molecular yardsticks of evolutionary change, virologists can gain new insight into viral evolution through the rigorous analyses afforded by the molecular phylogenetics of viral genes. For bacteriophages, such dissections of genomic sequences reveal fundamental flaws in the Linnaean paradigm that necessitate a new view of viral evolution, classification, and taxonomy.

Bacteriophages↗
PubMed2006

Hatena arenicola gen. et sp. nov., a katablepharid undergoing probable plastid acquisition.

Hatena arenicola gen. et sp. nov., an enigmatic flagellate of the katablepharids, is described. It shows ultrastructural affinities to the katablepharids, including large and small ejectisomes, cell covering, and a feeding apparatus. Although molecular phylogenies of the 18S ribosomal DNA support its classification into the katablepharids, the cell is characterized by a dorsiventrally compressed cell shape and a crawling motion, both of which are unusual within this group. The most distinctive feature of Hatena arenicola is that it harbors a Nephroselmis symbiont. This symbiosis is distinct from previously reported cases of ongoing symbiosis in that the symbiont plastid is selectively enlarged, while other structures such as the mitochondria, Golgi body, cytoskeleton, and endomembrane system are degraded; the host and symbiont have developed a morphological association, i.e., the eyespot of the symbiont is always at the cell apex of Hatena arenicola; and only one daughter cell inherits the symbiont during cell division, resulting in a symbiont-bearing green cell and a symbiont-lacking colorless cell. Interestingly, the colorless cells have a feeding apparatus that corresponds to the location of the eyespot in symbiont-bearing cells, and they are able to feed on prey cells. This indicates that the morphology of the host depends on the presence or absence of the symbiont. These observations suggest that Hatena arenicola has a unique "half-plant, half-predator" life cycle; one cell divides into an autotrophic cell possessing a symbiotic Nephroselmis species, and a symbiont-lacking colorless cell, which later develops a feeding apparatus de novo. The evolutionary implications of Hatena arenicola as an intermediate step in plastid acquisition are discussed in the context of other examples of ongoing endosymbioses in dinoflagellates.

Animals↗
PubMed2001

Morphological and molecular characterization of a new terrestrial allogromiid species: Edaphoallogromia australica gen. et spec. nov. (Foraminifera) from Northern Queensland (Australia).

The foraminiferal family Allogromiidae occurs mainly in marine environments, although some genera are described from brackish and freshwater habitats. We report here the occurrence of a terrestrial allogromiid foraminiferan. Phylogenetic relationships were investigated by sequencing part of the SSU rDNA. DNA sequence analysis confirms a close relationship of the new species to the genus Allogromia. Morphological studies corroborate the affiliation to the family Allogromiidae but the lack of an entosolenian tube and an internal septum as well as the different ecology do not allow a classification into a known genus of this family. Taking the molecular, morphological and ecological differences into account, a new genus Edaphoallogromia with the type species E. australica is erected.

Animals↗
PubMed2005

A developmental and genetic classification for malformations of cortical development.

Increasing recognition of malformations of cortical development and continuing improvements in imaging techniques, molecular biologic techniques, and knowledge of mechanisms of brain development have resulted in continual improvement of the understanding of these disorders. The authors propose a revised classification based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories are based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In those cases in which the precise developmental and genetic features are uncertain, classification is based on known relationships among the genetics, pathologic features, and neuroimaging features. The major change since the prior classification has been a shift to using genotype, rather than phenotype, as the basis for classifying disorders wherever the genotype-phenotype relationship is adequately understood. Other substantial changes include more detailed classification of congenital microcephalies, particularly those in which the genes have been mapped or identified, and revised classification of congenital muscular dystrophies and polymicrogyrias. Information on genetic testing is also included. This classification allows a better conceptual understanding of the disorders, and the use of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.

Cerebral Cortex↗
PubMed2005

[Oligodendrogliomas: historical background of classifications].

