Biomedical subjects
K Peterson
Publications and source records attributed to K Peterson.
Oligodendrogliomas.
Although oligodendrogliomas cannot be considered benign tumors, many are slow-growing indolent tumors for which prolonged life expectancy is the rule. Others behave in a more aggressive, malignant fashion, as would be predicted by their histologic characteristics. The treatment for oligodendrogliomas is evolving, with conservative management still reserved for nonanaplastic tumors, and increasingly aggressive systemic therapies being developed for more aggressive or recurrent tumors.
alpha-Amino butyric acid cannot reactivate the silenced gamma gene of the beta locus YAC transgenic mouse.
Butyric acid, a naturally occurring fatty acid, has been shown to increase fetal hemoglobin in BFUe cultures, in primates, and in patients with beta chain hemoglobinopathies. The precise mechanism of gamma gene induction by butyrate is unknown. Butyrate may induce fetal hemoglobin production in vivo by reactivation of silenced gamma globin genes, by inhibiting the silencing of gamma genes, or by both mechanisms. We examined the effects of butyrate on gamma gene expression in transgenic mice carrying three types of constructs: microLCRA gamma mice, which continue to express the gamma gene in the adult stage of development at a level of one-third to one-fifth of the expression in the fetus; microLCRA gamma psi beta delta beta mice, which display correct developmental regulation of gamma and beta human globin genes and have low level gamma globin expression in the adult; and beta locus YAC mice, which display correct developmental regulation of epsilon, gamma, and beta globin genes and have a totally silenced gamma gene in the adult stage. Animals were treated with a continuous infusion of alpha-amino butyric acid (alpha-ABA) for 7 days. In microLCRA gamma mice alpha-ABA produced up to a 43-fold induction of gamma and 9-fold induction of mouse alpha globin genes. In contrast, butyrate did not induce gamma globin expression in the beta locus YAC mice. However, the gamma globin genes of beta locus YAC mice were activated after administration of 5-azacytidine (5-azaC), and the level of gamma globin expression was further increased by administration of alpha-ABA. These results suggest that butyrate cannot reactivate a totally silenced gamma gene and that induction of fetal hemoglobin by this compound may require the presence of preactivated gamma globin genes.
Paraneoplastic sensorimotor neuropathy associated with breast cancer.
Paraneoplastic sensorimotor neuropathy occurs in association with many different types of cancer. The clinical findings are heterogeneous, and the pathogenesis is unknown. We have encountered 9 women with breast cancer and shared neurological features that suggest a distinct paraneoplastic syndrome. The syndrome is characterized by upper and lower extremity paresthesias and numbness, itching, muscle weakness and cramps, and in some, radicular symptoms and signs. Serum and CSF inflammatory changes suggested an immune pathogenesis but none had detectable antibodies directed at nervous system elements. Six patients presented with neuropathy 2 months to 8 years before the discovery of the breast cancer. In 7 the neoplastic disease was localized to the breast and axillary lymph nodes. The neurologic course was chronic in all, and while symptoms were annoying, disability was minimal until late. One improved transiently with plasmapheresis, and three had mild transient improvement with treatment of the cancer. Recognition of this paraneoplastic syndrome may forewarn the physician of an underlying breast malignancy.
A polymorphic residue in the amino terminal alpha 1 hemi-domain of the mouse Ld class I molecule affects its assembly and surface expression.
