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2.
Toxicol Sci ; 63(1): 22-8, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11509740

ABSTRACT

Ugilec 141 is a technical mixture of tetrachlorobenzyltoluenes (TCBTs). It was introduced in the early 1980s as a replacement for polychlorinated biphenyls (PCBs). Based on physicochemical properties and accumulation in the environment, the use of this mixture was prohibited. To gain more insight in the toxicokinetics of these compounds in mammals, rats were exposed to a single iv bolus injection of a mixture of 3 TCBTs. At different time points after dosing, the tissue and blood concentrations of the TCBTs were determined. The adipose tissue is the main storage compartment, followed by skin and muscle. The TCBTs were rapidly eliminated from the liver and the blood, with half lives ranging from 65 to 72 h. Additionally, the tissue concentration data for all 3 TCBTs were analyzed using a physiologically based pharmacokinetic (PB-PK) model. Sensitivity analysis illustrated that the elimination of the TCBTs was not influenced by metabolism only, but also by the blood flow through the liver. Furthermore, the metabolic rates derived from the model were compared to previously reported in vitro metabolic rates. The in vitro values for the TCBTs were only a factor 2 to 3 smaller than the in vivo metabolic rates, indicating the value of in vitro techniques for a priori parameterization of PB-PK models.


Subject(s)
Benzhydryl Compounds/pharmacokinetics , Models, Biological , Animals , Benzhydryl Compounds/administration & dosage , In Vitro Techniques , Injections, Intravenous , Rats , Rats, Inbred Strains
3.
Diabetes Care ; 20(3): 244-7, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9051365

ABSTRACT

OBJECTIVE: Many of the "antiseptic" practices recommended by health care professionals for insulin injection have been successfully challenged as unnecessary. Since people with diabetes have long been observed to inject their insulin through their clothing, this study was undertaken to determine the safety and perceived benefits of administering insulin by this "rogue" technique. RESEARCH DESIGN AND METHODS: Fifty people with insulin-treated diabetes were randomized into a 20-week single-blinded prospective crossover study comparing the conventional subcutaneous injection technique (with skin preparation) to an experimental injection technique through clothing. Skin assessment, glycated hemoglobin levels, and leukocyte count were determined before randomization, at 10 weeks (before crossover), and again at 20 weeks (at completion). The participants injected through a single layer of fabric, which ranged from nylon to denim. Problems, benefits, type of clothing, and other comments were recorded by the subjects in an injection log. RESULTS: Forty-two (84%) subjects completed the study. The mean age was 41 years (range, 23-63 years), 50% were women, 86% were Caucasian, and 80% had type I diabetes. The mean duration of diabetes was 14 years (range, 1-33 years). Fifty-one percent had > 16 years of education. The demographic characteristics of the dropouts were similar to those who completed the study. Over the 20-week period approximately 13,720 injections were performed by participants. None of the subjects experienced erythema, induration, or abscess at injection sites. Neither the glycated hemoglobin levels nor the leukocyte counts differed between the conventional and experimental regimens. During the injection-through-clothing phase of the study, only minor problems, such as blood stains on clothing and bruising, were recorded in the logbooks. However, subjects reported that injection through clothing offered benefits such as convenience and saving time. CONCLUSIONS: It is safe and convenient to inject insulin through clothing.


Subject(s)
Clothing , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Safety , Adult , Cell Count , Cohort Studies , Cross-Over Studies , Diabetes Complications , Diabetes Mellitus/blood , Female , Glycated Hemoglobin/analysis , Humans , Injections, Subcutaneous/methods , Leukocytes/cytology , Male , Middle Aged , Prospective Studies , Self Administration , Single-Blind Method , Time Factors
4.
Biochem Biophys Res Commun ; 220(3): 905-10, 1996 Mar 27.
Article in English | MEDLINE | ID: mdl-8607865

ABSTRACT

The glucagon receptor is a member of the G protein-coupled receptor superfamily. Since several G protein-coupled receptors undergo phosphorylation in response to agonist, we investigated the phosphorylation of the glucagon receptor following the addition of glucagon to a Chinese hamster ovary cell line expressing the human glucagon receptor (CHO/hGR). Glucagon induced a rapid, time and concentration-dependent phosphorylation of its receptor on serine residues. Neither forskolin nor phorbol ester increased receptor phosphorylation, suggesting that cAMP-dependent protein kinase and protein kinase C do not catalyze this phosphorylation event. Furthermore, two mutant cell lines expressing glucagon receptors with successively truncated receptor cytoplasmic tails were tested. A strong correlation between the number of potential phosphorylation sites, receptor phosphorylation and receptor internalization was observed, suggesting that phosphorylation of the glucagon receptor in CHO/hGR cells is functionally linked to its internalization.


