Insulin analog lispro decreases insulin resistance and improves glycemic control in an obese patient with insulin-requiring type 2 diabetes.
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Biomedical subjects
Publications and source records attributed to C Oliver.
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The breast is not classically included among the organs damaged by diabetic complications. The first cases of breast lesions associated with Type 1 diabetes mellitus were only described in 1984. The disease, designated as diabetic or fibrous mastopathy, is benign but may clinically simulate breast carcinoma. Its frequency is difficult to evaluate, and its pathogenesis is not yet clearly understood. We report two cases of diabetic mastopathy, together with a review of the medical literature on this subject and a description of the main characteristics of the disease. Diagnosis is based on the clinical context (premenopausal women with longstanding Type 1 diabetes mellitus who develop a hard, painless, mobile lump on one or both breasts), radiology (dense glandular tissue on mammography and marked acoustical shadowing of sound waves on sonography), and histopathology (fibrosis and perivascular and periductal lymphocytic infiltration).
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Genetic variation in the APOE gene and variation in chromosome 21 genotypes, including the APP locus, may influence age-associated cognitive decline in adults with Down syndrome. Molecular genetic and longitudinal neuropsychological analysis was performed for 41 unrelated Caucasian individuals (mean age 48.1 +/- 1.1 years (s.c.m.)) with free trisomy 21. Allele frequencies and genotype distributions were compared among subgroups with or without evidence of cognitive decline. Genetic variability at APOE and APP was not significantly associated with evidence of cognitive decline. However, aged individuals with Down syndrome, without evidence of cognitive decline, demonstrated unusual allelic variability at D21S11. These findings are discussed in the context of current hypotheses of Alzheimer-type dementia in Down syndrome and in the general population.
The ferromagnetism, and therefore the safety in a magnetic resonance (MR) examination, of the most widely available air gun pellets has been tested. While many are made of lead and are not ferromagnetic, some contain steel and are deflected strongly in a magnetic field. There must therefore be careful consideration before undertaking MR examinations of patients with embedded air gun pellets.
The lack of immunological or morphological markers makes identification of immature mast cells difficult. In the present study we have used a rat mast cell specific monoclonal antibody (mAb AA4) to immunolabel mast cells during repopulation of the peritoneal cavity. Peritoneal cells were collected six days after injection of distilled water and examined by light and electron microscopy. mAb AA4 stained immature mast cells in various stages of maturation including a population of very immature mast cells that could not be identified using conventional staining methods. These cells had virtually no cytoplasmic granules and peripherally located lobated nuclei. Thus, immunolabeling with mAb AA4 has revealed a population of very immature mast cells not previously reported during repopulation of the peritoneal cavity.
We studied the effect of various agonists of excitatory amino acid (EAA) receptor subtypes on somatostatin (SRIF) release from incubated rat hypothalamic slices. N-Methyl-D-aspartic acid (NMDA) and L-glutamate (1 x 10(-7) to 1 x 10(-3) M) stimulated, in a dose-dependent fashion, SRIF release. The maximal effect was obtained at a concentration of 1 x 10(-4) M for both drugs. The IC50 was 3.2 x 10(-5) M and 2.1 x 10(-5) M for NMDA and L-glutamate, respectively. Incubation with 2.5 x 10(-4) M D-2-amino-5-phosphonovalerate (a NMDA receptor antagonist) or 2-amino-4-phosphonobutyrate (a metabotropic receptor antagonist) was without significant effect on basal SRIF secretion and completely blocked the increase in SRIF release induced by 5 x 10(-5) M NMDA or L-glutamate, respectively. Incubation with 1 x 10(-4) M kainate or 0.5 x 10(-4) M alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) did not change basal SRIF secretion. Incubation with 2 x 10(-4) M gamma-D-glutamylglycine (a specific antagonist of kainate and AMPA receptors) had no effect under basal conditions or during exposure to kainate or AMPA. Our data demonstrate that EAAs stimulate SRIF secretion in vitro, by an action through NMDA and metabotropic receptors but not kainate or AMPA receptors.
