ABSTRACT
Neurodegenerative diseases may be caused by expansion of triplet repeats in human genes. To identify novel genes with CAG repeats, we screened a human brain cDNA library with an oligonucleotide probe. Four of the isolated cDNAs were sequenced, analyzed for polymorphisms, chromosomal localization, evolutionary conservation and expression. One of the repeats is bi-allelic with 10 triplets (80% of chromosomes) and 7 triplets (20% of chromosomes). In one of the genes two CAG repeats coding for 10 and 17 glutamines are localized in the same reading frame.
Subject(s)
Brain/physiology , Neurodegenerative Diseases/genetics , Trinucleotide Repeats/genetics , Animals , Blotting, Southern , Case-Control Studies , Cats , Cattle , Chromosomes, Human , Cloning, Molecular , Dogs , Gene Dosage , Gene Expression Profiling , Gene Expression Regulation , Humans , Molecular Sequence Data , Polymerase Chain Reaction , Restriction Mapping , Sequence Homology, Nucleic Acid , Species SpecificityABSTRACT
PURPOSE: Late solid tumors (STs) are a significant cause of morbidity and mortality in long-term survivors of Hodgkin's disease. To investigate the carcinogenic potential of two different therapeutic approaches, we measured the relative risk (RR) of STs in patients with early-stage disease cured after primary full-dose (approximately 40 Gy) radiation therapy (RT) and in patients with advanced disease who were treated with chemotherapy followed by low-dose (15 to 30 Gy) involved-field radiation (CMT). PATIENTS AND METHODS: Because therapy-induced STs generally begin after a latency period of 5 to 10 years, we restricted our analysis to patients treated before 1986 who achieved durable remissions. Patients who required salvage chemotherapy or who died of Hodgkin's disease were excluded from analysis. The RR of STs was calculated by dividing the observed number of cases by the expected number in a matched population from the Connecticut Tumor Registry. The actuarial incidence of STs was also measured. RESULTS: A total of 197 patients formed the RT group and 116 the CMT group. The median follow-up period in the RT group was 12.8 years, versus 13.5 years in the CMT group. The overall RR of STs in the CMT group was 1.5 (95% confidence interval [CI], 0.6 to 3.5; P = .122). There were no cases of lung or breast cancer. In the RT group, the overall RR of STs was 3.3 (95% CI, 2.0 to 5.3; P < .001). There were seven cases of lung cancer (RR = 10.8; 95% CI, 5.3 to 22.2; P < .001) and two cases of breast cancer (RR = 2; 95% CI, 0.6 to 7.4; P = .07). All six benign tumors occurred in the RT group. CONCLUSION: In patients cured by initial treatment for Hodgkin's disease, RT was associated with a statistically significant increase in STs, particularly lung cancer. CMT was not associated with a significant increase in STs. These data may have important implications for the design of newer therapies for early-stage Hodgkin's disease.
Subject(s)
Hodgkin Disease/therapy , Neoplasms, Second Primary/etiology , Actuarial Analysis , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Follow-Up Studies , Hodgkin Disease/drug therapy , Hodgkin Disease/radiotherapy , Humans , Male , Middle Aged , Neoplasms, Radiation-Induced/etiology , Radiotherapy/adverse effects , Radiotherapy Dosage , Radiotherapy, Adjuvant , Risk FactorsABSTRACT
BACKGROUND: Over a 15 year period, the authors followed 51 male patients with myelodysplastic syndromes whose clinical findings, laboratory data, and evolution demonstrated a wide spectrum of disease. METHODS: The following characteristics were assessed: age at diagnosis, risk factors, clinical presentation, laboratory features, category of myelodysplasia, leukemic conversion, and overall survival. RESULTS: The clinical manifestations included hemolytic episodes in two patients, antibody-mediated thrombopenia in one, marked marrow fibrosis in two; thrombocytosis in three, and simultaneous lymphoproliferative disorders in two. There were 21 patients whose marrow was either normo- or hypocellular. Six patients presented with single cytopenia but not anemia. There were six instances of overlapping of the French-American-British classification. Eighteen patients progressed to acute leukemia and 1 to chronic myelomonocytic leukemia. CONCLUSIONS: These observations indicate that patients with myelodysplastic syndromes may have single cytopenia without anemia that progresses to acute leukemia and may, rarely, evolve into chronic myelomonocytic leukemia. The clinical aspects of these syndromes may include autoimmune phenomena and myeloproliferative features.
