Familial aggregation of medial arterial calcification in Pima Indians with and without diabetes.

OBJECTIVE: Little is known about medial arterial calcification (MAC) other than its association with age, sex, diabetes, and diabetes complications. Familial aggregation of this disorder was studied to determine the importance of potential genetic factors and to assess whether such familial aggregation was independent of that of diabetes. RESEARCH DESIGN AND METHODS: Members of 1,256 Pima Indian nuclear families with 3,339 offspring were examined radiologically for MAC of the feet. Multiple logistic regression analyses were used to compare the presence of the disorder in a parent with the presence of MAC in an offspring and to determine whether familial aggregation of MAC was independent of parental diabetes. RESULTS: Controlled for age, sex, diabetes, serum cholesterol, and blood pressure, offspring of one parent with MAC had 3.3 (95% CI 1.5-7.6) times the odds of MAC as did offspring of parents without MAC, and offspring with both parents affected had an even higher risk (odds ratio, 8.1; 95% CI 3.4-18.8). Controlled for offspring age and sex and for parental age and diabetes, parental MAC was associated with the disorder in offspring (P < 0.001), but the effect of parental diabetes on MAC in the offspring was not significant when controlled for parental MAC (P = 0.36). Furthermore, offspring of nondiabetic parents with MAC, controlled for age, sex, diabetes, and diabetes duration, had 1.7 (95% CI 0.9-3.1) times the odds of MAC than did offspring of diabetic parents with MAC. CONCLUSIONS: Independent of parental age and diabetes and offspring age, sex, diabetes, and diabetes complications, parental MAC confers an increased risk of MAC in offspring. These findings suggest that the factors responsible for the familial clustering of MAC may be different from those for diabetes.

Homocysteine mediated endothelial cell toxicity and its amelioration.

In response to homocysteine induced toxicity in human umbilical vein endothelial cells, minimal changes in the concentration of cellular protein thiols but substantial changes in the concentration of intracellular soluble thiols were observed. The latter correlated closely with changes in cellular glutathione levels. No correlation existed between cellular glutathione levels and cell viability, whereas a close correlation between NAD+ levels and cell viability was demonstrated. Large decreases in cellular NAD+ occurred in response to homocysteine induced toxicity which were accompanied by the production of single stranded DNA. 3-Aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase preserved cell viability and cellular NAD+ levels. Evidence that DNA synthesis was also compromised was revealed by the decreased capacity of homocysteine treated cells to incorporate deoxyuridine. Radical scavengers were also effective in preventing homocysteine induced toxicity. It is likely that the major threat to cells derives from radicals generated intracellularly. Eicosanoid metabolism and the xanthine oxidase system have been identified as two potential sources of radicals.

Lipid peroxidation and homocysteine induced toxicity.

Homocysteine induced toxicity has been examined in cultures of human umbilical vein endothelial cells. The toxic effects of the amino acid alone and the amino acid plus Cu2+ could be prevented by catalase and decreased by desferal, when either was present in the culture medium. When desferal was allowed to accumulate intracellularly, no significant protection from homocysteine induced toxicity was observed. Even though lipid peroxidation accompanied the toxicity induced by homocysteine and homocysteine plus Cu2+, inhibition of lipid peroxidation in either case had no effect on cell viability. The significance of these results is discussed.

Homocysteine uptake by human umbilical vein endothelial cells in culture.

The characteristics of the uptake of L-homocysteine by cultures of human umbilical vein endothelial cells have been examined. Uptake occurred by Na(+)-dependent and Na(+)-independent systems, but was essentially independent of the pH of the uptake medium. The Na(+)-independent system corresponded to system L, being totally inhibited by the presence of beta-2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH) a system L analogue. It was concluded on the basis of starvation experiments coupled with failure to detect any inhibition in the presence of 2-methylaminoisobutyric acid (MeAIB), a system A analogue, that the Na(+)-dependent uptake was wholly accounted for by system ASC. The kinetic properties of systems L and ASC were determined by omitting Na+ from the uptake medium and incorporating BCH in the medium, respectively. It has been concluded on the basis of the inhibitory effects of a number of amino acids that uptake of homocysteine occurs by those systems which transport cysteine.

