Postpartum fevers, a rare presentation of secondary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease of excessive immune system activation. We report a case of HLH in a 20-year-old primigravid woman who presented with postpartum fevers. She was successfully treated with dexamethasone and anakinra, a deviation from the HLH-94 protocol, to preserve her ability to breastfeed.

Melanotic Xp11 translocation renal cancers: a distinctive neoplasm with overlapping features of PEComa, carcinoma, and melanoma.

We describe 2 cases of malignant melanotic epithelioid renal neoplasms bearing TFE3 gene fusions. Both neoplasms occurred in children (an 11-y-old boy and a 12-y-old girl), and presented with disseminated metastatic disease including mediastinal and mesenteric adenopathy. Both neoplasms featured sheets of epithelioid cells with clear to finely granular eosinophilic cytoplasm set in a branching capillary vasculature.

Epstein-Barr virus-associated central nervous system lymphoproliferative disease in a patient with acquired immunodeficiency syndrome responsive to highly active antiretroviral therapy.

A 20-year-old man with acquired immunodeficiency syndrome (AIDS) and central nervous system (CNS) lymphoproliferative disease experienced improvement with highly active antiretroviral therapy (HAART) without radiation therapy. Our experience highlights the importance of biopsy in evaluating multifocal radiographic CNS lesions and the central role of HAART in treating AIDS-related CNS disease.

New markers of pancreatic cancer identified through differential gene expression analyses: claudin 18 and annexin A8.

Background: New markers to distinguish benign reactive glands from infiltrating ductal adenocarcinoma of the pancreas are needed.

Design: The gene expression patterns of 24 surgically resected primary infiltrating ductal adenocarcinomas of the pancreas were compared with 18 non-neoplastic samples using the Affymetrix U133 Plus 2.0 Arrays and the Gene Logic GeneExpress Software System.

PAM4-reactive MUC1 is a biomarker for early pancreatic adenocarcinoma.

Purpose: The anti-MUC1 monoclonal antibody (MAb), PAM4, has a high specificity for pancreatic adenocarcinoma compared with other cancers, normal tissues, or pancreatitis. In order to assess its role in early pancreatic cancer development, we examined the expression of the PAM4-reactive MUC1 in the noninvasive precursor lesions, pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN).

Experimental Design: Tissue microarrays prepared from formalin-fixed, paraffin-embedded specimens were assessed by immunohistology for expression of the PAM4-reactive, non-variable number of tandem repeats (VNTR), MUC1 epitope, and the VNTR epitope bound by the MA5 MAb.

Generation and characterization of endonuclease G null mice.

Endonuclease G (endo G) is one of the most abundant nucleases in eukaryotic cells. It is encoded in the nucleus and imported to the mitochondrial intermembrane space. This nuclease is active on single- and double-stranded DNA.

DNA damage and aging.

The hypothesis discussed here is that a major component of aging in metazoans is oxidative damage to nuclear DNA. Such a viewpoint would be consistent with the fact that all of the thus far identified premature aging syndromes in mammals involve mutations in nuclear proteins. Several of these nuclear proteins are enzymes that are related to DNA metabolism or DNA repair.

Ageing, repetitive genomes and DNA damage.

The mitochondrial production of reactive oxygen species is inversely proportional to longevity in animals. A key question now is, which molecules, among those that are oxidized, affect the lifespan of the organism most significantly?

Developmental retinal apoptosis in Ku86-/- mice.

The nonhomologous DNA end-joining pathway (NHEJ), a major pathway for repairing DNA double-strand breaks (DSBs), is essential for maintaining genomic stability. Knockout animals for components in this pathway demonstrate a distinct pattern of cell death in the developing brain. Here we demonstrate that cell death is also present in the developing retina of E14.

Overexpression of Cu/Zn superoxide dismutase is lethal for mice lacking double-strand break repair.

The non-homologous DNA end joining (NHEJ) pathway is a major double-strand DNA break repair pathway in cells of multicellular eukaryotes. Ku is a heterodimeric protein consisting of Ku70 and Ku86, and it is thought to be the first component to bind to a broken double-strand DNA end. Mice lacking Ku86 show features of premature aging, live about 6-12 months, and show a characteristic loss of neurons in the central nervous system during development.

The embryonic lethality in DNA ligase IV-deficient mice is rescued by deletion of Ku: implications for unifying the heterogeneous phenotypes of NHEJ mutants.

There are two general pathways by which multicellular eukaryotes repair double-strand DNA breaks (DSB): homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). All mammalian mutants in the NHEJ pathway demonstrate a lack of B and T lymphocytes and ionizing radiation sensitivity. Among these NHEJ mutants, the DNA-PK(cs) and Artemis mutants are the least severe, having no obvious phenotype other than the general defects described above.

Two overlapping divergent transcription units in the human genome: the FEN1/C11orf10 locus.

Flap endonuclease 1 (FEN-1) is a nuclear enzyme involved in DNA metabolism, such as replication, repair, and recombination. Here, we report the comparative genomic organization of the chicken, mouse, and human FEN1 genes as well as the comparative organization of a small gene (C11orf10) located immediately upstream of the FEN1 gene in reverse orientation. Immunostaining revealed that the C11orf10 protein, unlike FEN-1, is located in the cytoplasm, suggesting that these two proteins do not form a physical complex.

