Biomedical subjects
K Wall
Publications and source records attributed to K Wall.
Potentiation of Rho-A-mediated lysophosphatidic acid activity by hyperinsulinemia.
We have shown previously that insulin promotes phosphorylation and activation of farnesyltransferase and geranylgeranyltransferase (GGTase) II. We have now examined the effect of insulin on geranylgeranyltransferase I in MCF-7 breast cancer cells. Insulin increased GGTase I activity 3-fold and augmented the amounts of geranylgeranylated Rho-A by 18%. Both effects of the insulin were blocked by an inhibitor of GGTase I, GGTI-286. The insulin-induced increases in the amounts of geranylgeranylated Rho-A resulted in potentiation of the Rho-A-mediated effects of lysophosphatidic acid (LPA) on a serum response element-luciferase construct. Preincubation of cells with insulin augmented the LPA-stimulated serum response element-luciferase activation to 12-fold, compared with just 6-fold for LPA alone (p < 0.05). The potentiating effect of insulin was dose-dependent, inhibited by GGTI-286 and not mimicked by insulin-like growth factor-1. We conclude that insulin activates GGTase I, increases the amounts of geranylgeranylated Rho-A protein, and potentiates the Rho-A-dependent nuclear effects of LPA in MCF-7 breast cancer cells.
Effects of insulin on prenylation as a mechanism of potentially detrimental influence of hyperinsulinemia.
To investigate the cause and effect relationship between hyperinsulinemia and the increased amounts of farnesylated p21Ras, we performed hyperinsulinemic euglycemic clamps in normal weight volunteers as well as in normal mice and dogs. Insulin infusions significantly raised the amounts of farnesylated p21Ras in the white blood cells of humans, in liver samples of mice and dogs, and in aorta samples of mice. Obese hyperinsulinemic individuals and dogs (made hyperinsulinemic by surgical diversion of the pancreatic outflow from the portal vein into the vena cava) displayed increased amounts of farnesylated p21Ras before the hyperinsulinemic clamps. Infusions of insulin did not alter the already increased levels of farnesylated p21Ras in these experimental models. To further investigate the role of acquired insulin resistance in modulating insulin's effect on p21Ras prenylation, we induced insulin resistance in rats by glucosamine infusion. Insulin-resistant glucosamine-treated animals displayed significantly increased farnesylated p21Ras in response to insulin infusion compared to that in control saline-treated animals. Transgenic models of insulin resistance (heterozygous insulin receptor substrate-1 knockout mice, A-ZIP/F-1 fatless mice, and animals overexpressing glutamine:fructose-6-phosphate amidotransferase) contained increased amounts of farnesylated p21Ras. We conclude that hyperinsulinemia, either endogenous (a prominent feature of insulin resistance) or produced by infusions of insulin, increases the amounts of farnesylated p21Ras in humans, mice, and dogs. This aspect of insulin action may represent one facet of the molecular mechanism of the potentially detrimental influence of hyperinsulinemia.
Increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals.
We have recently demonstrated that insulin activates farnesyltransferase (FTase) and thereby increases the amounts of cellular farnesylated p21Ras in 3T3-L1 fibroblasts, adipocytes and vascular smooth muscle cells. We postulated that hyperinsulinaemia might considerably increase the the cellular pool of farnesylated p21Ras available for activation by other growth factors. To examine the role of in vivo hyperinsulinaemia in regulating farnesylated p21Ras, we measured the amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals. Liver, aorta, and skeletal muscle of ob/ob mice, and mice made obese and hyperinsulinaemic by injection of gold-thioglucose contained greater amounts of farnesylated p21Ras than tissues of their lean normoinsulinaemic counterparts. Similarly, farnesylated p21Ras was increased (67 vs. 35 % in control animals, p<0.01) in the livers of hyperinsulinaemic Zucker rats (fa/fa). Reduction of hyperinsulinaemia by exercise training (2 h/day for 7-8 weeks) resulted in decreases in the amounts of farnesylated p21Ras in these animals. Increased farnesylated p21Ras in hyperinsulinaemic animals reflected increasing increments in the activity of FTase in ob/ob mice (2-fold increase) and fa/fa Zucker rats (3.5-fold increase), while the total amounts of Ras proteins remained unchanged. In contrast to insulin-resistant hyperinsulinaemic animals, denervated insulin-resistant rat soleus muscle (in the presence of normoinsulinaemia) showed normal amounts of farnesylated p21Ras. In summary, these data confirm increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals.
