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Maximum-likelihood estimation of coalescence times in genealogical trees.
We develop a method for maximum-likelihood estimation of coalescence times in genealogical trees, based on population genetics data. For this purpose, a Viterbi-type algorithm is constructed to maximize the joint likelihood of the coalescence times. Marginal confidence intervals for the coalescence times based on the profile likelihoods are also computed. Our method of finding MLEs and calculating C.I.'s appears to be more accurate than alternative numerical maximization methods, and maximum-likelihood inference appears to be more accurate than other existing model-free approaches to estimating coalescent times. We demonstrate the method on two different data sets: human Y chromosome DNA data and fungus DNA data.
Overview of rational and individualized therapeutic strategies for non-Hodgkin's lymphomas.
For nearly 20 years CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) has been the gold standard of therapy for aggressive non-Hodgkin's lymphomas (NHLs), curing = 30% of patients with diffuse large-cell NHL. A variety of strategies are being tested to identify regimens that might increase the disease-free survival rate for aggressive NHLs. One approach has been to intensify chemotherapy either by administering higher doses or by using shorter chemotherapy cycles. There are data suggesting that elderly patients benefit from CHOP given in 14-day cycles with granulocyte colony-stimulating factor. Based on in vitro observations that continuous exposure to cytotoxic agents can override multidrug-resistance pumps, several groups have studied combination chemotherapy regimens that include continuous 2- or 3-day intravenous infusions of cytotoxic agents. These studies have had short follow-up but encouraging early disease-free survival rates. There also has been interest in integrating monoclonal antibodies such as rituximab into therapies for aggressive NHLs. One randomized trial found CHOP/rituximab to be superior to CHOP alone in elderly patients with aggressive NHLs. With high-dose chemotherapy and stem cell support established as a salvage regimen for aggressive NHLs, many trials have evaluated the value of upfront high-dose therapy, especially in poor-prognosis patients. Other approaches to managing aggressive NHLs, which appear promising but are under investigation, are allogeneic transplants and lymphoma vaccines. An advance in the study of lymphoid malignancies is the development of a lymphoma classification system, the World Health Organization Classification of Lymphoid Malignancies, which recognizes the distinct molecular, morphologic, and genetic characteristics of differential lymphoma subtypes. It is anticipated that accurate and specific differential diagnosis, coupled with recognition of important clinical prognostic factors, will provide useful background for selecting and designing rational (and perhaps individualized) therapies for patients with aggressive NHLs.
Exploring developmental, functional, and evolutionary aspects of amphioxus sensory cells.
Amphioxus has neither elaborated brains nor definitive sensory organs, so that the two may have evolved in a mutually affecting manner and given rise to the forms seen in extant vertebrates. Clarifying the developmental and functional aspects of the amphioxus sensory system is thus pivotal for inferring the early evolution of vertebrates. Morphological studies have identified and classified amphioxus sensory cells; however, it is completely unknown whether the morphological classification makes sense in functional and evolutionary terms. Molecular markers, such as gene expression, are therefore indispensable for investigating the developmental and functional aspects of amphioxus sensory cells. This article reviews recent molecular studies on amphioxus sensory cells. Increasing evidence shows that the non-neural ectoderm of amphioxus can be subdivided into molecularly distinct subdomains by the combinatorial code of developmental cues involving the RA-dependent Hox code, suggesting that amphioxus epithelial sensory cells developed along positional information. This study focuses particularly on research involving the molecular phylogeny and expression of the seven-transmembrane, G protein-coupled receptor (GPCR) genes and discusses the usefulness of this information for characterizing the sensory cells of amphioxus.
[Neurodegenerative diseases of the spinal cord].
Numerous classifications have been applied to describe degenerative diseases of the spinal cord before the era of molecular analysis. The present challenge is to match in an appropriate manner old and new clinical classifications with the results of genetic analysis. This work is now well advanced for spinocerebellar degeneration but needs to be developed for hereditary spastic paraplegia, spinal muscular atrophies and amyotrophic lateral sclerosis. The widening of clinical spectrum observed in hereditary neurodegenerative diseases of the spinal cord raises the question of modulating factors (environmental or genetic). Clinicians in charge of patients with progressive spinal cord signs should bear in mind that the field of degenerative diseases is a moving one and that a degenerative aetiology has to be suspected more widely than in the past.
[Revolution in megataxonomy: prerequisites and results].
