Incipient and overt diabetic nephropathy in African Americans with NIDDM.

OBJECTIVE--To determine the prevalence of incipient and overt nephropathy in African-American subjects with non-insulin-dependent diabetes mellitus (NIDDM) attending a hospital clinic. Contributory factors, such as blood pressure (BP), duration and age at onset of diabetes, hyperglycemia, hyperlipidemia, and body mass index (BMI) also were evaluated. RESEARCH DESIGN AND METHODS--We recruited 116 African-American subjects with NIDDM for this cross-sectional, descriptive, and analytical study. BP, BMI, 24-h urine albumin excretion, creatinine clearance, serum creatinine, lipids, and GHb levels were measured. Albumin excretion rate (AER) was calculated, and subjects were divided into three groups: no nephropathy (AER < 20 micrograms/min), incipient nephropathy (AER 20-200 micrograms/min), and overt nephropathy (AER > 200 micrograms/min). Frequency of hypertension and nephropathy was analyzed by chi 2 testing, group means were compared using analysis of variance, and linear correlations were performed between AER and other variables. Multiple regression analysis was used to examine the association of these variables while controlling for the effects of other variables. RESULTS--Increased AER was present in 50% of our subjects; 31% had incipient and 19% had overt nephropathy. Hypertension was present in 72.4%; nephropathy, particularly overt nephropathy, was significantly more prevalent in the hypertensive group. Mean BP and diastolic blood pressure (dBP) were higher in the groups with incipient and overt nephropathy, and systolic blood pressure (sBP) was increased in overt nephropathy. Men with either form of nephropathy had higher sBP, dBP, and mean BP, whereas only women with overt nephropathy had increased sBP and mean BP. Subjects with incipient or overt nephropathy had a longer duration of diabetes, and those with overt nephropathy had a younger age at onset of diabetes. By multiple regression analysis, AER correlated with younger age at diabetes onset, but not with diabetes duration. No correlation with age, lipid levels, or GHb was noted. BMI correlated with AER. CONCLUSIONS--Incipient and overt nephropathy were observed frequently in these African-American subjects with NIDDM. Albuminuria correlated with BP, younger age at diabetes onset, and BMI. Association of albuminuria and increased cardiovascular mortality may place 50% of inner-city African-American patients with NIDDM at risk for developing cardiovascular complications.

Chicken liver fatty acid synthetase dimer: evidence of asymmetrical structure from iodoacetamide inhibition studies.

The condensing component of chicken liver fatty acid synthetase is inhibited by a sulfhydryl reagent, iodoacetamide, with a second-order rate constant of 0.23 M-1 sec-1 at pH 7.0 and 0 degrees. Complete inactivation requires the modification of approximately 8 -SH groups per dimer of the enzyme. Quantitation of the extent of inactivation in the presence of 1 mM acetyl CoA (which completely protects the enzyme against inactivation) and in its absence shows that complete inactivation results from the binding of approximately 1.1 mol of carboxamidomethyl residues per dimer. These data are consistent with the proposed functional asymmetry of the enzyme.

Oral health perceptions and adherence with dental treatment referrals among caregivers of children with HIV.

Results from a 3-year longitudinal study on the oral manifestations of AIDS (OMA) among seropositive children and their siblings indicated poor adherence with recommendations for dental treatment (Broder, Catalanotto, Reisine, & Variagiannis, 1996). The purposes of this study were to (a) to examine oral health behaviors, attitudes, and perceived barriers to care among caregivers of children with HIV and their siblings who were referred for dental care, and (b) develop and evaluate a 5-week summer pilot program to increase adherence with referral for dental treatment. Telephone interviews with caregivers were conducted to identify barriers to care and to implement services to increase attendance in the dental clinic for their children. Interviews were completed with 28 of the 38 (74%) caregivers recruited from the OMA study (previously cited) who had children referred for dental treatment at the final (sixth) oral health research exam. Twelve of their 58 children (21%) had obtained dental care privately, 25 (62.5%) initiated treatment and 2 (6.3%) completed treatment at the referred dental school during the 5-week pilot program. Although caregivers of children with HIV and their siblings were responsive to the initial efforts of the program's service coordinators, follow-up data from the coordinators' records and chart abstraction revealed that the majority of the participants did not appear for their second or third appointments. The interview reports suggested that caregivers expect dental treatment, such as restorations, at each appointment and do not regard exams/treatment planning as treatment. Personal/family and health care delivery system factors were expressed barriers to dental care. Implications for future programs and investigations are discussed.