No foot in the door: an experimental study of employment discrimination against older workers.
Pairs of testers, one aged 57 and one aged 32, applied for 102 entry-level sales or management jobs in the Washington, DC, metropolitan area. Although their credentials described them as equally qualified, the older applicants received less favorable responses from employers 41.2% of the time. Three quarters of these differences occurred before older applicants could fully present their qualifications. The negative employer assumptions about older workers implied by these differences in outcome were seldom explicitly stated.
Effect of insulin on farnesyltransferase. Specificity of insulin action and potentiation of nuclear effects of insulin-like growth factor-1, epidermal growth factor, and platelet-derived growth factor.
We have previously demonstrated that insulin activates farnesyltransferase (FTase) and augments the amounts of farnesylated p21 (Goalstone, M. L., and Draznin, B. (1996) J. Biol. Chem. 271, 27585-27589). We postulated that this aspect of insulin action might explain the "priming effect" of insulin on the cellular response to other growth factors. In the present study, we show the specificity of the effect of insulin on FTase. Insulin, but not insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), or platelet-derived growth factor (PDGF), stimulated the phosphorylation of the alpha-subunit of FTase and the amounts of farnesylated p21. Even though all four growth factors utilized the Ras pathway to stimulate DNA synthesis, only insulin used this pathway to influence FTase. Insulin failed to stimulate FTase in cells expressing the chimeric insulin/IGF-1 receptor and in cells derived from the insulin receptor knock-out animals. Insulin potentiated the effects of IGF-1, EGF, and PDGF on DNA synthesis in cells expressing the wild type insulin receptor, but this potentiation was inhibited in the presence of the FTase inhibitor, alpha-hydroxyfarnesylphosphonic acid. We conclude that the effect of insulin on FTase is specific, requires the presence of an intact insulin receptor, and serves as a conduit for the "priming" influence of insulin on the nuclear effects of other growth factors.
Survey of canine tear deficiency in veterinary practice.
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A cultural transformation model for nursing.
The rapidity and constancy of change, coupled with a culture of staff entitlement and passive and defensive leadership behaviors, prompted the development of an intensive plan for cultural transformation. The cultural transformation steps of leadership development, nominal group technique, quality improvement teams, and evaluation process are explored in detail. Lessons learned and outcomes obtained within the first 6 months after implementation are identified.
Effect of enteral nutritional products differing in carbohydrate and fat on indices of carbohydrate and lipid metabolism in patients with NIDDM.
Non-insulin dependent diabetes mellitus (NIDDM) is associated with chronic hyperglycemia, which increases the risk of developing microvascular and macrovascular complications. Elevated triglyceride (TG) and VLDL cholesterol levels and low levels of HDL cholesterol have also been frequently reported in NIDDM patients. A diet high in complex carbohydrate and low in fat is typically recommended for management of NIDDM, however, this has recently been challenged by scientific reports of the benefits of dietary intakes high in monounsaturated fat. Thirty-two individuals with NIDDM were randomized to receive either Ensure with Fibre (30% fat) or a high monounsaturated fatty acid product, Glucerna (50% fat). These products were consumed for 28 days at > 80% of daily energy intake. Post-treatment, dietary compliance was verified by a higher plasma TG 18:1 n-9 (p < 0.001) in the Glucerna group and a higher plasma TG 18:2 n-6 (p < 0.001) in the Ensure with Fibre group. The postprandial rise in blood glucose levels, determined by fingerprick samples, was significantly lower (p < 0.01) in the Glucerna group. Trends of clinical interest were greater mean decreases in the Glucerna group compared to the Ensure with Fibre group in: fructosamine, 9.13 umol/L vs 0.14 umol/L; glucose, 1.61 mmol/L vs 0.63 mmol/L; and insulin, 46.0 pmol/L vs 12.6 pmol/L; respectively. However, overall, fasting plasma glucose, fructosamine, TG and cholesterol levels were not significantly different between groups. Thus, in these patients, the high monounsaturated fat diet and the standard diet were similar with regard to usual indicators of carbohydrate and lipid metabolism. A high monounsaturated fat diet appears to pose no risk to lipoprotein metabolism in NIDDM patients.
