Treatment of recurrent premenstrual orogenital aphthae with implants of low doses of testosterone.
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Adult↗
Biomedical subjects
D C Anderson
Publications and source records attributed to D C Anderson.
The relationship between CR3 deficiency and neutrophil actin assembly.
Polymorphonuclear leukocytes (PMN) with a deficiency of the complement receptor type 3 (CR3) membrane glycoprotein family have impairments in the ability to adhere to surfaces as well as chemotactic and phagocytic defects, processes that require a functional contractile apparatus. PMN from the patient with neutrophil actin dysfunction (NAD) displayed similar functional characteristics to those with CR3 deficiency suggesting the two disorders may be the same disease. In order to evaluate the relationship between CR3 deficiency and actin assembly, actin filament assembly was measured in PMN from six previously reported homozygotes (two severe and four moderate CR3-deficient patients) as well as five heterozygotes for CR3 deficiency. PMN from all patients had normal unstimulated concentrations of F-actin and after exposure to the chemotactic peptide FMLP (5 x 10(-7) mol/L for 5 to 40 seconds at 25 degrees C) assembled actin normally. Pretreatment of normal PMN with concentrations of monoclonal anti-alpha CR3 antibody, capable of blocking PMN adherence, also failed to impair FMLP-induced actin filament assembly. CR3 glycoprotein expression was measured in PMNs from the mother, father, and older sister of the NAD patient (N Engl J Med 291:1093, 1974). Actin filament assembly was recently shown to be defective in PMNs from all three family members. The total concentrations of the alpha and beta CR3 subunits were below normal in PMN detergent extracts from the mother (25% of simultaneous controls) and older sister (56% of control). PMN surface expression of these two subunits was also found to be depressed (mother, 50%; older sister, 63% of control). These findings suggest these two NAD family members are heterozygote carriers for CR3 deficiency as well as NAD. Simultaneous studies of the father, however, demonstrated normal total concentrations of both the alpha and beta CR3 subunits (126% of controls) as well as normal surface expression of both subunits after phorbol myristate acetate stimulation and incubation at 37 degrees C (mean, 112% of controls) but slightly lower than normal levels after FMLP stimulation (mean, 83%). These findings indicate that CR3 deficiency generally is not associated with defective actin filament assembly and support the conclusion that NAD represents a unique kindred in which PMN actin function differs from previously reported genotypes of CR3 deficiency.
Actins↗
T cells sensitized to synthetic HLA-DR3 peptide give evidence of continuous presentation of denatured HLA-DR3 molecules by HLA-DP.
T cell clones raised against a synthetic peptide, identical to the third hypervariable region of the DR3 BI chain, were tested for secondary proliferative responses against a panel of PBLs. All seven DR3 DPw3+ stimulators could induce proliferation. DR3- DPw3+ PBLs were recognized when the synthetic peptide was added to the cultures. Inhibition studies with mAbs showed that in both cases the HLA-DP molecule is involved in the recognition of both types of stimulators. We conclude that the clones recognize the DR3 peptide presented by HLA-DPw3. This stimulus can be obtained in two different ways: (a) by addition of synthetic peptide to DPw3+ PBLs or (b) by using DR3 DPw3+ stimulator cells where DR3 peptides are present in the culture as a product of denaturation of the DR3 molecule. Because all DR3 DPw3+ PBLs tested could stimulate the line and clones, we assume that the presentation of the DR3 peptide by DP is a naturally and continuously occurring phenomenon.
Antibodies, Monoclonal↗
DR3-restricted T cells from different HLA-DR3-positive individuals recognize the same peptide (amino acids 2-12) of the mycobacterial 65-kDa heat-shock protein.