Thoracic outlet syndrome caused by a latissimus dorsi flap for breast reconstruction.

After undergoing bilateral breast reconstruction with latissimus dorsi flaps, a 34-year-old woman developed right-sided thoracic outlet syndrome. At operation, the latissimus dorsi flap was found to have formed a constrictive muscle sling that compressed the thoracic outlet. To the author's knowledge, thoracic outlet syndrome has not previously occurred under these circumstances.

Transport of L-cystine in human umbilical vein endothelial cells in culture.

The uptake of L-cystine into cultured human umbilical vein endothelial cells has been shown to occur by a Na+-independent system which is inhibited by L-glutamate and L-homocysteine, but not by other amino acids. It is likely that the system transporting L-cystine is shared by L-glutamate. Thiol groups associated with membrane bound components appear to be essential for L-cystine uptake but it is not yet evident whether these constitute an integral part of the transporter per se.

Medial arterial calcification and its association with mortality and complications of diabetes.

Medical arterial calcification was studied among 4,553 subjects in a 20-year, longitudinal study of Pima Indians. The prevalence and incidence of medial arterial calcification were highest among men, the elderly, and patients with Type 2 (non-insulin-dependent) diabetes mellitus. Medial arterial calcification was most commonly observed in the feet and appeared to progress proximally. Proportional hazards analysis was used to evaluate risk factors for medial arterial calcification in the feet and to evaluate medial arterial calcification as a risk factor for death and for complications of diabetes. Among diabetic patients, risk factors for medial arterial calcification were impaired vibration perception, long duration of diabetes, and high plasma glucose concentration (p less than 0.01 for each). Among nondiabetic subjects, age, male gender (p less than 0.01 for each), and high serum cholesterol concentration (p = 0.02) were risk factors for medial arterial calcification. Nondiabetic subjects with medial arterial calcification did not have higher mortality rates than subjects without medial arterial calcification (rate ratio = 0.95, 95% confidence interval = 0.7-1.3). Diabetic patients with medial arterial calcification, compared with diabetic patients without medial arterial calcification, had 1.5-fold the mortality rate (95% confidence interval = 1.0-2.1), 5.5-fold the rate of amputations (95% confidence interval = 2.1-14.1), 2.4-fold the rate of proteinuria (95% confidence interval = 1.3-4.5), 1.7-fold the rate of retinopathy (95% confidence interval = 0.98-2.8), and 1.6-fold the rate of coronary artery disease (95% confidence interval = 0.48-5.4).

Sulphoconjugation and sulphohydrolysis.

The formation of sulphoconjugates is a ubiquitous phenomenon and the addition of the sulphate moiety to a variety of endogenous and exogenous molecules dramatically alters their physico-chemical properties and also their biological functions. Large numbers of different types of sulphoconjugate exist and their formation is catalysed by the versatile sulphotransferases. An equally versatile family of enzymes, the sulphohydrolases exist that are capable of accomplishing the reverse reaction. This paper comprises an appraisal of sulphoconjugation and sulphohydrolysis in the metabolism of xenobiotics and addresses the wider issues of sulphur availability and the interplay between mammalian and microbial enzyme systems in the sulphate cycle.

The course of peripheral vascular disease in non-insulin-dependent diabetes.

The present report is an analysis of the course of peripheral vascular disease (PVD) in 619 patients with non-insulin-dependent diabetes (NIDDM) recruited within 1 yr of diagnosis and followed quarterly for up to 14 yr (X = 10.5 yr). At 13 yr duration, the actuarially determined cumulative risks for intermittent claudication (IC), nonpalpable dorsalis pedis pulse (NPUL), and arterial calcification (CALC) were, respectively, 37.9%, 34.5%, and 60.9% for men and 24.3%, 37.6%, and 32.2% for women. Major amputations (AMP) occurred in only 1.3% of the patients, equivalent to approximately one case per 1000 patients per year. The corresponding incidences of IC, NPUL, and CALC were, respectively, 29, 27, and 47 per 1000 men and 19, 27, and 25 per 1000 women per year. CALC and NPUL were strongly related to mortality. Baseline risk factors with probability levels that suggest a relationship to PVD were, in women, age versus CALC (P less than 0.01), age versus NPUL (P less than 0.05), weight versus NPUL (P less than 0.05), systolic BP versus CALC (P less than 0.01), summed glucose tolerance test versus CALC (P less than 0.01), and triglyceride level versus CALC (P less than 0.05). In men, the only significant risk factors were diminished vibration perception, which was related to NPUL (P less than 0.05), and the serum triglyceride level, which was related to IC (P less than 0.05). In patients who are carefully followed prospectively, IC is far more common, but AMP is far less common than has been generally appreciated. Further studies are needed to clarify the roles of the diverse risk factors that are possibly related.