Subject(s)
Glucagon/pharmacology , Receptors, Glucagon/metabolism , Amino Acid Sequence , Animals , Antibodies , CHO Cells , Colforsin/pharmacology , Cricetinae , Cyclic AMP-Dependent Protein Kinases/metabolism , Humans , Kinetics , Molecular Sequence Data , Peptide Fragments/chemical synthesis , Peptide Fragments/chemistry , Peptide Fragments/immunology , Phosphates/metabolism , Phosphoproteins/biosynthesis , Phosphoproteins/isolation & purification , Phosphoproteins/metabolism , Phosphorylation , Phosphoserine/analysis , Protein Kinase C/metabolism , Receptors, Glucagon/biosynthesis , Receptors, Glucagon/drug effects , Recombinant Proteins/biosynthesis , Recombinant Proteins/drug effects , Recombinant Proteins/metabolism , Tetradecanoylphorbol Acetate/pharmacology , Transfection
5.
Am J Hypertens ; 8(5 Pt 1): 445-53, 1995 May.
Article in English | MEDLINE | ID: mdl-7662219

ABSTRACT

Insulin resistance that exists in patients with essential hypertension and in those with non-insulin-dependent diabetes mellitus (NIDDM) may be the common denominator for the impaired glucose homeostasis and elevated blood pressure (BP) levels in patients with NIDDM. Therefore, treatment that improves insulin action may also improve BP levels. Consequently, a four-phase (glipizide v insulin) cross-over design study was conducted to determine a better effect of glipizide treatment on insulin sensitivity and the effect this has on BP in 19 NIDDM patients. Patients were subjected to 1 month of diet only (phase I) followed by 3 months of glipizide treatment (phase II), then an additional 1 month of diet only (phase III), and finally 3 months of insulin treatment (phase IV). At the end of phases I, II, and IV oral glucose tolerance tests (OGTT) were performed and plasma glucose, insulin, and C-peptide levels were analyzed. Fasting plasma glucose, insulin, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides, glycated hemoglobin, fructosamine, and 2-h postprandial plasma glucose were also analyzed at each phase. Supine and sitting BP levels and body weights were determined biweekly during the study. With the exception of higher plasma insulin and C-peptide levels during the OGTT (area under the curve) in phase IV (insulin) v phase II (glipizide) (both P < .05), and higher fasting plasma insulin levels (P < .06), there were no consistently significant metabolic differences between phases IV and II.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Blood Glucose/drug effects , Blood Pressure/drug effects , Diabetes Mellitus, Type 2/drug therapy , Glipizide/therapeutic use , Insulin/therapeutic use , Adult , Aged , Blood Glucose/metabolism , C-Peptide/blood , C-Peptide/drug effects , Cholesterol/blood , Cross-Over Studies , Diabetes Mellitus, Type 2/blood , Diet, Diabetic , Female , Glucose Tolerance Test , Humans , Insulin Resistance , Lipids/blood , Male , Middle Aged , Prospective Studies
6.
J Rheumatol ; 21(4): 700-4, 1994 Apr.
Article in English | MEDLINE | ID: mdl-8035396

ABSTRACT

OBJECTIVE: To determine if patients with gout with chronic alcoholism have lower serum urate levels than nonalcoholic patients. METHODS: Of 95 consecutive consults for acute gout at a VA medical center, 42 were excluded from study due to lack of crystal documentation, lack of urate value within 2 years, or treatment with allopurinol or probenecid. The remaining 53 patients were grouped by alcohol use and a retrospective chart review was done for these patients. RESULTS: Mean intercritical serum urate values for chronic alcoholics and nonalcoholics were similar at 9.7 +/- 2.1 for alcoholics and 9.5 +/- 2.1 for nonalcoholics. Yet, despite these similar intercritical serum urate values, and despite no difference between chronic alcoholics and nonalcoholics in frequency or severity of acute gout flares, patients with chronic alcoholism had index serum urate levels which were significantly lower than those of nonalcoholics. These mean index values, with standard deviations, were 7.7 +/- 1.3 for 15 chronic alcoholics and 10.1 +/- 1.3 for 34 nonalcoholics; p < 0.01). CONCLUSION: Alcoholics and nonalcoholics had comparable intercritical values. However, on presentation with acute arthritis, the index serum urate values for alcoholics were lower than in nonalcoholics. Values for serum urate below 8.5 mg/dl are of less value in excluding gout in chronic alcoholics than in nonalcoholics presenting with acute gout flares.