The story of the classifications for gliomas is related to the development of the techniques used for cytological and histological examination of brain parenchyma. After a review of these techniques and the progressive discovery of the central nervous system cell types, the main classifications are presented. The first classification is due to Bailey and Cushing in 1926. It was based on histoembryogenetic theory. Then Kernohan introduced, in 1938, the concept of anaplasia. The WHO classification was published in 1979, then revised in 1993 and 2000. It took into account some data from both previous systems and introduced gradually the notion of histological criteria of malignancy. More recently; molecular genetics data and clinical evolution were retained. The Sainte-Anne classification for oligodendrogliomas is based on both histological and imaging data. It includes the notion of spatial histological structure of oligodendrogliomas. Contrast enhancement is closely related to endotheliocapillary hyperplasia. Gliomas classifications are changing and confusions can be made because of lack of reproductibility and misinterpretations of samples.

Brain Neoplasms↗
PubMed1993

Defective organification of iodide causing hereditary goitrous hypothyroidism.

We present a survey of the current state of knowledge about the prevalence of the syndrome involved in defective organification of iodide, and the mechanism of iodination and coupling catalyzed by the thyroid peroxidase (TPO) enzyme. A brief summary of the recent developments in molecular cloning of TPO and regulation of TPO gene expression is also included. Methods for purification of the enzyme and details about the assessment of TPO activity in tissue are briefly explained. The classification of defective organification of iodide is primarily based on the site of the biochemical defect, being quantitative (TPO absent) or qualitative (TPO structure, localization or apoenzyme are defectives). The presence of TPO inhibitors is also briefly described. The rare possibility of an absent source of peroxide (H2O2) causing defective iodide organification is discussed. Analysis of the 118 reported cases shows that the biochemical classification covers a spectrum of abnormalities and it is likely that further molecular biology studies will increase this heterogeneity as well as refining it. Genetic studies have suggested linkage between the TPO gene polymorphisms and the iodide organification defect and can be of importance for carrier detection and prenatal diagnosis. Neonatal screening for hypothyroidism is likely to expand the number of cases available for DNA analysis and possibly the molecular diagnosis. The importance of the mutations that would affect the histidine (His) residues in the translated protein was recently documented by the finding of a deletion removing part of exon 9 and thus also deleting a proximal His residue. The resulting TPO enzyme was inactive for iodide organification and coupling reaction. It is hoped that in time we will be able to expand our knowledge of the molecular diagnosis of the inborn errors of iodide organification.

Amino Acid Sequence↗
PubMed2001

Molecular cytotaxonomy of New World monkeys (Platyrrhini) - comparative analysis of five species by multi-color chromosome painting gives evidence for a classification of Callimico goeldii within the family of Callitrichidae.

Chromosome rearrangements are considered as "rare genomic changes" and can provide useful markers and even landmarks for reconstructing phylogenies complementary to DNA sequence data and bio-morphological comparisons. Here, we applied multi-directional chromosome painting to reconstruct the chromosome phylogeny and evolutionary relationships among the New World monkey (Platyrrhini) species Callithrix argentata, Cebuella pygmaea, Saguinus oedipus, Callithrix jacchus and Callimico goeldii. The results clarified several aspects of New Wold monkey phylogeny. In particular the phylogenetic position of C. goeldii was elucidated, which has been controversially discussed and variously classified in the family Callitrichidae, in the family Cebidae or in its own family Callimiconidae. Comparative genome maps were established by multi-color fluorescence in situ hybridization (FISH) with human, S. oedipus and Lagothrix lagothricha chromosome- specific DNA probes. From these data we reconstructed the putative ancestral karyotype of all Callitrichidae. Various derived chromosomal syntenies are shared by all five species and cytogenetically define Callitrichidae - including Callimico goeldii -- as a distinctive group within the Platyrrhini. C. pygmaea and C. argentata share identical chromosomal syntenies from which S. oedipus and C. jacchus differ by single independent translocations. A common derived chromosomal change links Callimico with the marmosets to the exclusion of the tamarins, however, it has further diverged from an ancestral marmoset karyotype by at least four apomorphic rearrangements. Saimiri sciureus, representing the Cebinae, exclusively shares a derived syntenic association with all Callithrichidae, defining the genus Saimiri as a sister group.

Animals↗
PubMed2006

Affiliation of Cochlosoma to trichomonads confirmed by phylogenetic analysis of the small-subunit rRNA gene and a new family concept of the order Trichomonadida.