In comparison to Dd and most other mouse major histocompatibility complex class I molecules, the Ld molecule is poorly expressed on the cell surface, has a lower affinity for beta 2-microglobulin and is trafficked more slowly to the cell surface. Previous studies using Ld-Dd exon-shuffled constructs and the chimeric Ddm1 molecules suggested that the Ld alpha 1 domain was responsible for this phenotype. Two constructs, one containing an Ld-Dd hemi-exon-shuffled alpha 1 exon and the other containing a Dd-Ld hemi-exon-shuffled alpha 1 exon, were inserted into either Ld or Dd to replace the intact alpha 1 exon. These constructs were transfected into mouse L cells. Flow cytometric analyses of the resulting transfectants indicate that the Dd-Ld alpha 1/Ld molecules, similar to the Dd alpha 1/Dd alpha 2/Ld molecules, were expressed at a higher level on the cell surface than either the Ld-Dd alpha 1/Ld molecules or intact Ld molecules. Analyses of the molecules in lysates suggested that a higher proportion of the Dd-Ld alpha 1/Ld molecules, like the Dd alpha 1/Dd alpha 2/Ld molecules, as compared to the Ld-Dd alpha 1/Ld and intact Ld molecules were assembled as detected by alpha 2 domain-reactive monoclonal antibodies. Pulse-chase and lysate stability studies suggested that the lower steady state levels of assembled Ld-Dd alpha 1 molecules resulted from a slower assembly rate rather than instability. Collectively, these studies suggest that residues in the amino terminal half of the Ld alpha 1 domain are responsible for its inefficient assembly, probably leading to its low cell surface expression. To determine which polymorphic residues in the amino terminal alpha 1 hemi-domain might influence this phenotype, several Ld point mutants, in which a Dd amino terminal alpha 1 hemi-domain residue was substituted into the corresponding position of Ld, were analysed. These analyses suggested that, while the residue at position 9 has only a slight effect on beta 2-microglobulin association, it has a striking effect on assembly and cell surface expression.
Staged diabetes management. Toward an integrated model of diabetes care.
This paper introduces a new and innovative approach to diabetes management in the primary-care setting. Staged diabetes management (SDM) represents a four-year effort to develop and test a data-based approach to diabetes management that could be easily adapted to a variety of health-care settings in which diabetes management is principally under the direction of primary-care physicians was limited access to specialists. After testing under controlled circumstances at the International Diabetes Center (Minneapolis, MN), SDM was subjected to substantial field trials under conditions that represent the scope and variety of primary-care practices in diabetes. The following represents the work of several investigators who independently undertook a review of SDM.
The syntaxin family of vesicular transport receptors.
Syntaxins A and B are nervous system-specific proteins implicated in the docking of synaptic vesicles with the presynaptic plasma membrane. A family of syntaxin-related proteins from rat has been identified that shares 23%-84% amino acid identity. Each of the six syntaxins terminate with a carboxy-terminal hydrophobic domain that anchors the protein on the cytoplasmic surface of cellular membranes. The syntaxins display a broad tissue distribution and, when expressed in COS cells, are targeted to different subcellular compartments. Microinjection studies suggest that the nervous system-specific syntaxin 1A is important for calcium-regulated secretion from neuro-endocrine PC12 cells. These results indicate that the syntaxins are a family of receptors for intracellular transport vesicles and that each target membrane may be identified by a specific member of the syntaxin family.
The clinical spectrum of ocular lymphoma.
BACKGROUND: Ocular lymphoma is an uncommon cause of chronic vitreitis or uveitis, often refractory to steroid treatment, and frequently representing another site of multifocal primary central nervous system lymphoma (PCNSL). METHODS: The authors reviewed the medical and ophthalmologic records of 24 patients with ocular lymphoma; 23 had associated PCNSL: RESULTS: In half, the eyes were the initial site of disease; in the others central nervous system (CNS) lymphoma developed before, or concurrent with, ocular lymphoma. Most patients had bilateral ocular symptoms; slit-lamp examination revealed asymptomatic disease in four. Vitrectomy was not always diagnostic, particularly in patients who had received steroids. Ocular ultrasound, performed on seven patients, provided an objective measure of disease and treatment response. Patients received a variety of therapeutic combinations of steroids, radiation, and chemotherapy, including high-dose cytosine arabinoside. Despite therapy, eventual ocular or CNS relapse or both was common. Thirteen patients have died, 12 with known recurrent CNS disease. CONCLUSIONS: Ocular lymphoma frequently is associated with PCNSL: The diagnosis should be considered in patients with steroid-resistant chronic vitreitis or uveitis. Patients with PCNSL should be carefully evaluated for ocular involvement, regardless of symptoms. Treatment can contribute to prolonged remission, but eventual ocular or CNS relapse is the rule.
Brain contains two forms of synaptic vesicle protein 2.
