Successful immunosuppressive therapy in insulin resistant diabetes caused by anti-insulin receptor autoantibodies

The length of elastic fibers and the distribution of fiber diameters was determined by morphometry in the parenchyma of human lungs. Studies were done on 33 lungs from male subjects 1 to 85 years of age, including 9 lungs with mild emphysema. These studies suggest that the total length of elastic fibers is present early in life, possible by 10 years of age, and thereafter remains constant. Average fiber diameter increases between infancy and adulthood but probably does not change further beyond the third decade of life. No significant differences could be detected in either total fiber length or fiber diameter in the lungs with mild emphysema compared to normal lungs of the same age.     

Insulin kinetics in type I diabetic patients treated by continuous intraperitoneal insulin infusion: influence of anti-insulin antibodies

Continuous intraperitoneal insulin infusion (CIPII) is a promising therapy of patients with Type 1 (insulin-dependent) diabetes mellitus (IDDM), since it improves metabolic control and decreases frequency of severe hypoglycaemia. This could be due to more appropriate insulin kinetics. Our aim, therefore, was to compare plasma free insulin levels achieved in patients with Type 1 diabetes chronically treated with CSII or CIPII. Furthermore, as anti-insulin antibodies increase with this treatment, we wanted to assess their influence upon insulin kinetics. Plasma free insulin profiles were obtained during the night and then after the bolus for breakfast and the bolus for lunch in 11 patients with Type 1 diabetes treated successively by CSII and CIPII. In another group of 16 patients with long-term Type 1 diabetes, treated by CIPII, we examined the influence of anti-insulin antibody level on insulin kinetics after a bolus. During the night, plasma free insulin levels were lower with CIPII than with CSII (12:00 am: 10.1 +/- 1.7 vs 18.5 +/- 2.6 mU l-1; 4:00 am: 9.1 +/- 2 vs 15 +/- 3 mU l-1), p < 0.01. After the bolus, CIPII lead to an earlier (1h vs 3h) and higher (25.8 +/- 3.3 vs 18 +/- 2.7, p < 0.05) plasma free insulin peak than CSII. With CIPII, the return to baseline level was observed within 3 h. Conversely, during CSII, insulin levels did not return to baseline until the next meal. After the bolus, high insulin-antibody levels were associated with a reduced maximal value of plasma free insulin peak. Taken together, these findings suggest that CIPII provides plasma free insulin profiles which are much closer to physiology than CSII. This could explain the lower rate of severe hypoglycaemia observed with this type of treatment. But in long-term CIPII treated patients with high anti-insulin antibody level, insulin profile could be moderately modified. This emphasizes the need for a less immunogenic insulin preparation.     

Effect of anti-insulin serum on the hepatic lipid metabolism of BHE rats

Vascular injury or occlusion from intra-aortic balloon pumping (IABP) that results in actual or potential limb ischemia occurs more frequently than reported. In a series of 79 IABP patients, 36 lived long enough to have the balloon catheter removed; thirteen (36%) of them had vascular complications. The complications were in three patients with an injury at the insertion site, eight patients with arterial thromboses, and two with arterial occlusion by the large balloon catheter. Local artery revision, thrombectomy alone, or thrombectomy with femorofemoral cross-over grafting was required in 11 patients. Femorofemoral crossover graft was utilized when arterial occlusion would have ordinarily required premature balloon removal or when immediate arterial occlusion by the catheter was recognized at the time of balloon insertion. This was preferable to transferring, replacing, or discontinuing IABP, since the same factors that led to thrombosis in the first place would have eventually come into play again. Patients should be observed frequently and have Doppler limb pulse determinations every four hours to avoid ischemic catastrophies. Proper IABP weaning and the use of a Fogarty catheter at the time of balloon removal is mandatory to prevent complications. Femorofemoral crossover graft is indicated for ischemic limbs when IABP must be continued.     