The protozoan genus Cochlosoma includes parasitic intestinal flagellates of birds and mammals of uncertain taxonomic classification. The presence of an adhesive disc, superficially similar to that of Giardia, led to a proposal that Cochlosoma should be classified as diplomonads. Careful morphological and ultrastructural observations, however, revealed conspicuous homologies to trichomonads. We addressed the question of classification and phylogenetic affiliation of Cochlosoma using the methods of molecular phylogenetics. Analyses based on the 16S rRNA gene sequence of the species Cochlosoma anatis very robustly placed Cochlosoma in the clade of the parabasalid subfamilies Trichomonadinae, Trichomitopsiinae and Pentatrichomonoidinae of the order Trichomonadida (bootstraps >94 %). The data did not provide robust support for any particular position of Cochlosoma within this clade because the sequence suffered from mutational saturation and produced a long branch. The most probable sister taxon of Cochlosoma is the genus Pentatrichomonas, because their relationship was supported specifically by the slowest-mutating, least-saturated positions as determined using the method slow-fast. Classification of the order Trichomonadida was revised to accommodate knowledge about its phylogeny - the family Cochlosomatidae and subfamilies Trichomitopsiinae and Pentatrichomonoidinae were abandoned, Trichomonadidae was amended and new families Tritrichomonadidae (formerly a subfamily) and Trichomitidae were proposed.

Animals↗
PubMed1992

Molecular genetics, reductionism, and disease concepts in psychiatry.

The study of mental illness by the methods of molecular genetics is still in its infancy, but the use of genetic markers in psychiatry may potentially lead to a Virchowian revolution in the conception of mental illness. Genetic markers may define novel clusters of patients having diverse clinical presentations but sharing a common genetic and mechanistic basis. Such clusters may differ radically from the conventional classification schemes of psychiatric illness. However, the reduction of even relatively simple Mendelian phenomena to molecular genetics has been shown to be a surprisingly complex and problematic enterprise. Mental illnesses exist at many levels of including social, environmental, and developmental interactions. Reductionistic shifts in the classification of such a disease entity will have to address the interlevel dynamics that take place within the structure of theories of mental illness. The question of how molecular analysis of psychiatric disease will impact on the structure of existing theories and classification systems is the central topic of this paper.

Bipolar Disorder↗
PubMed2000

Characterization and construction of functional cDNA clones of Pariacoto virus, the first Alphanodavirus isolated outside Australasia.

Pariacoto virus (PaV) was recently isolated in Peru from the Southern armyworm (Spodoptera eridania). PaV particles are isometric, nonenveloped, and about 30 nm in diameter. The virus has a bipartite RNA genome and a single major capsid protein with a molecular mass of 39.0 kDa, features that support its classification as a Nodavirus. As such, PaV is the first Alphanodavirus to have been isolated from outside Australasia. Here we report that PaV replicates in wax moth larvae and that PaV genomic RNAs replicate when transfected into cultured baby hamster kidney cells. The complete nucleotide sequences of both segments of the bipartite RNA genome were determined. The larger genome segment, RNA1, is 3,011 nucleotides long and contains a 973-amino-acid open reading frame (ORF) encoding protein A, the viral contribution to the RNA replicase. During replication, a 414-nucleotide long subgenomic RNA (RNA3) is synthesized which is coterminal with the 3' end of RNA1. RNA3 contains a small ORF which could encode a protein of 90 amino acids similar to the B2 protein of other alphanodaviruses. RNA2 contains 1,311 nucleotides and encodes the 401 amino acids of the capsid protein precursor alpha. The amino acid sequences of the PaV capsid protein and the replicase subunit share 41 and 26% identity with homologous proteins of Flock house virus, the best characterized of the alphanodaviruses. These and other sequence comparisons indicate that PaV is evolutionarily the most distant of the alphanodaviruses described to date, consistent with its novel geographic origin. Although the PaV capsid precursor is cleaved into the two mature capsid proteins beta and gamma, the amino acid sequence at the cleavage site, which is Asn/Ala in all other alphanodaviruses, is Asn/Ser in PaV. To facilitate the investigation of PaV replication in cultured cells, we constructed plasmids that transcribed full-length PaV RNAs with authentic 5' and 3' termini. Transcription of these plasmids in cells recreated the replication of PaV RNA1 and RNA2, synthesis of subgenomic RNA3, and translation of viral proteins A and alpha.

