Leukemia inhibitory factor induces differentiation of pituitary corticotroph function: an immuno-neuroendocrine phenotypic switch.

Leukemia inhibitory factor (LIF) promotes differentiated cell function in several systems. We recently reported LIF and LIF receptor expression in human fetal pituitary corticotrophs in vivo and demonstrated LIF stimulation of adrenocorticotrophin (ACTH) transcription in vitro, suggesting a role for LIF in corticotroph development. We therefore assessed the action of LIF on proliferating murine corticotroph cells (AtT20).

Autoregulation of 1,25-dihydroxyvitamin D synthesis in macrophage mitochondria by nitric oxide.

Tissue macrophages from patients with granuloma-forming disease, most notably sarcoidosis, express a 25-hydroxyvitamin D-1-hydroxylase which can produce in vivo sufficient quantities of the active vitamin D metabolite 1,25-dihydroxyvitamin D to cause hypercalcemia. In contrast to the NADPH-dependent cytochrome P450-linked mixed function oxidase which is normally only expressed in significant quantity in proximal renal tubular cells and regulated in an endocrine fashion, the mitochondrial-based 1-hydroxylase in the macrophage [1] is stimulated in a paracrine mode by cytokines (i.e.

A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia.

The active form of vitamin D3 [1 alpha, 25-dihydroxyvitamin-D3 (1 alpha, 25(OH)2D3)] modulates the proliferation and differentiation of hematopoietic cells. Analogs of 1 alpha, 25(OH)2D3 that have greater potency may have the potential as adjuvant therapy for high-risk patients in remission for acute myelogenous leukemia (AML) and myelodysplastic syndromes. A new generation of 11 analogs of 1 alpha, 25(OH)2D3 has been synthesized, and we examined their effects on the human leukemic cell line HL-60.

Acromegaly.

Subcellular mechanisms support the notion of an intrinsic pituitary defect in acromegaly, with elevated growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels that affect the cardiovascular and respiratory system, as well as neoplastic cell proliferative activity. Surgery, even with external-beam irradiation adjuvant therapy, is only successful in less than 60% of patients, and there are side effects. Normalization of GH levels may improve survival rates.

A missense mutation in the neurofibromatosis 2 gene occurs in patients with mild and severe phenotypes.

We identified a missense mutation (T185-->C, Phe62-->Ser) in the neurofibromatosis 2 (NF2) gene in a family with mild and severe NF2 phenotypes. This mutation was previously reported in an unrelated family in which all affected individuals had mild phenotypes. These data demonstrate a lack of correlation between NF2 genotype and NF2 phenotype for this mutation.

Interleukin-10 gene expression in adult T-cell leukemia.

We studied the serum levels of interleukin-10 (IL-10), in patients with adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) infection. Elevated IL-10 levels were observed in 33 of 45 patients with ATL. Fresh leukemic cells from ATL patients as well as HTLV-I-infected T-cell lines MT-2, SLB-1, and C10/MJ expressed IL-10 mRNA by reverse transcription-polymerase chain reaction analysis, whereas IL-10 mRNA was not detected in normal peripheral mononuclear cells and an uninfected T-cell line Jurkat.

Unwanted effects of growth hormone excess in the adult.

This review discusses in vitro, animal and human studies which provide insights into the deleterious effects of excess GH and IGF-I. The systemic sequelae of hypersomatotrophism include disorders of the cardiovascular, respiratory and rheumatologic systems. Impaired carbohydrate metabolism and an increased incidence of gastrointestinal malignancy also contribute to morbidity and an average 10 year reduction in mortality.

Gastric intramural pH in mechanically ventilated patients.

Background: The hypothesis that gastric intramural pH (pHi) is predictive of outcome in haemodynamically stable, mechanically ventilated patients was tested in 25 patients on assisted mechanical ventilation for respiratory failure.

Methods: Simultaneous samples of arterial blood and gastric juice were obtained from patients on assist control, synchronised intermittent and pressure control ventilation during the first 48 hours of mechanical ventilation. Gastric pHi was calculated from the equation: pHi= 6.

Genetic mapping of the spinocerebellar ataxia type 2 gene on human chromosome 12.

The dominant spinocerebellar ataxias are a genetically heterogeneous group of diseases leading to premature death of neurons in the cerebellum and other parts of the nervous system. The mutation causing SCA1 is on human chromosome (CHR) 6p and SCA3 is on CHR 14q. To refine the location of the SCA2 gene on CHR 12q, we performed genetic linkage analysis between the SCA2 locus and nine Ioci (D12S58, D12S78, D12S317, D12S330, D12S353, D12S84, D12S105, D12S79, and PLA2) in three SCA2 families.

Infrequent alterations of the RAR alpha gene in acute myelogenous leukemias, retinoic acid-resistant acute promyelocytic leukemias, myelodysplastic syndromes, and cell lines.