Removal of tetrachloroethylene in an anaerobic column bioreactor

Removal of tetrachloroethylene (perchloroethylene; C2Cl4) by microbial consortia from two sites with different C2Cl4 exposure histories was examined in a bench-scale anaerobic column bioreactor. It was hypothesized that optimal removal would be observed in the reactor packed with sediments having an extensive exposure history. Microbial consortia were enriched from hyporheic-zone (HZ) sediments from the Portneuf aquifer near Pocatello, Idaho, and from industrial-zone (IZ) sediments from a highly contaminated aquifer in Portland, Oregon. Lactate and acetate were the electron donors during experiments conducted over 9 and 7 months for HZ and IZ sediments, respectively. In the HZ bioreactor, the retention time ranged from 31 h to 81 h, and inlet C2Cl4 concentrations ranged from 0.1 ppm to 1.0 ppm. Dechlorination of C2Cl4 averaged 60% and reached a maximum of 78%. An increase in C:N from 27:1 to 500:1 corresponded to an 18% increase in removal efficiency. Trichloroethylene production corresponded to decreased effluent C2Cl4; further intermediates were not detected. In the IZ bioreactor, the retention time varied from 34 h to 115 h; the inlet C2Cl4 concentration was 1.0 ppm. C2Cl4 removal averaged 70% with a maximum of 98%. Trichloroethylene and cis-dichloroethylene were detected in the effluent. Increases in C:N from 50:1 to 250:1 enhanced dechlorination activity.     

Combination insulin and sulfonylurea therapy in insulin-requiring type 2 diabetes mellitus

OBJECTIVES: To identify ethical dilemmas experienced by occupational and physical therapists working in the UK National Health Service (NHS). To compare ethical contexts, themes and principles across the two groups. DESIGN: A structured questionnaire was circulated to the managers of occupational and physical therapy services in England and Wales. SUBJECTS: The questionnaires were given to 238 occupational and 249 physical therapists who conformed to set criteria. RESULTS: Ethical dilemmas experienced during the previous six months were reported by 118 occupational and 107 physical therapists. The two groups were similar in age, grade, and years of experience. Fifty of the occupational therapy dilemmas occurred in mental health settings but no equivalent setting emerged for physical therapy. Different ethical themes emerged between the two groups, with the most common in occupational therapy being difficult/dangerous behaviour in patients and unprofessional staff behaviour, and for physical therapists resource limitations and treatment effectiveness. No differences were found in the ethical principles used. CONCLUSION: The ethical dilemmas reported by the therapists were primarily concerned with health care ethics, rather than the more dramatic ethics reported in much of the biomedical ethics literature. Differences were found between the two professional groups when ethical contexts and themes were compared but not when ethical principles were compared. This suggests that educators and researchers need to be aware of work settings and the interdisciplinary nature of employment as well as ethical principles held by individual therapists.     

Use of an alumina column in estimating total iron-binding capacity

I describe a simple, rapid technique for saturating the transferrin in serum and then removing unbound (excess) iron. This technique involves use of an easily prepared column of basic chromatographic alumina and a saturating solution of ferric chloride in citric acid. This method, when compared with the magnesium carbonate method of Ramsay (Clin. Chim. Acta 2: 221, 1957) by regression analysis and tests of precision, showed a negative bias for results by the alumina technique with respect to the magnesium carbonate method.     

Characterization of an N-acetylglucosamine-6-O-sulfotransferase from human respiratory mucosa active on mucin carbohydrate chains

A microsomal GlcNAc-6-O-sulfotransferase activity from human bronchial mucosa, able to transfer a sulfate group from adenosine 3'-phosphate 5'-phosphosulfate onto methyl-N-acetylglucosaminides or terminal N-acetylglucosamine residues of carbohydrate chains from human respiratory mucins, has been characterized. The reaction products containing a terminal HO3S-6GlcNAc were identified by high performance anion-exchange chromatography. Using methyl-beta-N-acetylglucosaminide as a substrate, the optimal activity was obtained with 0.1% Triton X-100, 30 mM NaF, 20 mM Mn2+, 5 mM AMP in a 30 mM MOPS (3-(N-morpholino) propanesulfonic acid) buffer at pH 6.7. The apparent Km values for adenosine 3'-phosphate 5'-phosphosulfate and methyl-beta-N-acetylglucosaminide were observed at 9.1 x 10(-6) M and 0.54 x 10(-3) M, respectively. The enzyme had more affinity for carbohydrate chains with a terminal GlcNAc residue than for methyl-beta-N-acetylglucosaminide; it was unable to catalyze the transfer of sulfate to position 6 of the GlcNAc residue contained in a terminal Galbeta1-4GlcNAc sequence. However, oligosaccharides with a nonreducing terminal HO3S-6GlcNAc were substrates for a beta1-4 galactosyltransferase from human bronchial mucosa. These data point out that GlcNAc-6-O-sulfotransferase must act before beta1-4 galactosylation in mucin-type oligosaccharide biosynthesis.     