Subject(s)
Myelodysplastic Syndromes/diagnosis , Adult , Aged , Aged, 80 and over , Humans , Leukemia/etiology , Male , Middle Aged , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/genetics , Retrospective Studies , Risk FactorsABSTRACT
The co-expression of M-CSF (CSF-1) and its receptor in specimens of ovarian cancer has recently been reported. Preliminary results have already suggested a possible influence of steroids on FMS (M-CSF receptor) expression. Fifty-five non-pretreated FIGO stage III/IV ovarian adenocarcinomas were studied for M-CSF transcripts and protein, as well as FMS transcripts and protein, using standard molecular biological techniques (Northern blot, slot blot analysis) and immunocytochemistry (ICC). Steroid receptor content was measured by DCC analysis in 44/55 specimens; in addition, ER/PR (oestrogen/progesterone) ICC was performed in 32/55 specimens. All tumours were shown to contain M-CSF-specific mRNA. Likewise, M-CSF protein was detected by ICC in the stroma and over the epithelium in all specimens. However, while most tumours were shown to contain FMS-specific mRNA, only 64 per cent of cases showed significant expression of FMS protein by tumour epithelium as shown by ICC. A statistically significant positive correlation was found between M-CSF and FMS mRNA expression levels. A week non-significant positive correlation was noted between FMS mRNA expression levels and tumour grade. Carcinomas were ER-positive in 66 per cent (DCC) or 34 per cent (ICC), and PR-positive in 73 per cent (DCC) or 34 per cent (ICC). A statistically significant positive correlation between ER (DCC) and M-CSF mRNA expression levels was found. Weak non-significant correlations were present between ER (ICC) and FMS (ICC), as well as between PR (DCC) and FMS mRNA expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Adenocarcinoma/chemistry , Macrophage Colony-Stimulating Factor/analysis , Ovarian Neoplasms/chemistry , Receptor, Macrophage Colony-Stimulating Factor/analysis , Receptors, Steroid/analysis , Adenocarcinoma/genetics , Adult , Aged , Aged, 80 and over , Blotting, Northern , Female , Gene Expression Regulation, Neoplastic , Humans , Macrophage Colony-Stimulating Factor/genetics , Middle Aged , Ovarian Neoplasms/genetics , RNA, Messenger/genetics , Receptor, Macrophage Colony-Stimulating Factor/geneticsABSTRACT
Increased plasma histamine levels were associated with significantly lowered diamine and type B monoamine oxidase activities in platelet-rich plasma of atopic eczema (AE) patients. The diamine oxidase has almost normal cofactor levels (pyridoxal phosphate and Cu(2+)) but the cofactor levels for type B monoamine oxidase (flavin adenine dinucleotide and Fe(2+)) are lowered. The biogenic amines putrescine, cadaverine, spermidine, spermine, tyramine and serotonin in the sera, as well as dopamine and epinephrine in EDTA-plasma were found to be normal. It is unlikely, therefore, that these amines are responsible for the decreased activities of monoamine and diamine oxidase in these patients. The most likely causative factors for the inhibition of the diamine oxidase are nicotine, alcohol, food additives and other environmental chemicals, or perhaps a genetic defect of the diamine oxidase.
ABSTRACT
Purine nucleotide concentrations in skin- and blood-cells of psoriatic patients are abnormal: The increase in the steady state level of cGMP and the decrease in the cAMP concentrations are associated with an enhanced rate of cellular proliferation. Concomitantly we found in the present study decreased ADP and ATP concentrations in blood cells (p less than 0.0001). The change in nucleotide concentrations suggests a defective purine nucleotide synthesis pathway. Stimulation of the Krebs cycle with fumaric acid raises ATP (p less than 0.0001) and most probably cAMP levels and at the same time slows down the purine nucleotide synthesis through end-product inhibition. Both effects can inhibit DNA and protein synthesis activity, which results in inhibition of cellular proliferation. Fumaric acid seems therefore a useful treatment for psoriatic lesions if liver and kidney functions (purine nucleotide and urea cycle) are controlled during treatment.