Amino Acid Sequence↗
PubMed2002

Molecular phenotyping of retinal ganglion cells.

Classifying all of the ganglion cells in the mammalian retina has long been a goal of anatomists, physiologists, and cell biologists. The rabbit retinal ganglion cell layer was phenotyped using intrinsic small molecule signals (aspartate, glutamate, glycine, glutamine, GABA, and taurine) and glutamate receptor-gated 1-amino-4-guanidobutane excitation signals as the clustering dimensions for formal classification. Intrinsic signals alone yielded 7 ganglion cell superclasses and 1 amacrine cell superclass; the addition of excitation signals ultimately resolved 14 natural ganglion cell classes and 3 amacrine cell classes. Ganglion cells comprise two-thirds to three-quarters of the cells in the ganglion cell layer and exhibited distinct metabolic, coupling, and excitation phenotypes, as well as characteristic sizes, population fractions, and patterns. Metabolic signatures (mixtures of glutamate, aspartate, glutamine, and GABA) chemically discriminated ganglion from amacrine cells. Coupling signatures reflected heterologous coupling states across ganglion cells: (1) uncoupled, (2) coupled to GABAergic amacrine cells, and (3) coupled to glycinergic amacrine cells. Excitation signatures reflected differential channel permeation rates across classes after AMPA activation. Extraction of unique size and patterning features from the data sets further validated the robustness of the classification. Because the classifications were explicitly blinded to structure, this is strong evidence that molecular phenotype classes are natural classes. Correspondences of molecular phenotype classes to functional classes were inferred from size, coupling, encounter, and physiological attributes. Ganglion cell classes display markedly different ionotropic drives, which may partly explain the physiological brisk-sluggish spectrum of ganglion cell spiking patterns.

Agmatine↗
PubMed2005

Molecular phylogenetics of subtribe Aeridinae (Orchidaceae): insights from plastid matK and nuclear ribosomal ITS sequences.

We conducted phylogenetic analyses using two DNA sequence data sets derived from matK, the maturase-coding gene located in an intron of the plastid gene trnK, and the internal transcribed spacer region of 18S-26S nuclear ribosomal DNA to examine relationships in subtribe Aeridinae (Orchidaceae). Specifically, we investigated (1) phylogenetic relationships among genera in the subtribe, (2) the congruence between previous classifications of the subtribe and the phylogenetic relationships inferred from the molecular data, and (3) evolutionary trends of taxonomically important characters of the subtribe, such as pollinia, a spurred lip, and a column foot. In all, 75 species representing 62 genera in subtribe Aeridinae were examined. Our analyses provided the following insights: (1) monophyly of subtribe Aeridinae was tentatively supported in which 14 subclades reflecting phylogenetic relationships can be recognized, (2) results are inconsistent with previous classifications of the subtribe, and (3) repeated evolution of previously emphasized characters such as pollinia number and apertures, length of spur, and column foot was confirmed. It was found that the inconsistencies are mainly caused by homoplasy of these characters. At the genus level, Phalaenopsis, Cleisostoma, and Sarcochilus are shown to be non-monophyletic.

Base Sequence↗
PubMed1996

[A molecular approach to the structure, polymorphism and function of blood groups].