Main stages of development of megataxonomy (the science of organic world dividing into large taxa) are considered. Prerequisites and first results of "revolution in megataxonomy" (cardinal reorganization during last years) are analyzed. Matter of "revolution" is considered: changing of main megataxonomic criteria from morpho-physiological to cytological and genetical ones. Advantages of classifications of organic world based on cytological and genetical criteria, and main arguments of their opponents are discussed. Some taxonomic changes based on published data are suggested: the kingdom Lamellitubulicristata (lamellicristate and tubulicristate eukaryots) is created, Cryptophyta, Prymnesiophyta, Percolozoa and Actinozoa are risen up to the kingdom rank. Original megasystem of dominion Eukaryota is build up, including 2 subdominions (Hypochondria and Epichondria), 3 superkingdoms (Hypocrystata, Discocrystata and Lamellitubulicristata) and 14 kingdoms (Archaeomonadobiontes, Microsporobiontes, Euglenobiontes, Percolobiontes, Myxobiontes, Actinobiontes, Alveolobiontes, Chromobiontes, Prymnesiobiontes, Cryptobiontes, Rhodobiontes, Chlorobiontes, Mycobiontes and Zoobiontes). Characters of these taxa and an outline of their evolutionary connections based on published data are provided.
Genomic structure and evolution of Legionella species.
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[Neoplastic intraepithelial lesions of pancreatic ducts: new entities].
Intraductal neoplastic lesions of the pancreas have been the focus of recent efforts aiming to better characterize several entities. Beside reactive papillary hyperplastic lesion of pancreatic ducts whose limits and significance are unclear, two different entities, intraductal papillary mucinous neoplasm (IPMN) with its variant intraductal oncocytic papillary neoplasm, and pancreatic intraepithelial neoplasia (PanIN), the precursors of pancreatic adenocarcinoma have been recognized. Each has been carefully described at the microscopic level with classification into several grades of dysplasia. IPMNs are intraductal, papillary, often diffuse and mucus hypersecreting neoplastic lesions. Mucin accumulation gives to the lesion a cystic pattern. Treatment is surgical resection of the whole lesion. Intraductal oncocytic papillary neoplasm is a rare variant of IPMN. The prognosis of IPMN is globally favorable, but these tumors display the risk of malignant transformation into a mucinous or a tubular pancreatic adenocarcinoma. Although IPMN can induce symptoms, PanIN are silent and always discovered at the vicinity of an invasive adenocarcinoma. The usefulness and the reproducibility of the classification of PanIN remain to be determined. PanIN classification might resume the different successive steps of molecular genetic or epigenetic events associated with the development of a pancreatic carcinoma.
[Molecular genetic progression on nasopharyngeal carcinoma].
The aim of this paper was to discuss the molecular genetic events in the development and progression of nasopharyngeal carcinoma (NPC), and the correlation between genetic alterations and clinicopathological changes of NPC. Analyzed by LOH (loss of heterozygosity) and CGH (comparative genomic hybridization) in primary NPC, high frequent allelic losses were observed on chromosomes 1p, 3p, 9p, 9q, 11q, 13q, 14q, 16q, and 19q, and the minimum deletion regions were also localized; there are closely association between LOH on certain deletion regions in NPC and the clinicopathological parameters. In the group of NPC with higher LOH value (FAL), together with higher antibody titers of EBV IgA/VCA and IgA/EA, most of the NPC showed more invasive of primary T stage (T3 + T4), TNM (III + IV stage) and far lymph node metastasis. High frequent chromosomal gain regions were observed on chromosomes 1q, 2q, 3q, 6p, 6q, 7q11.2, 8q, 11q13, 12, 15q, 17q, and 20q, indicating that there may exist oncogenes which are activated on the gain regions in NPC. CGH analysis showed that gains on chromosome 1q, 8q, 18q, and loss on 9p were closely related to advanced stage of NPC. LOH study also showed high frequent LOH on 3p in normal nasopharyngeal epithelium (74%) and dysplasia lesions (75%) from the Southern Chinese, suggesting that LOH at 3p may be an earlier genetic event of NPC tumorigenesis. Linkage analysis indicate that the HLA gene and cytochrome p4502E gene may be susceptibility genes of NPC. New potential susceptibility gene locus has also been localized by this study. cDNA microarray demonstrated differential expression of cell cycle proteins, anti-apoptotic factors, oncogenes/tumor suppressors, growth-enhancing factors of EGR1, tumor-derived growth factor 1, platelet-derived growth factor A chain; differential expression were also observed in different clinical stage NPC. Genetic instabilities (losses and gains) are common molecular events in NPC, and play very important role in the development and progression of NPC. Through LOH, CGH, linkage, and cDNA microarray study, we can find specific biomarkers of NPC, and will support us biomarkers which can be used for earlier diagnosis and prognosis of NPC. More importantly, these biomarkers may be useful in the development of a NPC molecular staging system, which could augment current clinicopathological classification and staging systems.
Mitochondrial encephalomyopathies.