Subject(s)
Psoriasis/blood , Purine Nucleotides/biosynthesis , Adenosine Diphosphate/blood , Adenosine Monophosphate/blood , Adenosine Triphosphate/blood , Adult , Cell Division , Fumarates/therapeutic use , Humans , Middle Aged , Purine Nucleotides/bloodABSTRACT
Free plasma catecholamines were measured by means of a standardized HPLC method in 50 adult patients with psoriasis and in 18 healthy volunteers. The concentrations of circulating norepinephrine were significantly higher in the psoriasis group (p less than 0.005); by contrast only slight differences were found in the epinephrine and dopamine concentrations. The possible mechanisms leading to these changes are discussed.
Subject(s)
Norepinephrine/blood , Psoriasis/blood , Adolescent , Adult , Chromatography, High Pressure Liquid , Dopamine/blood , Epinephrine/blood , Humans , Middle AgedABSTRACT
Increased plasma histamine levels were associated with significantly lowered diamine and type B monoamine oxidase activities in platelet rich plasma of atopic eczema (AE) patients. The diamine oxidase has almost normal cofactor levels (pyridoxal phosphate and Cu2+) but the cofactor levels for type B monoamine oxidase (flavin adenine dinucleotide and Fe2+) are lowered.
Subject(s)
Amine Oxidase (Copper-Containing)/blood , Dermatitis, Atopic/enzymology , Histamine/blood , Isoenzymes/blood , Monoamine Oxidase/blood , Adolescent , Adult , Copper/blood , Female , Flavin-Adenine Dinucleotide/blood , Humans , Iron/blood , Male , Pyridoxal Phosphate/bloodABSTRACT
By means of a standardized HPLC method, we determined free plasma catecholamines both in 41 adult patients with severe atopic dermatitis and in 18 healthy volunteers. The levels of circulating noradrenaline were significantly higher in the atopic group (p less than 0.005), whereas the concentrations of adrenaline and dopamine, in contrast, were only slightly elevated. We discuss the possible mechanisms leading to these changes in spite of normal activities of DBH.
Subject(s)
Dermatitis, Atopic/enzymology , Norepinephrine/blood , Adolescent , Adult , Arousal/physiology , Chromatography, High Pressure Liquid , Dopamine/blood , Dopamine beta-Hydroxylase/blood , Epinephrine/blood , Humans , Middle AgedABSTRACT
We have recently shown that increased plasma histamine levels were associated with significantly lowered diamine and type B monoamine oxidase activities in platelet rich plasma of atopic eczema patients. We now report almost normal cofactor (pyridoxal phosphate and Cu2+) levels for diamine oxidase but lowered cofactor (flavin adenine dinucleotide and Fe2+) levels for type B monoamine oxidase.
Subject(s)
Amine Oxidase (Copper-Containing)/blood , Dermatitis, Atopic/enzymology , Monoamine Oxidase/blood , Adolescent , Adult , Amine Oxidase (Copper-Containing)/antagonists & inhibitors , Histamine/blood , HumansABSTRACT
Monoamine- and diamine oxidase activities were measured by a sensitive photometric assay in 25 psoriasis vulgaris patients. Results were compared with plasma histamine values determined fluorimetrically. Increased plasma histamine levels were associated with significantly lowered diamine--and type B monoamine oxidase activities in platelet-rich plasma of the psoriasis patients. Our data suggest that cofactor levels and/or inhibiting factors are responsible for the observed monoamine- and diamine oxidase activities.
Subject(s)
Amine Oxidase (Copper-Containing)/blood , Monoamine Oxidase/blood , Psoriasis/enzymology , Adolescent , Adult , Histamine/blood , HumansABSTRACT
Free plasma catecholamines were measured by means of a standardized HPLC method in 41 adult patients with severe atopic eczema and in 18 healthy volunteers. The circulating norepinephrine levels were significantly higher in the atopic group (P less than 0.005), by contrast only slight differences were found in the epinephrine and dopamine concentrations. The possible mechanisms leading to these changes at concomitant normal DBH activities are discussed.
Subject(s)
Catecholamines/blood , Dermatitis, Atopic/blood , Dopamine beta-Hydroxylase/blood , Adult , Chromatography, High Pressure Liquid , HumansABSTRACT
Increased plasma histamine levels were associated with significantly lowered diamine and type B monoamine oxidase activities in platelet rich plasma of atopic eczema patients.