Somatostatin binding sites have been localized and quantified in the sheep brain using 125I-Tyr0-DTrp8-somatostatin, by quantitative high resolution light microscopic autoradiography. Sections were analyzed by densitometry on radioautographic film, and subsequently on slides coated with photoemulsion. Specific somatostatin binding sites were concentrated in the medial habenula, superior colliculus, dorsal motor nucleus of the vagus nerve, inferior olive, spinal trigeminal nucleus, and cerebellum. In competition experiments, octreotide, a sst2/sst3/sst5 selective agonist only partially displaced 125I-Tyr0-DTrp8-somatostatin in the three cerebellar layers while it was fully active as compared to somatostatin 14 and 28 in the deeper layers of the parietal cortex. Moderate to low somatostatin receptor densities were present in the mesencephalic periaqueductal gray, dorsal raphe, thalamic paraventricular nucleus, interpeduncular nucleus, pineal gland, dorsal tegmental, dorsolateral tegmental and parabrachial nuclei, nucleus of the solitary tract. The distribution of somatostatin binding sites generally correlates with the data obtained on slides dipped in photoemulsion which provided better resolution and more precise localization. In most of the labeled areas, 125I-Tyr0-DTrp8-somatostatin receptor binding was distributed between both neuropil and perikarya. Perikarya bearing 125I-Tyr0-DTrp8-somatostatin receptors were observed in areas which did not display detectable binding sites on film such as the preoptic-anterior hypothalamic complex and arcuate nucleus and in the locus coeruleus. In conclusion, the distribution of 125I-Tyr0-DTrp8-somatostatin binding sites in sheep brain is very reminiscent of other mammals being closer to the human than to rodents.
It is known that in vivo excitatory amino acids (EAA) stimulate the hypothalamo-pituitary-adrenal axis. However their site of action is not fully understood. We investigated the possibility of a direct action of EAA on the secretion of the major adrenocorticotropin hormone (ACTH) secretagogue: corticotropin-releasing factor (CRF) from incubated rat hypothalamic slices. N-methyl-D-aspartic acid (NMDA) or L-glutamate (1 x 10(-7) to 1 x 10(-3) M) stimulated in a dose-dependent fashion CRF release. The maximal effect was obtained at a concentration of 1 x 10(-4) M for both drugs. The IC50 was 1.3 x 10(-5) M and 3.3 x 10(-5) M for NMDA and L-glutamate, respectively. Incubation with 2.5 x 10(-4) M D-2-amino-5-phosphonovalerate (a NMDA receptor antagonist) or 2-amino-4-phosphonobutyrate (a metabotropic receptor antagonist) was without significant effect on basal CRF secretion and completely blocked the increase in CRF release induced by 5 x 10(-5) M NMDA or L-glutamate, respectively. Incubation with 1 x 10(-4) M kainate or 0.5 x 10(-4) M AMPA did not change basal CRF secretion. Incubation with 2 x 10(-4) M gamma-D-glutamylglycine (a specific antagonist of kainate and AMPA receptor) had no effect under basal conditions or during exposure to kainate or AMPA. Our data demonstrate that EAA could stimulate directly CRF secretion, by an action through NMDA and metabotropic receptors, but not kainate or AMPA receptors. These findings may be relevant to the regulation of the hypothalamo-pituitary adrenal axis, both under basal conditions and during exposure to stress.
Neutralizing polyclonal antibody to respiratory syncytial virus (RSV) has been shown to be an effective prophylactic agent when administered intravenously in high-risk infants. This study describes the generation of a humanized monoclonal antibody, MEDI-493, that recognizes a conserved neutralizing epitope on the F glycoprotein of RSV. The affinity of MEDI-493 was found to be equal to or slightly better than an isotype-matched chimeric derivative of the parent antibody. In plaque reduction, microneutralization, and fusion-inhibition assays, MEDI-493 was significantly more potent than the polyclonal preparation. Broad neutralization of a panel of 57 clinical isolates of the RSV A and B subtypes was demonstrated. Pretreatment of cotton rats with MEDI-493 resulted in 99% reduction of lung RSV titers at a dose of 2.5 mg/kg, corresponding to a serum concentration of 25-30 microg/mL. Further, MEDI-493 did not induce increased RSV infection or pathology in either a primary or a secondary challenge.