Molecular genetic studies are now bringing a new classification and new insights into already recognized mitochondrial encephalomyopathies. There are, however, numerous reports on an overlap pattern between mitochondriopathies. In addition, the link between the defect in oxidative phosphorylation (OXPHOS) in the brain and the specific neuropathological pattern is unclear. A better knowledge of nuclear mutations in mitochondriopathies and of the interactions between nuclear and mitochondrial genomes will probably allow new developments.
Malignancies of undetermined primary origin.
Unknown primary malignancy (UPM) is not a disease entity. Rather, it represents a variety of different metastatic, malignant neoplasms all presenting with either an occult primary or having such a highly undifferentiated histologic appearance that an accurate pathologic classification on routine hematoxylin-eosin section is not possible. UPM is a spectrum of malignancies that includes those that are treatable and curable and those for which no specific treatment exists. For the physician, a diagnosis of UPM represents a beginning rather than an end. The minimal workup of such patients includes a thorough history and physical examination, complete blood counts, urine analysis, multichannel chemistries, a chest radiograph, and computed tomography of the abdomen and pelvis. Having completed this workup, further tests are unnecessary and unwarranted unless specific symptoms or physical signs exist. Once the aforementioned workup is completed, the physician must communicate frequently and freely with the pathologist as further diagnostic tests will be laboratory based and include electron microscopy, histochemical stains, and immunocytochemistries. Immunocytochemistries are relatively new laboratory procedures which have made a significant contribution in the accurate pathologic diagnosis of a tissue specimen that in years past would have been classified as an unidentified malignant neoplasm. An initial panel of immunocytochemistries (vimentin, cytokeratin, CEA, and common leukocyte antigen) should be performed on the tissue block in patients with UPM as they provide direction in the accurate classification of the malignant neoplasm. Chromosomal analysis of tissue is useful in the recognition of lymphomas or soft-tissue sarcomas which would otherwise be classified as UPM. In years to come, when specific DNA probes capable of identifying specific chromosomal rearrangeaments are widely available, pathologic classification of UPM will be performed on a molecular level. Some unknown primary malignancies are treatable and potentially curable. These include large cell lymphoma, extragonadal germ cell malignancies, squamous cell carcinoma metastatic to cervical lymph nodes without an obvious primary, metastatic adenocarcinoma to axillary lymph nodes in women (invariably on occult breast primary), and malignant ascites in women, which usually represents ovarian cancer. Metastatic adenocarcinoma of unknown primary origin, with the exception noted above and the rare presentation of an occult prostate cancer as UPM, is an ultimately fatal malignancy with a relatively shor clinical course.(ABSTRACT TRUNCATED AT 400 WORDS)
Renal tubular acidosis.
Renal tubular acidosis (RTA) is a form of metabolic acidosis due to abnormal alkali (bicarbonate) loss by the kidneys or their failure to excrete net acid. While the latter does occur in chronic renal failure, the term RTA is usually applied only when the glomerular filtration rate is normal or near normal. As well as a cause of metabolic acidosis, RTA often presents as renal stone disease with nephrocalcinosis, rickets/osteomalacia, and growth retardation in children. In this brief review, we have summarized the classification, clinical features and the underlying cell and molecular pathophysiology of RTA. However, despite significant advances in our understanding of the mechanisms of RTA, its treatment is still empirical and based largely on alkali replacement therapy; but its wider significance in renal stone and bone disease is becoming increasingly recognized.
Comparison of cytogenetics and clinical manifestations between M5a and M5b of acute monocytic leukemia.
To compare the cytogenetic difference between M5a and M5b of acute monocytic leukemia and to study the correlation between karyotypes and clinical manifestations, a total of 58 cases of de novo adult AML M5 have been investigated. Chromosome metaphases of bone marrow cells were prepared by using direct method and 24 hours short-term culture. The karyotypes were analyzed by G-banding. Meanwhile, clinical information of these cases were studied retrospectively. The results showed that there were 28 with normal karyotype and 30 with aberrant karyotype in 58 cases. The frequency of normal karyotype in patients with M5b was significantly higher than that in patients with M5a (P = 0.0001). The 11q23 aberrations and trisomy 8 were more common in patients with M5a in comparison with patients with M5b (P < 0.01). The patients with AML M5 with aberrant karyotype had a higher incidence of hyperleukocytosis, extramedullary central nerve system infiltration, lower complete remission (CR) rate and shorter overall survival. It is concluded that acute monocytic leukemia is a series of heterogeneous diseases, a distinctive cytogenetic features can be observed between patients with AML M5a and M5b, these results will provide insights into the classification and pathogenesis mechanism of AML M5 at molecular level.
[New molecular markers within the chronic myeloproliferative disorders. II: the JAK2 mutation].