Studies in experimental animals have demonstrated that the T cell response to immunogenic proteins is limited to one or a few epitopes on such proteins and that the MHC haplotype of the responder is an important factor in determining which epitope is recognized (immune response gene effect). However, if and to what extent MHC genes control the immune response to pathogens in man is virtually unknown. We have studied the human T cell response to the mycobacterial 65-kDa heat-shock protein, a major immunogen of Mycobacterium leprae and M. tuberculosis, the causative agents of leprosy and tuberculosis, respectively, in relation to HLA-DR phenotype. In a large panel of short-term cultured polyclonal anti-mycobacterial T cell lines, from 45 different individuals representing all DR-restriction specificities, only DR1 and DR3-restricted T cell lines proliferated to the 65-kDa protein. The DR1-restricted T cell lines responded to three new epitopes on the mycobacterial 65-kDa protein, one of which is specific for the M. tuberculosis complex. Altogether nine T cell epitope-containing regions have now been mapped on the 65-kDa protein and the response to each of them was exclusively restricted via one HLA-DR allele. Most importantly, all six 65-kDa-responsive DR3-restricted T cell lines from different individuals recognized an epitope on the same peptide, representing amino acids 2-12 of the 65-kDa protein, that was previously mapped using DR3-restricted T cell clones. From these data we conclude that the human T cell response to both the whole mycobacterial 65-kDa heat-shock protein and to defined epitopes on this protein is controlled by HLA-DR genes. The mycobacterial 65-kDa protein has been implicated in the design of subunit vaccines against tuberculosis and leprosy as well as the induction of immunopathology. In both instances the Ir gene control of the T cell response to this protein may have to be taken into account.
Antigen-Presenting Cells↗
The effect of tartrate on bone cell acid phosphatase activity: a quantitative cytochemical study.
Tartrate-resistant acid phosphatase activity (TRAPase) is widely used as a cytochemical marker to distinguish osteoclasts from macrophages and other related cell types. The degree of tartrate resistance, however, may depend on which reaction methods, tissues, or species are used. To investigate this further, we have measured the amount of cytochemical reaction product by microdensitometry. We compared osteoclast acid phosphatase (APase) activity in fresh frozen sections of neonatal rat calvaria using two different reaction methods; one is commonly employed for qualitative histochemistry and includes alpha naphthyl phosphate as substrate, simultaneous coupling to the chromagen Fast Garnet, and a 30-minute reaction time (method A). The other may be used to measure enzyme reaction rates in cells in situ and employs conditions suitable for initial velocity kinetics, namely naphthol-ASBI phosphate as substrate, post coupling to Fast Garnet, and a 2-minute reaction time. Although enzyme reaction rates differed greatly between the two methods, significant inhibition of APase activity by tartrate was observed in calvarial osteoclasts (69% and 59% with methods A and B, respectively), osteoblasts, and spleen macrophages. Using method B, mouse calvarial osteoclasts had similar APase activity to that seen in the rat. Tartrate produced little inhibition in these mouse cells, in contrast to the observations made with rat tissue, but murine spleen macrophages were significantly tartrate sensitive (40% inhibition with tartrate). On this basis, conclusions regarding the cell specificity of TRAPase should be treated cautiously.
Acid Phosphatase↗
Apolipoprotein E polymorphism and lipoproteins in insulin-treated diabetes mellitus.
Apolipoprotein E (apo E), a component of VLDL, HDL and chylomicron remnants, is inherited at a single genetic locus with 3 common alleles (epsilon 2, epsilon 3 and epsilon 4). epsilon 2 homozygosity is found in 0-2% of healthy populations, but in 75-100% of subjects with type III hyperlipoproteinaemia, in whom an increased prevalence of glucose intolerance has previously been reported. The lipoprotein abnormality associated with diabetes mellitus has features in common with type III hyperlipoproteinaemia and both conditions lead to accelerated atherogenesis with a similar anatomical distribution. We have therefore examined the frequency of apo E genotypes in 120 subjects with insulin-treated diabetes mellitus (ITDM) and 107 healthy controls, and examined the effect of apo E polymorphism on lipoproteins in the diabetic group. As in the general population, the apo E phenotype in ITDM was a significant determinant of the total serum and LDL cholesterol concentrations which were lowest in patients possessing the epsilon 2 allele, intermediate in those homozygous for epsilon 3 and highest in those with an epsilon 4 allele. The observed gene frequencies of epsilon 2 (0.091), epsilon 3 (0.780) and epsilon 4 (0.130) were similar to those of the healthy control group and those in the general population. However, there was an unexpected increase (P less than 0.0002) in epsilon 2 homozygosity of 6.7% compared to a prevalence of 0.8% predicted both from the Hardy-Weinberg equilibrium and the 0.9% prevalence observed in the healthy control group. This suggests either that epsilon 2 homozygosity increases susceptibility to the development of ITDM or that the two conditions are genetically linked.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Spectrum of disease in macaque monkeys chronically infected with SIV/SMM.