Inhibition of the condensing component of chicken liver fatty acid synthase by iodoacetamide and 5,5'-dithiobis-(2-nitrobenzoic acid).

Chicken liver fatty acid synthase is inhibited by the thiol-modifying reagents 5,5'-dithiobis-(2-nitrobenzoic acid) and iodoacetamide. Total inactivation of the activity for fatty acid synthesis requires the modification of about 8 of the nearly 50 freely accessible thiol groups per molecule. The differential binding of iodo[14C]acetamide to phenylmethylsulphonyl fluoride-modified enzyme in the absence and in the presence of excess acetyl-CoA shows complete modification of one cysteine-SH site of the condensing enzyme and partial modification of the pantetheine-SH site for a total of approx. 1.4 mol of iodoacetamide bound per mol of enzyme. The reaction of the enzyme with 5,5'-dithiobis-(2-nitrobenzoic acid) generates disulphide cross-links for each molecule of the reagent added, but 95% of these cross-links are intrasubunit. Both the iodoacetamide- and 5,5'-dithiobis-(2-nitrobenzoic acid)-modified species catalyse all the component partial reactions of fatty acid synthesis except the condensation reaction. The results obtained with iodoacetamide show that in the dimeric fatty acid synthase modification of one cysteine-SH condensing site and/or one pantetheine-SH site per dimer is sufficient to affect inhibition of condensing activity and the activity for fatty acid synthesis, and are in accord with a recently proposed model for the mechanism of action of animal fatty acid synthases [Kumar (1982) J. Theor. Biol. 95, 263-283].

Diminished proteinuria in diabetes mellitus by sorbinil, an aldose reductase inhibitor.

Proteinuria was diminished by concomitant oral administration of sorbinil, an aldose reductase inhibitor to streptozotocin-induced diabetic rats. Animals were placed in one of three groups: control, diabetic, sorbinil-treated diabetic. For a period of 10 weeks, 24-hour urine samples were analyzed weekly for volume, glucose, ketone, total protein (Pesce-Strande) and individual protein components having molecular weights between 15,000 and 120,000 daltons. The latter were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Results indicated that controls excreted albumin (68,000 daltons) and low-molecular weight proteins between 15,000 and 20,000 daltons. Throughout the 10-week period of diabetes, there was a 7- to 12-fold increase in total urinary protein excreted in 24 h. Diabetic-induced proteinuria primarily resulted from excretion of newly detected proteins having molecular weights of 30,000-100,000 daltons and an increase amount of albumin. Sorbinil treatment prevented approximately 70% of the increase in total protein excretion despite persistent hyperglycemia, glycosuria and ketonuria. Laser densitometric analysis indicated that the aldose reductase inhibitor decreased by 70% the excretion of newly detected proteins and albumin while maintaining the 15,000- to 20,000-dalton proteins. These results suggest that the polyol pathway is implicated in diabetic-induced proteinuria and inhibition of aldose reductase may represent a therapeutic approach for management of diabetic nephropathy.

Reversal of stage-I sugar cataract by Sorbinil, an aldose reductase inhibitor.