Biochemical and molecular genetic studies have contributed to our molecular knowledge of blood group-associated molecules in the past few years. Among the 23 blood group systems presently identified, almost all have a molecular basis and present investigations are oriented towards the analysis of genetic polymorphisms, tissue-specific expression and structure-function relationships. Antigens defined by carbohydrate structures, among which ABO, Hh, Lewis and Secretor are the main representative species, are indirect gene products. They are synthesized by Golgi-resident glycosyltransferases, which are the direct products of the blood group genes. Many of these enzymes have been cloned and the molecular basis of the silent phenotypes, for instance 0, Bombay/paraBombay, Le(a-b-) and non-secretor, has been elucidated. However, the glycosyltransferases involved in the biosynthesis of Pk, P and P1 antigens are not yet characterized. A large number of blood group antigens carried by red cell polypeptides expressed at the cell surface are not related to a carbohydrate structure, and these proteins are direct blood group gene products. Most have been cloned and characterized recently, for instance MN antigens (glycophorin A), Ss antigens (glycophorin B), Gerbich antigens (glycophorins C and D) and antigens encoded by the RH, LW, KEL, FY, JK, XG, LU and XK loci. Other antigens have been located on proteins already identified, for instance the Cromer antigens on DAF, Knops antigens on CR1, Indian and AnWj antigens on CD44, Yt antigens on AChE, Diego, Wr, Rga and Warr on Band 3, Colton antigens on AQP-1 (water channel). The SC (Scianna) et DO (Dombrock) systems, however, still resist to molecular cloning. On the basis of this information, a tentative classification of blood group antigens into five functional categories is emerging: - Transporters and channels, - Receptors and ligands, - Adhesion molecules, - Enzymes, - Structural proteins. This review will focus on these recent findings and will illustrate how these studies may bring new information for analysis of normal and abnormal phenotypes and for understanding both the mechanisms of tissue specific expression and the potential function of these antigens, particularly those expressed in non-erythroid lineage. In addition, since our knowledge of the molecular basis of blood group polymorphisms has significantly increased, new genotyping techniques potentially useful in clinical applications will become available.

ABO Blood-Group System↗
PubMed1985

T-cell differentiation and maturation.

Understanding of the differentiation and maturation of T cells has been greatly enhanced by several technical developments. Certainly, the most important of these has been the rapid expansion in the availability of monoclonal antibodies to identify surface markers on T cells. Utilization of these antibodies has permitted the description of the developmental sequence of T cells both within the thymus and peripherally. Equally impressive have been the rapid advances in the understanding of the cellular events involved in antigen activation of T cells. These events are MHC restricted. The biochemical description of the class I and class II molecules that are involved in antigen presentation and the biochemical description of the T-cell receptor have provided a framework that should allow a more definitive picture of these specificity-determining molecular structures to emerge in the coming years. Several soluble growth and maturation factors (IL-1, IL-2, and BCGF), which are involved in the generation of cellular immune responses, have also been integrated into the above framework. Finally, ongoing studies on products of activated T lymphocytes (lymphokines) are providing clearer insights into the mechanisms by which immune T cells influence other cells. An additional benefit from the study of T cell development has been a more biochemically based classification of T-cell malignancies. The powerful tools of molecular genetics are beginning to have an impact on research in T-cell differentiation and maturation, and will likely have an ever-growing influence on research into the phenomena surrounding the activities of these immune cells.

Antigens, Surface↗
PubMed1999

Classifications in psychiatry: a conceptual history.

BACKGROUND: Historical accounts of psychiatric classifications have hitherto been written in terms of a 'received view'. This contains two assumptions, that: (i) the activity of classifying is inherent to the human mind; and (ii) psychiatric 'phenomena' are stable natural objects. OBJECTIVES: The aim of this article is to provide an outline of the evolution of psychiatric classifications from the perspective of conceptual history. This is defined as a theoretical and empirical inquiry into the principles, sortal techniques and contexts in which alienists carried out their task. It assumes that all psychiatric classifications are cultural products, and endeavours to answer the question of whether classificatory models imported from the natural sciences can be applied to man-made constructs (such as mental illness) definitionally based on 'personalised semantics'. METHODS: Exemplars of classificatory activity are first mapped and contextualised. Then, it is suggested that in each historical period crafting classifications has been like playing a game of chess with each move being governed by rules. This is illustrated by offering an analysis of the 1860-1861 French debate on classification. RESULTS AND CONCLUSIONS: (1) Medicine is not a contemplative but a modificatory activity and hence classifications are only valuable if they can release new information about the object classified. (2) It should not be inferred from the fact that psychiatric classifications are not working well (i.e. that they only behave as actuarial devices) that they must be given up. Conceptual work needs to continue to identify 'invariants' (i.e. stable elements that anchor classifications to 'nature'. (3) Because mental disorders are more than unstable behavioural epiphenomena wrapped around stable molecular changes, 'neurobiological' invariants may not do. Stability depends upon time frames. Furthermore, it is unlikely that gene-based classifications will ever be considered as classifications of mental disorders. For once, they would have low predictive power because of their lack of information about the defining codes of mental illness. 'Social' and 'psychological' invariants have problems of their own.