Molecular cloning of a cDNA encoding synaptic vesicle protein 2 (SV2) revealed that it is homologous to a family of proton cotransporters from bacteria and fungi and to a related family of glucose transporters found in mammals. The similarity to proton cotransporters raised the possibility that SV2 might mediate the uptake of neurotransmitters into vesicles, an activity known to require a proton gradient. To determine whether SV2 is a member of a family of vesicular proteins, we used the SV2 clone to screen for similar cDNAs in rat brain. We characterized 42 clones, 25 of which encode SV2 and 4 of which encode a protein, SV2B, that is 65% identical and 78% similar to SV2. The protein encoded by SV2B cDNA is recognized by the monoclonal antibody that defines the SV2 protein. When SV2B is expressed in COS cells, antibody labeling is reticular in nature, suggesting that SV2B, like SV2 (hence, SV2A), is segregated to intracellular membranes. The expression of SV2B is limited to neural tissue. While both forms of SV2 are expressed in all brain regions, SV2B is expressed at highest levels in the cortex and hippocampus, whereas the highest level of expression of SV2A is in subcortical regions. Therefore, the SV2 proteins, like other characterized synaptic vesicle proteins, comprise a small gene family.
Microinjection of intact 200- to 500-kb fragments of YAC DNA into mammalian cells.
DNA of yeast artificial chromosomes (YACs) was prepared for microinjection by separation from most of the natural yeast chromosomes on a pulsed-field gel, treatment with agarase, and centrifugation. A salt concentration of 100 mM NaCl was necessary to protect the DNA from shear during these procedures. Injection of a 590-kb YAC, yGART2, into Chinese hamster ovary cells gave rise to cells expressing the 40-kb human GART gene carried on the YAC. Nine of 12 cell lines analyzed contained an intact stretch of at least 110 kb of YAC DNA surrounding the GART gene, and one cell line contained at least 480 kb, but not the entire 590 kb, intact. Mouse L A-9 cells were similarly injected with DNA of a 230-kb YAC containing the human beta-globin gene cluster and a mammalian selectable marker. Seven of 10 of the resulting cell lines contained both YAC vector arms plus the intact 140-kb SfiI fragment spanning the beta-globin gene. Three cell lines were analyzed by RecA-assisted restriction endonuclease (RARE) cleavage and found to contain the entire intact 210-kb YAC insert. Introduction of similarly prepared DNA into mammalian cells by lipofection gave rise to cell lines with multiple YAC fragments that were generally shorter than the YAC fragments found in microinjected cell lines. The results show that microinjection of gel-purified YAC DNA into mammalian cells is an efficient method of transferring DNA fragments several hundred kilobase pairs in size into mammalian cells.
Imprinting the genome: imprinted genes, imprinting genes, and a hypothesis for their interaction.
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Effect of brain irradiation on demyelinating lesions.
Demyelinating lesions, such as those in multiple sclerosis, may resemble primary or metastatic brain tumors on CT or MRI, and even be mistaken for neoplasms on biopsy. We encountered five such patients in whom an incorrect diagnosis of CNS neoplasm was made on the basis of radiologic appearance (five) and biopsy (four). All five received radiation therapy, and three chemotherapy. Review of the pathologic findings indicated that the original lesions were not neoplastic but demyelinative. The four patients who received radiation in full tumoricidal doses had unexpectedly poor clinical outcome, suggesting that radiation is especially injurious to patients with demyelinating disease.
The health care Titanic: women and children first?
The plight of people who lack access to health care has captured national attention and led to a number of proposals to remedy the problem. The authors look at three types of proposals being advanced--"pro-competition" plans, "pay-or-play" plans, and a national health care system--and find that they fail to address adequately the pressing needs of two groups of the poor: women of childbearing age and elderly women.
Glucose intolerance as a consequence of oral terbutaline treatment for preterm labor.