The aim of the present study is to evaluate the in vivo toxicologic effects of a phosphorothioate oligodeoxynucleotide (PS oligo) and three of its analogs [PS oligo containing four methylphosphonate linkages at the 3' and 5'-ends (MBO 1), PS oligo containing four 2'-O-methylribonucleosides at both the 3'- and 5'-ends (MBO 2), and PS oligo containing an 8 bp loop region at the 3'-end (self-stabilized oligo)]. Oligodeoxynucleotides were administrated intravenously to male and female rats at doses of 3, 10, and 30 mg/kg/day for 14 days. Rats were killed on day 15, blood samples were collected for hematology and clinical chemistry determinations, and tissues, including lymph nodes, spleens, livers, and kidneys, were subjected to pathologic examinations. The toxicity profiles of the four oligodeoxynucleotides were very similar, but differed in magnitude. In terms of the severity of the abnormalities caused by the oligodeoxynucleotides, the order was MBO 2 > PS oligo > self-stabilized oligo > MBO 1. Alterations in hematology parameters included thrombocytopenia, anemia, and neutropenia. Abnormalities in clinical chemistry parameters observed with PS oligo or MBO 2 were dose-dependent elevation of liver transaminases and reduction of the levels of alkaline phosphatase, albumin, and total protein. In addition, MBO 2 caused elevation of the total bilirubin level in male rats at the 30 mg/kg dose. No major alterations in hematology or clinical chemistry were observed in rats receiving MBO 1 or self-stabilized oligo. Dose-dependent enlargements of spleen, liver, and kidney were observed, especially in rats receiving PS oligo and MBO 2. Pathologic studies showed a generalized hyperplasia of the reticuloendothelial (RE) system in the tissues examined. Alterations in the spleen were mainly RE cell hyperplasia and hematopoietic cell proliferation. In addition to RE cell hyperplasia, lymph nodes showed necrosis, hepatocytes showed cytologic alterations and necrosis, and kidneys showed renal tubule regeneration. The severity of pathologic changes observed was oligodeoxynucleotide dependent, in the order of MBO 2 > PS oligo > self-stabilized oligo > MBO 1.
The origin and function of decidual stromal cells (DSC), the main cellular component of the decidua, are uncertain. Although the general consensus is that they are fibroblastic cells involved in fetal trophoblast nutrition, several authors have demonstrated that these cells can carry out immunological functions and that at least a subpopulation of them may be of hematopoietic origin. Human DSC precursors or predecidual cells (preDSC) purified by expansion in culture express a surface phenotype recalling that of dendritic cells. In the present study, we show by flow cytometry that these cells also express B7-1 (CD80) and B7-2 (CD86), two antigens involved in the costimulation of T cells by antigen-presenting cells. Cultured DSC were also able to stimulate allogenic T cells in vitro. Using an immunohistochemical technique, we found that in cryostatic sections of early human decidua, CD80 and CD86 were expressed mainly by DSC located around the decidual vessels, a location compatible with preDSC rather than fully differentiated DSC. Our results suggest that preDSC are involved in antigen presentation.
OBJECTIVES: To investigate the potential of quantitative magnetic resonance imaging (MRI) to differentiate between therapeutically induced changes in inflammation and synovial proliferation in rheumatoid arthritis (RA) of the knee. METHODS: MRI of the knee was performed on patients with RA before and one week after injection with corticosteroid (triamcinolone acetonide, TA group, n = 9) and before, four, and 12 weeks after injection with yttrium-90 plus TA (TA+Y group, n = 7). MRI scans were analysed by subjective visual grading by a trained observer and by computer aided quantitation for three features: synovial fluid volume, synovial pannus volume, and synovial enhancement after intravenous contrast agent. RESULTS: All TA subjects improved clinically at one week but the effects of TA+Y were more variable. TA significantly reduced synovial enhancement and effusion volume, whereas TA+Y at 12 weeks tended to increase synovial enhancement and decrease pannus volume. Quantitative MRI values agreed well with subjective assessment of scans. Comparison of calculated change on MRI scan before and immediately after aspiration with actual volume aspirated showed high correlation (r = 0.96). CONCLUSIONS: Quantitative MRI correlates with subjective visual assessment and, at least for synovial fluid, is accurate. MRI can differentiate actions of two therapeutic modalities on various pathological processes and is sensitive enough to detect change after one week. With the additional advantage of lack of observer bias, it will probably become a useful tool in the development and assessment of existing and novel treatments.