Subject(s)
Alcoholism/blood , Alcoholism/complications , Arthritis, Gouty/blood , Arthritis, Gouty/complications , Uric Acid/blood , Aged , Arthritis, Gouty/diagnosis , Creatinine/metabolism , Humans , Middle Aged , Retrospective Studies , Risk Factors , Temperance
7.
J Biol Chem ; 267(28): 20317-25, 1992 Oct 05.
Article in English | MEDLINE | ID: mdl-1400350

ABSTRACT

The activity of p34cdc2 kinase is regulated in the phases of vertebrate cell cycle by mechanisms of phosphorylation and dephosphorylation. In this paper, we demonstrate that casein kinase II (CKII) phosphorylates p34cdc2 in vivo and in vitro at Ser39 during the G1 phase of HeLa cell division cycle. Human p34cdc2 shows a typical phosphorylation sequence motif site for CKII at Ser39 (ES39EEE). In our experiments, either p34cdc2 expressed and purified from bacteria or p34cdc2 immunoprecipitated from HeLa cells enriched in G1 by elutriation were substrates for in vitro phosphorylation by CKII. Phosphoamino acid analysis, N-chlorosuccinimide mapping, and two-dimensional tryptic mapping of p34cdc2 phosphorylated in vitro were performed to determine the phosphorylation site. A synthetic peptide spanning residues 33-50 of human p34cdc2, including the CKII site, was used to map the site. In addition, phosphorylation at Ser39 also occurs in vivo, since p34cdc2 is phosphorylated during G1 on serine, and its two-dimensional tryptic map shows two phosphopeptides that comigrate exactly with the synthetic peptides used as standard.


Subject(s)
CDC2 Protein Kinase/metabolism , G1 Phase , Protein Serine-Threonine Kinases/metabolism , Amino Acid Sequence , Blotting, Western , Casein Kinase II , Cell Division , Electrophoresis, Gel, Two-Dimensional , Flow Cytometry , HeLa Cells , Humans , Molecular Sequence Data , Peptide Mapping , Phosphorylation , Substrate Specificity
8.
Mol Cell Biol ; 12(10): 4694-705, 1992 Oct.
Article in English | MEDLINE | ID: mdl-1328860

ABSTRACT

c-jun is a member of the family of immediate-early genes whose expression is induced by factors such as serum stimulation, phorbol ester, and differentiation signals. Here we show that increased Jun synthesis after serum stimulation is accompanied by a concomitant increase in phosphorylation. Several serine-threonine kinases were evaluated for their ability to phosphorylate Jun in vitro. p34cdc2, protein kinase C, casein kinase II, and pp44mapk phosphorylated Jun efficiently, whereas cyclic AMP-dependent protein kinase and glycogen synthase kinase III did not. The sites phosphorylated by p34cdc2 were similar to those phosphorylated in vivo after serum induction. The major sites of phosphorylation were mapped to serines 63, 73, and 246. Phosphorylation of full-length Jun with several kinases did not affect the DNA-binding activity of Jun homodimers or Fos-Jun heterodimers. Comparison of the DNA binding and in vitro transcription properties of wild-type and mutated proteins containing either alanine or aspartic acid residues in place of Ser-63, -73, and -246 revealed only minor differences among homodimeric complexes and no differences among Fos-Jun heterodimers. Thus, phosphorylation of Jun did not produce a significant change in dimerization, DNA-binding, or in vitro transcription activity. The regulatory role of phosphorylation in the modulation of Jun function is likely to be considerably more complex than previously suggested.