Aldose reductase is implicated in the pathogenesis of sugar cataracts; therefore, inhibition of this enzyme subsequent to cataractogenesis may represent a therapeutic approach for the restoration of lens physiology despite the persistence of diabetes or galactosemia. In the present study, the effect of aldose reductase inhibition subsequent to stage-I cataract formation was investigated in the galactose-maintained rat. Our results indicated that despite continuation of galactose feeding the aldose reductase inhibitor, Sorbinil, a spirohydantoin, arrested further progression and promoted a reparative process. Quantitative analysis of scanning electron micrographs indicated that the afflicted lens regions were contained and their cellular components stabilized with regard to fiber hydration and interdigitation. The reparative process involved: decrease in lens dulcitol, gradual recovery of fiber thickness and partial restoration of lens myo-inositol content. At this stage of cataractogenesis, despite continuance of galactose feeding, the effects of Sorbinil treatment were comparable to the reparative process achieved by restoration of a normal diet.

On the neurochemistry of an adult form of ceroid lipofuscinosis (Kuf's disease).

Little progress has been made in procedures for diagnosis of this baffling group of diseases known as ceroid lipofuscinoses (CL), which exhibit infantile, juvenile, and adult forms. Although these have been shown for the most part to be genetic in origin, the enzymatic or other defects leading to accumulation of lipopigments in tertiary lysosomes of neurons or astrocytes re unknown. Among the more commonly discussed theories is the role of peroxy radicals or their products formed by lipoperoxidation of polyunsaturated fatty acids. Although peroxy radicals are damaging to tissues and biological processes, no differences were observed in levels of leucocyte peroxidase (metabolizing H2O2) for Kuf's patients in comparison to age-matched controls. Also, no differences were observed in levels of blood factors that affect the rates of lipoperoxidatin by rat or human brain homogenates in vitro (measured by formation of MDA or other TBA positive materials).

Sorbinil protection of lens protein components and cell hydration during diabetic cataract formation.

Topical application of Sorbinil, a potent aldose reductase inhibitor, preserved lens growth, cell hydration and protein components--alpha, beta and gamma crystallins. The concomitant protective effects of Sorbinil were established on the three lenticular parameters because their quantitation offered a comprehensive index of lens integrity during galactose cataractogenesis. The fused eyelids of the rat neonate provided a natural delivery chamber, an orbital pouch, for topical administration of inhibitor to the treated lens; the contralateral pouch served as an untreated control. Protein preservation was determined by gel filtration chromatography. In galactose-maintained neonates, untreated lenses exhibited only 50% of the normal fraction-II component, whereas Sorbinil treatment maintained 95% of the protein. Likewise, quantitative analysis of scanning electron micrographs indicated that Sorbinil protected lenses against both intra- and extracellular fluid accumulation as determined by measurements of individual fiber cell thickness, density (the number of cells/10 micrometer cortex), and interdigitation. In addition, Sorbinil-treatment maintained normal growth as evidenced by radius and dry weight measurements. In normal neonates, Sorbinil had no effect on these parameters. These results indicate that changes in lens growth, fiber ultrastructure and protein components respond to aldose reductase inhibition by Sorbinil, thereby diminishing cataractogenesis.

Xanthone-2-carboxylic acid effect on lens growth, hydration and proteins during diabetic cataract development.

The concomitant protective effects of the aldose reductase inhibitor, 7-dimethylsulfamoyl-xanthone-2-carboxylic acid, were established by three lens parameters (soluble crystallin proteins, growth and cell hydration) because their quantitation provided a comprehensive index of lens physiology during sugar cataractogenesis in the rat neonate. Their fused eyelids provided the orbital pouch for topical administration of inhibitor to the treated lens; the contralateral pouch served as an untreated control. Protein preservation was determined by gel filtration chromatography. In galactose-maintained neonates, untreated lenses exhibited only 50% of the normal Fraction II protein whereas xanthone-treatment maintained 73% of this component. Quantitative analysis of scanning electron micrographs indicated that xanthone-treatment partially protected lenses against both intra and extracellular fluid accumulation as determined by measurements of individual fiber cell thickness, density (the number of cells/10 micron cortex), and interdigitation. In addition, xanthone-treatment improved lens growth as evidenced by radius and dry weight measurements. Our results suggest that topically applied xanthone partially inhibited sugar cataractogenesis.