Twelve rhesus and one pig-tailed macaque have been monitored for 28-41 months following experimental infection with 10(4) TCID of SIV/SMM. Twelve of the 13 animals became virus positive and seroconverted within 3 to 6 weeks of exposure; the remaining animal seroconverted at 6 months, but has remained virus negative. Six of the 13 animals (46%) died between 14 and 28 months post-infection, following prolonged clinical disease characterized by chronic diarrhea and weight loss, peripheral lymphadenopathy and hemogram abnormalities. Histologic findings ranged from prominent follicular hyperplasia to severe lymphoid depletion, with lymphoid tissues often showing an infiltrate of syncytial giant cells. One animal had intestinal cryptosporidiosis and two had brain lesions comparable to those seen in AIDS encephalopathy in humans. Three of the remaining seven animals have an ARC-like disease and are showing gradual deterioration of their clinical condition. These animals, as well as animals that died, had progressive decreases in CD4+ cells and CD4+/CD8+ cell ratios. These observations further document the marked clinical, pathologic and immunologic similarities between human AIDS and the SIV-infected macaque model.
Acquired Immunodeficiency Syndrome↗
Effects of age and sex on bone density in the rhesus monkey.
Normative data for bone density of cortical and trabecular bone in the rhesus monkeys is described in the present study. Changes of bone density (g/cm2) for the humerus, the third lumbar vertebra, and the eighth caudal vertebra of the rhesus monkey show differences due to age and sex of the subjects (males n = 57; females n = 49). In general, bone density increased with age and then reached a plateau at approximately 3 to 4 years in all bones measured. In the humerus, older females (greater than 30 years) had a significantly lower bone density than females of 4 to 24 years, while bone density in older males did not decrease. In the vertebrae, some evidence of advanced age-related decreases in bone density was found in both sexes. These results indicate that the rhesus monkey shows a natural pattern of change in bone mineralization which parallels that seen in humans. The physiological similarity between the rhesus monkey and human further suggests a potential role for this species in the future investigation of osteoporosis.
Aging↗
A comparison of direct measures of glycaemia and glycated blood proteins in insulin-dependent diabetes mellitus.
We have studied associations between various direct measures of glycaemia and glycated blood proteins in 113 subjects with insulin-dependent diabetes mellitus (IDDM), and examined whether or not the 'fructosamine' assay results were affected by differing patient serum concentrations of lipids, albumin or C peptide. Serum fructosamine correlated less closely with HbA1 (r = 0.44) than did HbA1 with glycated serum albumin (GSA) (r = 0.68). Serum fructosamine and GSA also were poorly correlated (r = 0.48). Although fructosamine, HbA1 and GSA correlated to a similar degree with fasting blood glucose (r range 0.34 to 0.37), GSA was most closely related to mean blood glucose (r = 0.39 vs. 0.30-0.35) and the M value (a marker of diurnal glycaemic instability) (r = 0.42 vs. 0.33-0.35). The serum concentration of fructosamine was not significantly affected by a variation in serum cholesterol, but tended to be lower in subjects with moderate hypertriglyceridaemia (p = 0.05). The fructosamine assay may be altered by moderately lipaemic serum but is not affected by serum albumin concentration in normoalbuminaemic patients with IDDM. Our study indicates, however, that GSA is a more reliable marker of short-term glycaemic control in IDDM than fructosamine.
Adolescent↗
Synthesis, in vitro acetylcholine-storage-blocking activities, and biological properties of derivatives and analogues of trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol).