History, 18th Century↗
PubMed1983

Analysis of low molecular weight fractions in human senile cataractous lens.

Previous studies have suggested that changes occur in low molecular weight proteins during the progression of human senile cataract. In this report we have employed the reverse phase mode of high performance liquid chromatography (HPLC) and characterized the patterns of changes in the fractions of low molecular weight substances. Two different types of cataractous lenses, brown and yellow types, were used. Classification of cataract stages in each type was determined by measuring the Na+/K+ ratio in each lens. The profile of low molecular weight substances loosely bound to the reverse phase column changed significantly during cataract progression. In the brown type cataractous lenses, however, the low molecular weight substances changed after the middle stage of cataract progression, while in the yellow type cataractous lenses, the changes started during the early stages of cataract development. These experiments demonstrated that the reverse phase mode of HPLC is a sensitive and specific method for characterization of the quantitative differences in low molecular weight compounds during the progression of human senile cataract.

Aged↗
PubMed2004

The presence of clonal cell subpopulations in peripheral blood and bone marrow of patients with refractory cytopenia with multilineage dysplasia but not in patients with refractory anemia may reflect a multistep pathogenesis of myelodysplasia.

A clonal origin of hematopoiesis was studied by investigation of X-chromosome inactivation patterns (XCIP) in isolated granulocyte, CD14(+) and CD3(+) subpopulations obtained from bone marrow and peripheral blood of 36 female patients with primary myelodysplastic syndrome (MDS). Clonality was assessed by PCR amplification of polymorphic short tandem repeats of the human androgen receptor (HUMARA) gene and by investigation of silent polymorphism of iduronate sulphatase (IDS) or p55 genes. On the basis of results in a control group of 20 healthy age related females, a ratio of at least 9:1 between the two alleles was considered a significant marker of monoclonal hematopoiesis. Ten of the 11 patients with advanced forms of MDS (RAEB, RAEB-T, CMML) had clonal granulocytes and CD14(+) cells in peripheral blood. In patients with early disease, only 2 out of 11 patients (18%) with RA or RARS, according to WHO classification, had clonal granulocytes and CD14(+) cells in peripheral blood and bone marrow and 2 other patients with 5q-syndrome exhibited extremely oligoclonal granulocyte subpopulation in bone marrow. In contrast, we found clonal granulocytes in 12 out of 14 patients (86%) with refractory cytopenia with multilineage dysplasia (RCMD) and 8 of them simultanously exhibited clonal CD14(+) cells. Estimated 3 years survival of patients with early disease and clonal cell subpopulations was 61% as compared with 88% in patients without clonal hematopoiesis. Karyotype abnormalities were detected in 11 of the 25 females with early disease. Clonal patterns were present in 7 out of 8 patients with abberations diagnosed by routine cytogenetics, nevertheless, FISH revealed 5q deletion in 3 patients without signs of clonality in XCIP assay. No correlation was found between the presence of clonal subpopulations and the degree of telomere shortening in early MDS. Despite some limitations, the measurement of XCIP remains a sensitive tool for diagnosis of the first transforming mutation in the clonal development of MDS especially when combined with FISH and when an age related group is used to establish an appropriate allele ratio to exclude constitutional or acquired skewing. The occurrence of clonal cell subpopulations in most of the RCMD patients in contrast to RA may reflect a proposed multistep pathogenesis of MDS with dysplastic changes limited to erythropoiesis in early step and with subsequent development of multilineage dysplasia. The results also support the usefulness of separation of RCMD from 'pure' RA; however, a more complex insight combining different molecular techniques performed in a large number of patients is needed for refined classification of MDS on the basis of new molecular prognostic factors and for indication of more effective targeted therapy.

Anemia, Refractory↗
PubMed2003

Chronic myeloproliferative disorders.