Oxygen metabolism causes chromosome breaks and is associated with the neuronal apoptosis observed in DNA double-strand break repair mutants.

Cells deficient in a major DNA double-strand break repair pathway (nonhomologous DNA end joining [NHEJ]) have increased spontaneous chromosome breaks; however, the source of these chromosome breaks has remained undefined. Here, we show that the observed spontaneous chromosome breaks are partially suppressed by reducing the cellular oxygen tension. Conversely, elevating the level of reactive oxygen species by overexpressing the antioxidant enzyme superoxide dismutase 1 (SOD1), in a transgenic mouse, increases chromosome breakage.

The mammalian FEN-1 locus: structure and conserved sequence features.

Flap endonuclease 1 (FEN-1) is an enzyme that is very important for DNA replication in all eukaryotes because it cleaves the 5' DNA flaps that arise between Okazaki fragments. In addition, FEN-1 is important for base excision repair and for nonhomologous DNA end joining in all eukaryotes from yeast to human. Here we report the structure and sequence of the murine genomic FEN-1 locus, and we compare it to the human FEN-1 locus.

The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes.

We performed a genome scan at an average resolution of 8 cM in 719 Finnish sib pairs with type 2 diabetes. Our strongest results are for chromosome 20, where we observe a weighted maximum LOD score (MLS) of 2.15 at map position 69.

Complete maternal isodisomy of chromosome 8 in an individual with an early-onset ileal carcinoid tumor.

Uniparental disomy (UPD) is a condition in which diploid individuals possess a chromosome pair from a single parent. In some instances, UPD causes an abnormal phenotype due to imprinting effects, reduction to homozygosity at recessive disease loci, or trisomy mosaicism. Here we report the first account of an individual with apparently nonmosaic complete maternal isodisomy of chromosome 8.

Localization of multiple melanoma tumor-suppressor genes on chromosome 11 by use of homozygosity mapping-of-deletions analysis.

Loss-of-heterozygosity (LOH) studies have implicated one or more chromosome 11 tumor-suppressor gene(s) in the development of cutaneous melanoma as well as a variety of other forms of human cancer. In the present study, we have identified multiple independent critical regions on this chromosome by use of homozygosity mapping of deletions (HOMOD) analysis. This method of analysis involved the use of highly polymorphic microsatellite markers and statistics to identify regions of hemizygous deletion in unmatched melanoma cell line DNAs.

The nonhomologous DNA end joining pathway is important for chromosome stability in primary fibroblasts.

There are two types of chromosome instability, structural and numerical, and these are important in cancer. Many structural abnormalities are likely to involve double-strand DNA (dsDNA) breaks. Nonhomologous DNA end joining (NHEJ) and homologous recombination are the major pathways for repairing dsDNA breaks.

A large sample of finnish diabetic sib-pairs reveals no evidence for a non-insulin-dependent diabetes mellitus susceptibility locus at 2qter.

In the first reported positive result from a genome scan for non-insulin-dependent diabetes mellitus (NIDDM), Hanis et al. found significant evidence of linkage for NIDDM on chromosome 2q37 and named the putative disease locus NIDDM1 (Hanis et al. 1996.

Methods for precise sizing, automated binning of alleles, and reduction of error rates in large-scale genotyping using fluorescently labeled dinucleotide markers. FUSION (Finland-U.S. Investigation of NIDDM Genetics) Study Group.

Large-scale genotyping is required to generate dense identity-by-descent maps to map genes for human complex disease. In some studies the number of genotypes needed can approach or even exceed 1 million. Generally, linkage and linkage disequilibrium analyses depend on clear allele identification and subsequent allele frequency estimation.

Substrate nucleotide-determined non-templated addition of adenine by Taq DNA polymerase: implications for PCR-based genotyping and cloning.

The Applied Biosystems PRISM fluorescence-based genotyping system as well as the Invitrogen TA Cloning vector system are influenced by the tendency of Taq DNA polymerase to add an adenine nucleotide to the 3' end of PCR products after extension. Incomplete addition of adenine to a majority of PCR product strands creates problems in allele-calling during genotyping and potentially diminishes the cloning efficiency of such products. Experiments reported here show that certain terminal nucleotides can either inhibit or enhance adenine addition by Taq and that PCR primer design can be used to modulate this activity.

Conversion of Allylic Alcohols into Allylic Nitromethyl Compounds via a Palladium-Catalyzed Solvolysis: An Enantioselective Synthesis of an Advanced Carbocyclic Nucleoside Precursor(1).

A two-step reaction sequence to homoallylic nitro compounds from allylic alcohols is presented. Ethoxy carbonylation of the alcohols with ethyl chloroformate provides the corresponding allylic ethyl carbonates in high yields. Exposure of these substrates to catalytic palladium(0) in CH(3)NO(2) initiates a reaction sequence, ionization-decarboxylation-nitromethylation, that culminates with the formation of nitroalkenes.