Lurcher mutant mice which are mainly known for their cerebellar degeneration, also display a hyperinducibility of proinflammatory cytokines, such as interleukin-1alpha and beta (IL-1) and tumor necrosis factor alpha (TNF-alpha), in peripheral macrophages. To assess whether this increased responsiveness to inflammatory stimuli is accompanied by a higher pituitary-adrenal response, we compared the adrenocorticotropic hormone (ACTH) and corticosterone response of Lc and wild-type mice to intraperitoneal (i.p.) administration of a cytokine inducer, lipopolysaccharide (LPS). Lurcher mice display resting levels of ACTH and corticosterone similar to those of wild-type mice. LPS (1.25 microg/g) induces a corticosterone surge 2-fold higher in Lurcher than in wild-type mice. By contrast, the response to IL-1alpha (10 ng/g, i.p.) is similar in both genotypes, suggesting that a differential reactivity of the hypothalamo-pituitary adrenal axis to IL-1 does not account for the higher reactivity of Lurcher mice to LPS. To test whether the increased responsiveness of the pituitary-adrenal axis of Lurcher mice generalizes accross stressors, mice were exposed to a novel environment. This condition also induced a surge of ACTH and corticosterone 3.5- and 2-fold higher in Lurcher than in wild-type mice. Prior blockade of IL-1 receptors by injection of IL-1 receptor antagonist (10 microg/g, i.p.) failed to block the response to LPS injection and exposure to novelty. In contrast, immunoneutralization of hypothalamic corticotropin-releasing hormone (CRH) significantly attenuated the ACTH surge and abrogated the difference between Lurcher and wild-type mice in their responses to a novel environment, suggesting that hypothalamic CRH neurons are involved in this excessive response.
Mast cells are difficult to purify from heterogeneous cell populations and to preserve, especially for pre-embedding immunostaining at the ultrastructural level. We have developed a technique that permits the isolation of a pure population of mast cells suitable for immunocytochemical studies. A rat mast cell-specific monoclonal antibody (MAb AA4) conjugated to tosylactivated Dynabeads 450 was used to immunomagnetically separate mast cells from rat bone marrow and peritoneal cell suspensions. Approximately 85% of the mast cells were recovered in the positive population that comprised virtually pure mast cells. After microwave fixation, morphological examination showed that the cells were intact and retained their ultrastructural detail. Mast cells in all stages of maturation were immunolabeled with a panel of antibodies after immunomagnetic separation. The combination of immunomagnetic separation followed by immunostaining should prove useful for the study of mast cell maturation and for the characterization of other specific cell types that are present in tissues in only limited numbers.
The pituitary is a rich source of peptidylglycine alpha-amidating monooxygenase (PAM). This bifunctional protein contains peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase catalytic domains necessary for the two-step formation of alpha-amidated peptides from their COOH-terminal glycine extended precursors. Expression of PAM was evaluated in the anterior pituitary of intact cycling adult female rat and after experimental manipulation of estrogen status. PAM messenger RNA (mRNA) levels showed changes inversely related to the physiological variations of plasma estrogen levels during the estrous cycle. Chronic treatment of ovariectomized (OVX) rats with 17 beta-estradiol decreased PAM mRNA levels to values comparable with those found in intact rats at proestrus. In situ hybridization of anterior pituitary sections using 35S-labeled full length RNA antisense transcripts of rat PAM-1 complementary DNA showed that 17 beta-estradiol treatment induced an overall decrease of the hybridization signal, as compared with OVX rats. Progesterone treatment did not change PAM mRNA levels both in OVX or OVX + E2 rats. Based on Northern blot analysis and amplification of fragments derived from rat PAM-1 by RT-PCR, it was found that estrogen status does not affect the distribution of PAM mRNA among its various alternatively spliced forms. In OVX 17 beta-estradiol treated rats, the specific activity of PAM in the anterior pituitary decreased in both soluble and particulate fractions compared with OVX animals. Western blot analysis demonstrated a 105-kDa PAM protein in particulate fractions prepared from OVX and OVX-17 beta-estradiol treated animals. The soluble fraction from OVX animals contained major PAM proteins of 105, 95, 84, 75, and 45 kDa, and 17 beta-estradiol treatment caused a decrease in the prevalence of these proteins. These results indicate that estrogens are involved, either directly or indirectly, in regulating the expression of PAM in several cell types in the anterior pituitary gland.