Novel methods of insulin delivery: an update

Conventional insulin therapies involve multiple daily subcutaneous injections. However, the resultant disposition of insulin and blood glucose differs considerably from that following the physiological secretion of pancreatic insulin. A variety of alternative routes/methods have been investigated to improve systemic insulin delivery. Peroral and nasal insulin administration have demonstrated good potential for the treatment of diabetes. Facilitated transdermal delivery has also enjoyed success in promoting the systemic delivery of insulin. In addition, pulmonary, buccal, and ocular insulin administration have been shown to decrease serum glucose concentrations. Other methods that have been investigated for their potential in systemic insulin delivery include rectal, vaginal, and uterine routes.     

Megalin is an endocytic receptor for insulin

Renal clearance is a major pathway for regulating the levels of insulin and other low molecular weight polypeptide hormones in the systemic circulation. Previous studies have shown that the reabsorption of insulin from the glomerular filtrate occurs by binding to as yet unidentified sites on the luminal surface of proximal tubule cells followed by endocytosis and degradation in lysosomes. In this study, an insulin binding site was identified in renal microvillar membranes by chemical cross-linking procedures. By immunoprecipitation it was demonstrated that this binding site is megalin, the large multiligand binding endocytic receptor that is abundantly expressed in clathrin-coated pits on the apical surface of proximal tubule cells. Moreover, using cytochemical procedures, it was also shown that megalin is able to internalize insulin into endocytic vesicles. In ligand blotting assays, megalin also bound several other low molecular weight polypeptides, including beta2-microglobulin, epidermal growth factor, prolactin, lysozyme, and cytochrome c. These data suggest that megalin may play a significant role as a renal reabsorption receptor for the uptake of insulin and other low molecular weight polypeptides from the glomerular filtrate.     

Chemiluminescence flow-through sensor for copper based on an anodic stripping voltammetric flow cell and an ion-exchange column with immobilized reagents

A novel chemiluminescence (CL) flow-through sensor based on immobilizing all the ingredients involved in the analytical reaction for the determination of copper is proposed. The analytical reagents including luminol and cyanide were coimmobilized permanently on an anion-exchange column, while the analyte copper was retained temporarily by electrochemical preconcentration on a gold electrode placed in an anodic stripping voltammetric flow cell. By injection of a volume of sodium hydroxide through the column with immobilized reagents, luminol and cyanide were eluted from the resins in alkaline aqueous solution and then reacted with copper stripped from the gold electrode to produce a CL signal, by means of which copper could be sensed. The sensor was not susceptible to interference by other metal ions associated with the CL reaction. The response to the concentration of copper was linear in the range of 0.01-10 micrograms/L and an extremely low detection limit of 8.0 x 10(-3) micrograms/L was achieved. A complete analysis could be performed in 4 min with a relative standard deviation of less than 8%. The column with immobilized reagents was readily prepared and could be reused over 200 times. The sensor was applied successfully to the determination of copper in human serum and natural water samples.     

Bovine fetuin is an inhibitor of insulin receptor tyrosine kinase

Fetuin has been identified earlier as the bovine homolog of the human plasma protein, alpha2-Heremans Schmid glycoprotein (alpha2-HSG). Although bovine fetuin shares over 70% amino acid sequence similarity with alpha2-HSG and rat fetuin, no common function(s) have been identified. We report that immunoaffinity purified bovine fetuin acts as an inhibitor of insulin receptor tyrosine kinase activity (IR-TKA) with half-maximal inhibition at 1.5 microM. In vitro, bovine fetuin (1.5 microM) blocked insulin-induced autophosphorylation of the human IR completely and the half-maximal inhibitory effect was observed at 0.5 microM. Incubation of HIRcB cells (rat1 fibroblasts transfected with wild-type human insulin receptor cDNA) with bovine fetuin (1.5 microM) inhibited insulin-induced tyrosine phosphorylation of the IR beta-subunit by 40%. In addition, bovine fetuin (2 microM) completely blocked insulin-stimulated DNA synthesis in H-35 rat hepatoma cells. Our results, together with earlier reports on rat fetuin and human alpha2-HSG, indicate a common IR-TK inhibitory function for fetuin homologs.