Eighty-four analogues and derivatives of the acetylcholine-storage-blocking drug trans-2-(4-phenylpiperidino)-cyclohexanol (vesamicol) were synthesized, and their potencies were evaluated with the acetylcholine active-transport assay utilizing purified synaptic vesicles from Torpedo electric organ. The parent drug exhibits enantioselectivity, with (-)-vesamicol being 25-fold more potent than (+)-vesamicol. The atomic structure and absolute configuration of (+)-vesamicol were determined by X-ray crystallography. The absolute configuration of (-)-vesamicol is 1R,2R. Structure-activity evidence indicates that (-)-vesamicol does not act as an acetylcholine analogue. Alterations to all three rings can have large effects on potency. Unexpectedly, analogues locking the alcohol and ammonium groups trans-diequatorial or trans-diaxial both exhibit good potency. A potent benzovesamicol family has been discovered that is suitable for facile elaboration of the sort useful in affinity labeling and affinity chromatography applications. A good correlation was found between potencies as assessed by the acetylcholine transport assay and LD50 values in mouse.
Acetylcholine↗
Does residual insulin secretion (assessed by C-peptide concentration) affect lipid and lipoprotein levels in insulin-dependent diabetes mellitus?
1. Residual endogenous insulin secretion can be assessed by the circulating C-peptide concentration and is present in up to 15% of subjects with established insulin-dependent diabetes mellitus (IDDM). Its role in lipid metabolism in IDDM is not clearly defined. We examined the relationships between serum lipid and lipoprotein concentrations and the response of circulating C-peptide to a test meal in 205 subjects with IDDM. 2. Lipid and lipoprotein levels and glycaemic control did not differ significantly between patients with undetectable, low or high C-peptide responses. 3. High density lipoprotein (HDL) cholesterol and its subfractions were inversely related to concentrations of serum triacylglycerols (P less than 0.01-0.001), but not to C-peptide or glycated haemoglobin (HbA1) levels. Levels of HbA1 and triacylglycerols were correlated with one another (P less than 0.01). Analysis of variance revealed that differences in gender and triacylglycerol concentrations were the most important determinants of HDL and HDL2 cholesterol levels. C-peptide only exerted a weak effect on HDL2 cholesterol levels and no significant predictors of HDL3 cholesterol were found. 4. It is concluded that endogenous insulin secretion (assessed by C-peptide concentration) is relatively unimportant in modifying HDL metabolism in IDDM and that associated clinical features, in particular ambient hypertriglyceridaemia, are of greater importance.
Adolescent↗
A novel member of the integrin receptor family mediates Arg-Gly-Asp-stimulated neutrophil phagocytosis.
Human neutrophils (PMN) express a heterodimeric receptor that has ligand binding specificity for the Arg-Gly-Asp (RGD) sequence within many adhesive proteins. A monoclonal antibody, B6H12, which binds to this receptor, inhibits both RGD-mediated ligand binding and stimulation of IgG-mediated phagocytosis by fibronectin, fibrinogen, vitronectin, von Willebrand's factor, and collagen type IV. By several criteria this receptor is neither a known very late antigen, a known cytoadhesin (gp IIb/IIIa-vitronectin receptor), nor a member of the LFA-1, Mac-1, p150,95 group of integrin receptors. Ligand binding via this receptor is rapidly inactivated by products of the myeloperoxidase-hydrogen peroxide-halide system of PMN. We conclude that this receptor, for which we propose the name leukocyte response integrin, is a signal-transducing molecule on PMN which may have a significant early role in modulation of PMN function at inflammatory sites.
Amino Acid Sequence↗
Identification and biologic characterization of an acutely lethal variant of simian immunodeficiency virus from sooty mangabeys (SIV/SMM).