The Philadelphia chromosome-negative chronic myeloproliferative disorders (CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF), have overlapping clinical features but exhibit different natural histories and different therapeutic requirements. Phenotypic mimicry amongst these disorders and between them and nonclonal hematopoietic disorders, lack of clonal diagnostic markers, lack of understanding of their molecular basis and paucity of controlled, prospective therapeutic trials have made the diagnosis and management of PV, ET and IMF difficult. In Section I, Dr. Jerry Spivak introduces current clinical controversies involving the CMPD, in particular the diagnostic challenges. Two new molecular assays may prove useful in the diagnosis and classification of CMPD. In 2000, the overexpression in PV granulocytes of the mRNA for the neutrophil antigen NBI/CD177, a member of the uPAR/Ly6/CD59 family of plasma membrane proteins, was documented. Overexpression of PRV-1 mRNA appeared to be specific for PV since it was not observed in secondary erythrocytosis. At this time, it appears that overexpression of granulocyte PRV-1 in the presence of an elevated red cell mass supports a diagnosis of PV; absence of PRV-1 expression, however, should not be grounds for excluding PV as a diagnostic possibility. Impaired expression of Mpl, the receptor for thrombopoietin, in platelets and megakaryocytes has been first described in PV, but it has also been observed in some patients with ET and IMF. The biologic basis appears to be either alternative splicing of Mpl mRNA or a single nucleotide polymorphism, both of which involve Mpl exon 2 and both of which lead to impaired posttranslational glycosylation and a dominant negative effect on normal Mpl expression. To date, no Mpl DNA structural abnormality or mutation has been identified in PV, ET or IMF. In Section II, Dr. Tiziano Barbui reviews the best clinical evidence for treatment strategy design in PV and ET. Current recommendations for cytoreductive therapy in PV are still largely similar to those at the end of the PVSG era. Phlebotomy to reduce the red cell mass and keep it at a safe level (hematocrit < 45%) remains the cornerstone of treatment. Venesection is an effective and safe therapy and previous concerns about potential side effects, including severe iron deficiency and an increased tendency to thrombosis or myelofibrosis, were erroneous. Many patients require no other therapy for many years. For others, however, poor compliance to phlebotomy or progressive myeloproliferation, as indicated by increasing splenomegaly or very high leukocyte or platelet counts, may call for the introduction of cytoreductive drugs. In ET, the therapeutic trade-off between reducing thrombotic events and increasing the risk of leukemia with the use of cytoreductive drugs should be approached by patient risk stratification. Thrombotic deaths seem very rare in low-risk ET subjects and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy might be justifiable in young, asymptomatic ET patients with a platelet count below 1500000/mm(3) and with no additional risk factors for thrombosis. If cardiovascular risk factors together with ET are identified (smoking, obesity, hypertension, hyperlipidemia) it is wise to consider platelet-lowering agents on an individual basis. In Section III, Dr. Gianni Tognoni discusses the role of aspirin therapy in PV based on the recently completed European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study, a multi-country, multicenter project aimed at describing the natural history of PV as well as the efficacy of low-dose aspirin. Aspirin treatment lowered the risk of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (relative risk 0.41 [95% CI 0.15-1.15], P =.0912). Total and cardiovascular mortality were also reduced by 46% and 59%, respectively. Major bleedings were slightly increased nonsignificnsignificantly by aspirin (relative risk 1.62, 95% CI 0.27-9.71). In Section IV, Dr. Giovanni Barosi reviews our current understanding of the pathophysiology of IMF and, in particular, the contributions of anomalous megakaryocyte proliferation, neoangiogenesis and abnormal CD34(+) stem cell trafficking to disease pathogenesis. The role of newer therapies, such as low-conditioning stem cell transplantation and thalidomide, is discussed in the context of a general treatment strategy for IMF. The results of a Phase II trial of low-dose thalidomide as a single agent in 63 patients with myelofibrosis with meloid metaplasia (MMM) using a dose-escalation design and an overall low dose of the drug (The European Collaboration on MMM) will be presented. Considering only patients who completed 4 weeks of treatment, 31% had a response: this was mostly due to a beneficial effect of thalidomide on patients with transfusion dependent anemia, 39% of whom abolished transfusions, patients with moderate to severe thrombocytopenia, 28% of whom increased their platelet count by more than 50 x 10(9)/L, and patients with the largest splenomegalies, 42% of whom reduced spleen size of more than 2 cm.

Antineoplastic Agents↗