A simple DHEAS loading test in the antepartum diagnosis of placental sulphatase deficiency.

The accurate antenatal diagnosis of placental sulphatase deficiency (PSD) is essential if this condition is to be distinguished from others in which levels of oestrogen are low. In this study we have evaluated a simple protocol determining the serum oestradiol response to 50 mg of dehydroepiandrosterone sulphate (DHEAS) given intravenously to twelve women with low serum or urinary oestrogens. Seven of the women had PSD confirmed by other means, the remaining five had other reasons for the low oestrogen levels. In affected pregnancies the rise in oestradiol was lower, the peak occurred earlier and the level fell towards baseline at 60 min. In the unaffected women, timing of the peak value was not consistent and there was no trend towards basal values at 60 min. There was clear discrimination between the two groups at all times after the injection, but the separation was greater at 60 min.

Aesthetic cervicofacial surgery for head and neck tumor patients.

Carefully selected head and neck tumor patients can safely undergo a wide variety of aesthetic surgical procedures. The malignancy must first be adequately treated and clinically controlled before elective surgery. Each tumor patient's general health and life expectancy must be honestly assessed prior to aesthetic surgery, because operating on an individual who cannot survive to enjoy the benefits is injudicious. Through the combined efforts of sophisticated oncology and plastic surgery, the patient survival rate can be improved as quality of life is enriched in appropriately selected and carefully managed individuals.

Platelet coagulopathy secondary to topical salicylate use.

The use of topical salicylate-containing creams and ointments is widespread. A case is presented which implicates the use of one such cream (Aspercreme) as a potential cause of platelet coagulopathy after rhytidectomy.

Vascular augmentation of skin and musculocutaneous flaps.

In a series of rats, pigs, and dogs, a method for ligating an expendable vessel and placing it under a skin flap or using the vessel to create a new pedicle (neovascular pedicle) for a musculocutaneous flap by the process of neovascularization is demonstrated. No ischemic stimulus is necessary to induce this process of transmural neovascularization.

Biochemical and cellular reaction of PVS paste polymers and latex following intratracheal instillation into rats.

Rats were given different doses (0.25-25 mg) of two forms of PVC past polymers and polystyrene by intratracheal instillation and monitored for cellular and biochemical changes in the lung lavage fluid and remaining lung tissue after 1 and 4 weeks of exposure. Changes were observed in free cell morphology, the level of pulmonary surfactant, and hydrolytic enzyme activities with all three compounds at high concentrations. Some differences in the extent of changes produced per given mass identified were noted with different formulations and the relationship between particle numbers, surface areas, and detergent coatings of samples is discussed. It is argued that PVC paste polymers and polystyrene cannot be considered totally biologically inert but that, in comparison with active cytoxic and inflammatory minerals such as chrysotile asbestos, the extent of their initial reaction in the lung is relatively weak.

Effects in the rat of inhaling PVC dust at the nuisance dust level (10 mg/m3).

Rats inhaled a paste polymer polyvinyl chloride dust at an aerosol concentration of 10 mg/m3 for 6 hr/day, 5 days/wk for a 15-wk period. A small number of randomly scattered lung lesions were detected at 15 wk; these lesions were also present 15 wk after exposure to polyvinyl chloride had ceased. Few if any biochemical changes were detected at the alveolar surface in lung tissues or other organs of polyvinyl chloride-exposed rats. It is therefore concluded that at "nuisance" dust level this form of polyvinyl chloride polymer exhibits a weak biological reactivity.