A virus pool isolated from lymphoid tissue of a macaque (PBj) infected for 14 months with SIV/SMM was found to be associated with acute disease and death. Six of six pig-tailed macaques, one of three rhesus macaques, and three of four SIV/SMM-seronegative mangabeys developed acute disease within 5 days and died from 7 to 13 days postinoculation; however, neither of two SIV/SMM-infected mangabeys died or developed disease. The virus associated with acute disease and death was shown by electron microscopy to be a lentivirus and was serologically indistinguishable from SIV/SMM by immunofluorescence and radioimmunoprecipitation assays. A biologic clone generated from lymphoid tissue of an animal that died 7 days after inoculation of the lethal pool resulted in death within 8 days of three of three pig-tailed macaques. Comparison of the lethal virus, designated SIV/SMM(PBj14), with the parent virus, SIV/SMM-9 (the isolate with which macaque PBj was originally inoculated), showed that although the kinetics of replication in peripheral blood mononuclear cells (PBMC) from pig-tailed macaques and mangabey monkeys were similar, SIV/SMM(PBj14) replicated more efficiently than SIV/SMM-9 in human PBMC and also replicated in chimpanzee PBMC whereas SIV/SMM and other SIV isolates did not. In addition, the variant was shown to replicate efficiently in some established cell lines whereas replication of SIV/SMM-9 in cell lines could be demonstrated only occasionally. That parental SIV/SMM-9, but not SIV/SMM(PBj14), was neutralized by serum from macaque PBj suggests that the variant may have been generated by immune selection. Comparison of sequential virus isolates from macaque PBj for host range and the ability to be neutralized and of sequential serum samples for neutralization activity indicated that changes in biologic properties were detected in virus isolates and serum obtained at 6 months after infection and later. Normal macaque PBMC infected in vitro with SIV/SMM(PBj14), but not with SIV/SMM-9 or other virus pools from PBj, formed syncytia with Sup-T1 cells, whereas all isolates formed syncytia with MOLT-4 clone 8 cells. These data suggest that, relative to SIV/SMM-9, SIV/SMM(PBj14) acquired multiple mutations, at least one (or more) of which is in the gene coding for the envelope glycoprotein. Continued analysis of this series of SIV/SMM isolates with diverse properties may lead to the identification of specific regions of the viral genome that influence defined biologic properties. Furthermore, the availability of a strain of SIV that induces rapid onset of disease and death may facilitate screening of drugs for antiviral activity against lentiviruses.
Animals↗
Skin blood flow and limited joint mobility in insulin-dependent diabetes mellitus.
Hand skin blood flow in 32 insulin-dependent (IDDM) diabetics was compared with 13 healthy controls at room temperature and after immersion of the hands in warm and cold water. Subjects were examined for limited joint mobility (LJM) to analyse the association between this and blood flow. Digital arteries remained patent in IDDM compared to controls after cold challenge (p = 0.0001), and the difference persisted to a lesser degree 15 min (p = 0.009) and 30 min (p = 0.03) after recovery. Capillary blood flow was reduced in IDDM at room temperature at the finger nailbeds (p less than 0.02) and the palms (p = 0.004) and remained so after warm water immersion in the palms (p = 0.002), where further vasoconstriction was observed immediately after cold water immersion (p less than 0.001) and 15 and 30 min into recovery (p = 0.07 and p = 0.009 respectively). Thermographic analysis confirmed a pattern of predominantly distal rewarming after cold challenge in IDDM with a greater mean index finger temperature than the controls. Together, these features suggested enhanced arteriovenous anastomotic blood flow. All IDDM and IDDM males with LJM had reduced palm capillary flow immediately after cold challenge (p less than 0.05). After warm water (p less than 0.03) and 30 min after cold challenge (p less than 0.05) IDDM males with LJM had reduced palm capillary flow compared to those IDDM without. A microvascular aetiology for LJM is proposed by virtue of reduced nutritional blood flow and evidence of enhanced arteriovenous shunting in the hands of insulin-dependent diabetics.
Adolescent↗
An analysis of glycosylated blood proteins and blood glucose profiles over one year in patients with type 1 diabetes.
The clinical value of prospective measurement of several direct and indirect measures of blood glucose control in the management of Type 1 diabetes has been investigated. Ninety-eight Type 1 diabetic patients were followed over a period of 1 year after a 6-week period of intensification of management, with monthly measurements of blood glucose profiles and 3-monthly HbA1, glycosylated serum albumin, and fructosamine measurements. All measures improved markedly after the initial 6-week period (p less than 0.001), and all except glycosylated serum albumin and fructosamine then remained relatively stable. Of fourteen serial comparisons, glycosylated blood proteins were significantly correlated more often with levels of mean blood glucose and M value (on 4-7 occasions, rs 0.30-0.58) than with fasting blood glucose levels (on only 2-3 occasions, rs 0.34-0.44). Serum fructosamine levels correlated significantly with mean blood glucose on four occasion (rs 0.30-0.50), whilst glycosylated serum albumin and HbA1 correlated with mean blood glucose on six occasions (rs 0.36-0.54). Glycosylated serum albumin correlated with HbA1 and fructosamine levels throughout the year (rs 0.47-0.68 and 0.48-0.76, respectively), but HbA1 and fructosamine were less clearly correlated with each other (rs 0.38-0.44), with no significant association immediately after the period of intensive management or 3 months later.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Analysis of human antibody epitopes on the 65-kilodalton protein of Mycobacterium leprae by using synthetic peptides.