Subject(s)
Amine Oxidase (Copper-Containing)/metabolism , Dermatitis, Atopic/enzymology , Monoamine Oxidase/metabolism , Adolescent , Adult , Amine Oxidase (Copper-Containing)/blood , Blood Platelets/enzymology , Humans , Monoamine Oxidase/bloodABSTRACT
When isolated, detergent solubilized and affinity chromatographically purified nicotinic acetylcholine receptor of Torpedo californica electric organ is incubated with [gamma-32P]ATP/Mg2+, phosphatidylinositol 4-phosphate (PIP) is formed from receptor associated phosphatidylinositol (PI). This receptor associated endogenous kinase activity is enhanced by orthovanadate and, remarkably, also by acetylcholine. Exogenously added PI-kinase only increases the phosphorylation rate if vanadate is present. PIP as the main phosphorylation product (up to 95%) remains bound to the beta-, gamma- and delta-subunits of the receptor and to the receptor associated v-protein. The alpha-subunits do not carry 32p phosphate; no phosphatidylinositol 4,5-bisphosphate formation has been observed. Concomitant to lipid phosphorylation tyrosine and serine residues are phosphorylated (5% of total incorporated 32P phosphate).
Subject(s)
Phosphatidylinositols/metabolism , Receptors, Nicotinic/metabolism , 1-Phosphatidylinositol 4-Kinase , Acetylcholine/pharmacology , Animals , Phosphorylation , Phosphotransferases/metabolism , TorpedoABSTRACT
Factor VIII coagulant antigen (FVIII:Ag) and FVIII coagulant activity (FVIII:C) were measured in 102 healthy individuals, in 5 hemophilia A carriers and in 21 hemophilia A patients before and after infusion of heat-treated high-purity FVIII concentrates. Factor VIII:Ag was determined by a solid-phase micro enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies and by a conventional solid-phase immunoradiometric assay (IRMA). Factor VIII:C was assessed using a one-stage assay. The micro ELISA was decidedly more precise than the IRMA. There was a close correlation between the results obtained by the three assays in the plasma of healthy subjects and in hemophilia A carriers. After transfusion of FVIII concentrates to hemophilia A patients, the FVIII:Ag recoveries were significantly lower than the FVIII:C recoveries and the biological half-life of FVIII:Ag was significantly shorter than for FVIII:C. The calculated half-life of FVIII:C was longer than in any previous study.
Subject(s)
Factor VIII/analysis , Hemophilia A/blood , Adolescent , Adult , Antigens/analysis , Child , Enzyme-Linked Immunosorbent Assay , Factor VII/analysis , Factor VII/immunology , Factor VIII/metabolism , Factor VIII/therapeutic use , Female , Humans , Immunoassay/methods , Male , Middle Aged , RadiometryABSTRACT
Factor VIII:C recovery and half-life was measured in 16 hemophilia A patients under comprehensively standardized conditions. Each patient received the same lot of a steam-treated high purity FVIII concentrate at a dose of 19-33 U/kg body weight. A comparison was made between the one-stage assay, the two-stage assay and a chromogenic substrate test for FVIII:C determination using a FXa-sensitive chromogenic substrate. Factor VIII:C potency of the administered FVIII concentrate was measured using calibration curves derived from a concentrate standard and FVIII:C plasma levels were read from calibration curves derived from a plasma standard. The chromogenic assay showed a good reproducibility at FVIII:C levels between 0.015 and 0.50 U/ml. The FVIII:C recoveries calculated from the results of the one-stage assay, the two-stage assay and the chromogenic substrate test were 109 +/- 20, 92 +/- 14 and 81 +/- 11% (mean +/- SD), respectively. The elimination half-lives of FVIII:C were calculated by non-linear least square analysis using a modified computerized Gauss-Newton algorithm. The half-lives calculated from the FVIII:C plasma levels measured by the one-stage assay, the two-stage assay and the chromogenic test were 23.8 +/- 6.4, 22.2 +/- 5.7 and 17.1 +/- 4.8 h (mean +/- SD), respectively. No previous study has reported such long half-life values. Our findings indicate that measurements of recoveries and half-lives by the chromogenic FVIII:C assay and by computerized non-linear least square analysis allow the possibility of individualized FVIII replacement therapy.