BACKGROUND: In this case series, glucose regulation is examined prospectively during treatment with terbutaline sulfate for premature labor in women who were (1) previously documented as nondiabetic, (2) found to have gestational diabetes mellitus (GDM), and (3) tested for glucose intolerance while terbutaline was being administered. The glucose profiles of women treated with terbutaline were contrasted with the profiles of nondiabetic women and women known to have GDM who were not in premature labor. METHODS: Subjects tested capillary blood glucose an average of five times a day during terbutaline treatment and for 1 week after terbutaline treatment was discontinued. They used memory-based reflectometers that stored and transmitted self-monitored blood glucose data to a personal computer. RESULTS: A significant difference (P = .001) was found between average fasting glucose values (111 +/- 23 mg/dL) for the five nondiabetic subjects treated with terbutaline and values of patients in an historical control group (41 nondiabetic pregnancies [72 +/- 22 mg/dL]) who were not in premature labor. The four diabetic subjects and the one subject who had not been previously tested also experienced higher blood glucose levels during tocolytic therapy. Glucose levels returned to preintervention values with the cessation of terbutaline therapy. CONCLUSIONS: It has been previously suggested that terbutaline increases hepatic glycogenolysis, which may aggravate glucose intolerance. This phenomenon, combined with normal pregnancy-induced insulin resistance, may explain abnormal ambulatory glucose patterns in women who are euglycemic before introduction of terbutaline therapy.
SV2, a brain synaptic vesicle protein homologous to bacterial transporters.
Synaptic vesicle protein 2 (SV2) is a membrane glycoprotein specifically localized to secretory vesicles in neurons and endocrine cells. As a first step toward understanding the function of SV2 in neural secretion, a rat brain complementary DNA (cDNA) that encodes SV2 was isolated and characterized. Analyses of this cDNA predict that SV2 contains 12 transmembrane domains. The NH2-terminal half of the protein shows significant amino acid sequence identity to a family of bacterial proteins that transport sugars, citrate, and drugs. Expression of the SV2 cDNA in COS cells yielded a high level of SV2-like immunoreactivity distributed in a reticular and punctate pattern, which suggests localization to intracellular membranes. Its localization to vesicles, predicted membrane topology, and sequence identity to known transporters suggest that SV2 is a synaptic vesicle-specific transporter.
Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas.
Neuroblastomas have been characterized genetically by N-myc amplification and by deletions or loss of heterozygosity (LOH) for the short arm of chromosome 1. However, recent studies have suggested deletion or allelic loss involving at least three other chromosome arms, 11q, 14q, and 17p. Therefore, we undertook an analysis of allelic loss for these respective chromosomal arms to determine the frequency and pattern of LOH as well as the correlation of these findings with other biological and clinical variables. A group of 24 pairs of normal and tumor DNAs was chosen that were representative of patients of different ages and stages. A substantial frequency of LOH (greater than or equal to 20%) was found only for 1p and 14q, whereas LOH for the other chromosome arms occurred in less than or equal to 5% of cases. On the basis of these results, we extended the analysis to a total of 59 neuroblastomas, and we found 1p LOH in 15 of the 59 cases (25%) and 14q LOH in 10 of 43 informative cases (23%). N-myc amplification was found in 15 of the 59 cases (25%). This analysis confirmed that 1p LOH and 14q LOH occurred almost exclusively in patients with advanced stages of disease. Furthermore, LOH for 1p and 14q usually occurred independent of each other, and 1p LOH frequently was associated with N-myc amplification, whereas 14q LOH was not. Thus, our results demonstrate that neuroblastomas are complex genetically and that there are at least two distinct loci for putative suppressor genes that are deleted independently in this tumor, both of which are associated with advanced stages of disease.
Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients.
We reviewed the clinical findings in 55 patients with cerebellar degeneration associated with the anti-Yo antibody (an anti-Purkinje cell antibody identified in this study by histochemistry and Western blot). The patients were all women, 26 to 85 years old. Fifty-two of them proved to have malignancies, almost exclusively breast or gynecologic cancers and usually confined to the involved organs and local lymph nodes. One woman had adenocarcinoma of the lung, and in three no malignancy has yet been identified. In 34 of 52 patients with cancer, the neurologic syndrome preceded the diagnosis of cancer and in many led to that diagnosis. Patients subacutely developed a pancerebellar disorder that was substantially disabling in most, with 37 of 48 assessable patients being unable to walk or sit unassisted. Laboratory evaluation revealed lymphocytic pleocytosis in 35 patients, with eventual cerebellar atrophy on imaging studies in seventeen. The disabling neurologic syndrome generally did not respond to treatment, but the cancer was often successfully treated. The presence of the anti-Yo antibody in patients with cerebellar symptoms warrants an aggressive approach to diagnosis and treatment of the underlying cancer, as many are curable at the time neurologic symptoms develop.
Placing decisionmaking in the hands of those who can make a difference.
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