Subject(s)
Protein Kinases/metabolism , Proto-Oncogene Proteins c-jun/metabolism , Blood , CDC2 Protein Kinase/metabolism , Calcium-Calmodulin-Dependent Protein Kinases , Casein Kinases , DNA/metabolism , DNA Mutational Analysis , Fibroblasts/metabolism , Glycogen Synthase Kinases , HeLa Cells , Humans , Phosphorylation , Protein Binding , Protein Kinase C/metabolism , Proto-Oncogene Proteins c-jun/biosynthesis , Serine/metabolism , Transcription, Genetic
9.
J Cell Biochem ; 45(4): 391-400, 1991 Apr.
Article in English | MEDLINE | ID: mdl-2045431

ABSTRACT

Synthetic peptide substrates for the cell division cycle regulated protein kinase, p34cdc2, have been developed and characterized. These peptides are based on the sequences of two known substrates of the enzyme, Simian Virus 40 Large T antigen and the human cellular recessive oncogene product, p53. The peptide sequences are H-A-D-A-Q-H-A-T-P-P-K-K-K-R-K-V-E-D-P-K-D-F-OH (T antigen) and H-K-R-A-L-P-N-N-T-S-S-S-P-Q-P-K-K-K-P-L-D-G-E-Y-NH2 (p53), and they have been employed in a rapid assay of phosphorylation in vitro. Both peptides show linear kinetics and an apparent Km of 74 and 120 microM, respectively, for the purified human enzyme. The T antigen peptide is specifically phosphorylated by p34cdc2 and not by seven other protein serine/threonine kinases, chosen because they represent major classes of such enzymes. The peptides have been used in whole cell lysates to detect protein kinase activity, and the cell cycle variation of this activity is comparable to that measured with specific immune and affinity complexes of p34cdc2. In addition, the peptide phosphorylation detected in mitotic cells is depleted by affinity adsorption of p34cdc2 using either antibodies to p34cdc2 or by immobilized p13, a p34cdc2-binding protein. Purification of peptide kinase activity from mitotic HeLa cells yields an enzyme indistinguishable from p34cdc2. These peptides should be useful in the investigation of p34cdc2 protein kinase and their regulation throughout the cell division cycle.


Subject(s)
CDC2 Protein Kinase/metabolism , Peptides/metabolism , Amino Acid Sequence , CDC2 Protein Kinase/isolation & purification , Cell Cycle , Cell Separation , HeLa Cells , Humans , Immunoblotting , Molecular Sequence Data , Peptides/chemical synthesis , Phosphorylation , Precipitin Tests , Substrate Specificity
10.
N Z Med J ; 98(793): 1075-8, 1985 Dec 25.
Article in English | MEDLINE | ID: mdl-3865090

ABSTRACT

Data from a survey of all post-neonatal deaths for 12 months to 28 February 1979, together with population data, were used to assess maternal cigarette smoking as a risk factor for post-neonatal death and cot death. Smoking was estimated to be a risk factor, but only where the smokers (Maori and non-Maori) were under 25 years of age. The infants most at risk were those of Maori smokers aged 20-24. As a risk factor for post-neonatal death smoking during pregnancy ranked third, with Maori maternity second and low infant birthweight first. Results indicate that the relevance of maternal smoking to post-neonatal mortality may depend on the total psycho-social-cultural context in which it occurs. It is suggested that factors that initiate and maintain smoking behaviour in young women need to be identified and strategies developed to counteract them. Concurrently, non-smoking behaviour needs to be positively promoted as a more attractive option for young women to adopt.


Subject(s)
Smoking , Sudden Infant Death/etiology , Adolescent , Adult , Epidemiologic Methods , Ethnicity , Female , Humans , Infant , Infant, Newborn , Male , Maternal Age , New Zealand , Pregnancy , Risk , Sudden Infant Death/epidemiology
11.
N Z Med J ; 98(773): 97-9, 1985 Feb 27.
Article in English | MEDLINE | ID: mdl-3856165

ABSTRACT

Four thousand and forty-one infants aged 1-4 months were included in a national survey to determine the position in which New Zealand infants usually sleep. Infants were most commonly put down on the side or on the front with the face to one side. Many changed position during sleep. By far the most common position in which infants ended up sleeping was on the front with the face to one side. The proportion of infants in the various sleep positions changed with age. Speculation as to a possible relationship between sleep position and sudden infant death must take into account that many infants do not sleep in the position in which they are put down and that there are changes in position with age.


Subject(s)
Posture , Sleep , Humans , Infant , New Zealand , Sudden Infant Death/etiology
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