Retinoids are important regulators of cell growth and differentiation in vitro and in vivo and they exert their biologic activities by binding to nuclear retinoic acid receptors (RARs; alpha, beta, and gamma) and retinoid X receptors (RXRs; alpha, beta, and gamma). All-trans retinoic acid (RA) induces complete remission in patients with acute promyelocytic leukemia (APL) presumably by binding directly to RAR alpha of APL cells. Leukemic blasts from APL patients initially responsive to RA can become resistant to the agent.

Protracted, gross hematuria in sickle cell trait: response to multiple doses of 1-desamino-8-D-arginine vasopressin.

Gross and microscopic hematuria are well-known complications in patients with sickle cell hemoglobinopathy. Most of these episodes of gross hematuria are self limiting, but rarely may be severe and persistent requiring definitive intervention. Before subjecting these patients to surgical management such as partial or total nephrectomy, several medical therapies of variable benefit have been suggested.

Molecular analysis of the cyclin-dependent kinase inhibitor family: p16(CDKN2/MTS1/INK4A), p18(INK4C) and p27(Kip1) genes in neuroblastomas.

Background: Chromosomal abnormalities involving band 1p32, especially deletions, are frequent in neuroblastomas, indicating that a tumor suppressor gene(s) is localized at this region. The p18 gene, one of the cyclin-dependent kinase inhibitor (CDKI) genes, maps to this chromosomal region. Complexes of cyclin and cyclin-dependent kinase (CDK) play important roles in the cell cycle.

Analysis of p16INK4a and its interaction with CDK4.

The interaction between cyclin-dependent kinase 4 (CDK4) and its inhibitor p16INK4a (p16) was studied by random mutagenesis and yeast two-hybrid system. The gene encoding p16 was mutagenized randomly and the amino acid changes that affect the binding of p16 to CDK4 were identified. Several amino acid residues were shown to be important for the binding and many of these changes occur at residues conserved in all known human p16 family proteins Most of the mutant p16 proteins that failed to bind to CDK4 contained multiple amino acid changes, and these alterations were observed throughout the entire gene with no apparent mutational patterns or hot spots.

20-Epi-vitamin D3 analogs. Potent modulators of proliferation and differentiation of breast cancer cell lines in vitro.

Breast cancer is a devastating disease. New approach in therapy are needed. In this chapter, we describe our efforts to identify novel vitamin D3 analogs which may have a potent antiproliferative effect on breast cancer without causing hypercalcemia.

IGF-I receptor signalling: lessons from the somatotroph.

Insulin-like growth factor 1 (IGF-I) is a major feedback regulator of pituitary GH secretion, with defined actions occurring at both the hypothalamus and pituitary. The IGF-I gene is expressed in the anterior pituitary in a GH-dependent manner thus providing for both endocrine-as well as autocrine-mediated GH regulation. In turn, IGF-I selectively and specifically inhibits GH gene transcription and secretion, its attenuating effects on nascent GH mRNA synthesis being demonstrable within 1 h.

Heparin-binding secretory transforming gene (hst) facilitates rat lactotrope cell tumorigenesis and induces prolactin gene transcription.

We have shown previously that human prolactinomas express transforming sequences of the heparin-binding secretory transforming gene (hst) which encodes fibroblast growth factor-4 (FGF-4). To elucidate the role of hst in pituitary tumorigenesis we treated primary rat pituitary and pituitary tumor cell cultures with recombinant FGF-4 and also stably transfected pituitary cell lines with full-length human hst cDNA. Transfectants were screened for hst mRNA expression and FGF-4 production.

Expression of Id2 and Id3 mRNA in human lymphocytes.

Helix-loop-helix (HLH) transcription factors are involved in cellular growth and differentiation. The Id (inhibitor of DNA binding and differentiation) HLH proteins, in a dominantly negative fashion, regulate transcriptional activities of basic HLH proteins. We examined by northern hybridization the expression of Id2 and Id3 mRNA in human leukemia/lymphoma lines and patient samples, as well as resting and activated normal human lymphocytes from peripheral blood (PBL).

Characterization of adenosine-uridine-rich RNA binding factors.

The adenosine-uridine (AU)-rich sequences within the 3' untranslated region (UTR) of many short-lived mRNAs are important in their rapid degradation. We present evidence that human embryonic lung fibroblasts (W138) contain five major proteins of 70, 45, 40, 38, 32.5 kd, which specifically bind the AU-rich region of human granulocyte-macrophage colony-stimulating factor (GM-CSF) 3'UTR containing 7 x AUUUA motifs.

Isolated reduction in single-breath diffusion capacity in young, healthy, asymptomatic women.

The clinical significance of an isolated reduction in the carbon monoxide diffusing capacity (DLCO) in nonsmoking, asymptomatic individuals is not known. Whether a reduced DLCO despite otherwise normal pulmonary function tests warrants further investigation remains unanswered. In this article, the authors describe five healthy, asymptomatic, young women who had isolated, reduced DLCO and subsequent follow-up examinations over a span of 6 years.