The Philadelphia-negative chronic myeloproliferative disorders feature autonomous myeloid hyperproliferation and hypersensitivity to a number of growth factors, which most recently have been shown to be explained by a guanine-to-thymidine mutation in the Janus tyrosine kinase (JAK2) gene, implicating that phenylalanine is substituted with valine in position 617 (V617F mutation). JAK2 is of particular importance to haematopoiesis, since JAK2 proteins are activated mainly by the haematopoietic growth factors. The JAK2 mutation is present in most patients with polycythaemia vera and about 50% of patients with essential thrombocytosis and idiopathic myelofibrosis. The identification of the JAK2 mutation is a major molecular breakthrough in the understanding of the pathobiology of these disorders, and it is a new molecular marker to be used in the future classification of the diseases as well as a simple and rapid diagnostic test. The mutated JAK2 tyrosine kinase is an obvious potential target for a small-molecule inhibitor of tyrosine kinase activity.
[Benign (reactive) lymphoproliferation or malignant lymphoma?].
Pre-stages and early stages of malignant Non-Hodgkin's-lymphomas mark the border area between benign, reactive lymphoproliferation and neoplastic transformation. The advances of immunological classification of lymphoid cells with monoclonal antibodies and molecular genetic analysis have contributed to our present knowledge of pathomorphology, pathophysiology and nosology of malignant lymphomas. The stepwise evolution between polyclonal reactive lymphoproliferation and clonal autonomous growth in malignant lymphomas are presented by discussion of the mucosa-associated lymphomas (MALT-lymphomas) and typical lymphoproliferative diseases.
Contextual diagnosis of Hodgkin's disease and non-Hodgkin's lymphoma.
The pathologic evaluation of microscopic slides from patients with possible HD or NHL must be performed in the context of complete chronology of the patient's history. Advances in flow cytometry (S-phase analysis), immunophenotyping, and molecular genetics may be of value in diagnosis, classification, and prognostication. The Rye modification of the Lukes-Butler classification of HD has been stable since 1966 and is widely accepted because of its proven reliability. By contrast, the proliferation of classifications of NHL since 1966 speaks for imperfection, partially due to the still incomplete understanding of this diverse group of lymphoreticular malignancies. Successive classifications have incorporated immunologic relationships and concepts and added a clinically significant grading system. A goal of the working formulation was to allow translatability between classifications in the interest of comparison and communication of clinical and research results. Knowledge of the patterns of involvement and spread by HD and by the different categories of NHL helps to narrow the differential diagnosis of radiologic findings. An awareness of the benign, reactive processes and nonlymphoreticular malignant neoplasms that mimic HD and NHL is essential to avoiding misdiagnosis.
[Porphyria cutanea tarda, pseudoporphyria and hemodialysis of chronic renal failure patients].
With the help of the observation of a bullous dermatosis in a 52-year-old male with cystic kidneys, terminal renal insufficiency and chronic hemodialytic treatment the authors adopt a definite attitude to the pathogenesis of this coincidence frequently reported on. Since the determination of porphyrin in the urine does not reflect the plasma porphyrin content in the combination, after sonography by means of a liver blind puncture and missing fluorescence of the liver bioptate in the long-wave ultraviolet light a porphyria cutanea tarda could be excluded. The bullous dermatosis observed is to be ascribed to the pseudoporphyrias (idiopathically; phototoxically by drugs). Renal insufficiency and long-term haemodialysis apparently on the one hand further the manifestation of genetically conditioned diseases of porphyria cutanea tarda, on the other hand there are references that the chronic renal insufficiency itself leads to the disturbance of the hemobiosynthesis at the level of the uroporphyrinogen decarboxylase and that plasma porphyrins bound to highly molecular proteins are not capable to dialysis. A classification of skin changes accompanied by vesicles in patients with chronic renal insufficiency who were haemodialysed is proposed.
The Rhesus D antigen. A dicyclohexylcarbodiimide-binding proteolipid.
Previous studies on the human Rhesus D antigen revealed several similarities between the D antigen and proteolipids. Proteolipids are a family of low-molecular-weight, hydrophobic proteins that are soluble in chloroform/methanol. In addition, many proteolipids bind dicyclohexylcarbodiimide (DCCD), an ATPase inhibitor. For determination of whether the D antigen was a proteolipid, the chloroform/methanol solubility and DCCD binding of the antigen were investigated. DCCD specifically inhibited the binding of anti-D IgG to Rh-positive red blood cells and to partially purified D antigen as determined by enzyme-linked immunoassays. The antigen was not only soluble in chloroform/methanol but was purified to apparent homogeneity by extraction with these solvents and subsequent discontinuous sucrose gradient centrifugation. The antigen's chloroform/methanol solubility, DCCD binding, low molecular weight, and previously reported phospholipid dependence allow classification of the D antigen as a proteolipid. The discovery that the D antigen is a proteolipid provides further clues to the antigen's cellular function.