In order to study antibody reactivity to the Mycobacterium leprae 65-kilodalton (kDa) antigen, peptides representing overlapping sequences of the 65-kDa protein were synthesized, and a recombinant protein expression system for r65-kDa was constructed. Mouse monoclonal antibodies and leprosy patient seroreactivity to peptides and r65-kDa were tested by an enzyme-linked immunosorbent assay. All seven of the monoclonal antibodies used in this study reacted with their previously defined epitopes when tested against peptides. All monoclonal antibodies also reacted with r65-kDa. Leprosy patient seroreactivity to peptides and r65-kDa was seen in about one-third of active multibacillary cases. Specimens from patients positive for antibodies to peptides were seen to recognize different epitopes than did mouse monoclonal antibodies used in this study. It is concluded that substantial differences exist between mouse monoclonal antibodies and human leprosy patient reactivity to the 65-kDa antigen and that human seroreactivity to the 65-kDa antigen is indicative of a highly elevated bacillary load.
Amino Acid Sequence↗
HIV infection of chimpanzees as a model for testing chemotherapeutics.
Following inoculation of chimpanzees, the human immunodeficiency virus (HIV) establishes a long-term persistent infection characterized by seroconversion and the presence in peripheral blood cells of recoverable virus which can be quantitated. Because most HIV-infected chimpanzees have developed no signs of clinical diseases or hematologic abnormalities, their virologic, serologic and other immune responses can be compared with those of asymptomatic HIV-infected persons. This analysis might lead to the identification of factors important in preventing the development of disease. There are now approximately 100 HIV-infected chimpanzees in the United States, and many of these animals could be made available for testing chemotherapeutic agents for the ability to alter virus load or to enhance immune responses.
Acquired Immunodeficiency Syndrome↗
Canine neutrophil activation by cardiac lymph obtained during reperfusion of ischemic myocardium.
Cardiac lymph from a canine model of myocardial ischemia and reperfusion was examined for evidence of chemotactic activity. Lymph was continuously collected from awake animals before and during a 60-minute coronary artery occlusion and up to 6 hours after the initiation of reperfusion. It was assessed for the ability to activate the following proinflammatory functions in neutrophils isolated from the blood of healthy dogs: 1) morphological changes characteristic of chemotactic stimulation, which were assessed by phase contrast microscopy, 2) orientation of canine neutrophils in a gradient of cardiac lymph, which was assessed in Zigmond chambers, 3) the binding of monoclonal antibodies reactive with CD11b and CD18 adherence glycoproteins, which was assessed by flow cytometry, and 4) adherence of canine neutrophils to monolayers of canine jugular vein endothelium, which was assessed in vitro by a visual assay. Lymph samples collected after 1 hour of reperfusion in animals demonstrating ECG evidence of ischemia and histological evidence of infarction exhibited significant stimulatory activity for each of the functions tested. Shape change-inducing activity was evaluated at more frequent intervals than other functions and was found to peak at 1 hour after initiation of reperfusion and to disappear by 6 hours. In addition, the CD11b/CD18 levels on neutrophils isolated from cardiac lymph collected during reperfusion were significantly greater than neutrophils obtained before or during occlusion. Animals that failed to exhibit evidence of infarction also failed to exhibit increased stimulatory activity in lymph collected during reperfusion, and surface levels of CD11b/CD18 on neutrophils collected from reperfusion lymph were not elevated. This study provides direct evidence supporting the hypothesis that chemotactic activity is generated in ischemic and reperfused myocardium.
Animals↗