Effect of medium-chain triglycerides on calbindin-D9k expression in the intestine.
These studies determined the effect of the saturated fat source in infant formula on the expression of calbindin-D9k (CaBP-9k). Piglets were fed from birth to 8 d with milk or formula containing saturated fatty acids as medium-chain triglycerides (MCT), coconut oil, palm oil (Palm 1), or synthesized triglycerides with 16:0 directed to the sn-2 position (Palm 2). Levels of intestinal CaBP-9k mRNA were significantly (P < 0.01) higher in piglets fed formula with MCT than in piglets fed the other formula or milk; and higher in piglets fed the Palm-1 than in piglets fed Palm-2 formula. This is the first evidence that MCT alter piglet intestinal CaBP-9k mRNA.
An unusual case of pruritus ani. Anal margin squamous cell carcinoma (SCC).
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Schooling the family. Going through nursing school is a family affair.
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Serum amino acids in fibrositis/fibromyalgia syndrome.
Free plasma tryptophan levels in patients with fibrositis syndrome were measured by Moldofsky and Warsh with the view that the pathogenesis of fibrositis syndrome might involve a functional deficiency of serotonin. The hypothesis was supported by the finding of an inverse relationship between tryptophan concentration and the severity of musculoskeletal pain. Our study examined the total serum amino acid pool in fibrositis syndrome. Twenty patients with primary fibrositis syndrome and matched normal controls were evaluated clinically. After denaturation of macromolecules, serum amino acids were quantitated by automated analysis. Patients with fibrositis syndrome exhibited significantly lower levels of total serum tryptophan (p = 0.002), as well as 6 other amino acids: alanine (p less than 0.0005), histidine (p = 0.001), lysine (p = 0.02), proline (p = 0.039), serine (p = 0.028), and threonine (p = 0.013). These findings support the serotonin deficiency hypothesis for fibrositis syndrome pathogenesis but also imply a more generalized defect in amino acid homeostasis among affected individuals.
Quality of life 20 and 30 years after surgery in patients operated on for tetralogy of Fallot and for atrial septal defect.
Follow-up studies on patients operated on for congenital heart defects have shown good anatomical results and long-term survival. To date, there have been few studies on such patients with regard to long-term psychosocial outcome and quality of life. In this study, two cohorts of patients operated on before the age of 15 years, one for tetralogy of Fallot (TOF) and the other for atrial septal defect (ASD), were investigated 20 and 30 years after operation regarding quality of life. The combined cohort had a higher educational level than average. There was no connection between quality of life and physical health as judged from the New York Heart Association classification. The TOF group rated their quality of life higher than the ASD group, but both groups had lower figures at the 30-year than at the 20-year follow-up. Fewer patients in the TOF than in the ASD group considered that their lives were affected by the heart disease. It is concluded that the severity of the heart disease is not necessarily congruent with estimated quality of live and that mild heart defects, such as ASD, can have a considerable impact on later life quality. Surprisingly few TOF patients were affected negatively, a finding which might reflect development of a specific coping strategy in these patients during childhood.
Carbohydrate-deficient transferrin in vitreous humour: a marker of possible withdrawal-related death in alcoholics.
The possibility of performing reliable post-mortem analysis of carbohydrate-deficient transferrin (CDT) concentration in vitreous humour (VH) by using a commercial assay designed for serum analysis (CDTect(TM)) as well as the usefulness of VH-CDT as a marker of alcohol misuse and possible withdrawal-related death were evaluated in a forensic sample. Detectable VH-CDT was found in 20 of 21 alcoholic subjects and in two of seven controls. By using the detection limit of the CDTect(TM) method (VH-CDT = 5 U/l) as cut-off level for a positive test, the alcoholic group was significantly separated from the control group (P = 0.0024, Fisher's exact test). The sensitivity and specificity of the test was 95% and 71%, giving a positive and a negative predictive value of 91% and 83%, respectively. Time-dependent changes of VH-CDT in the dead body could not unequivocally be excluded, which must be considered when selecting cases suitable for VH-CDT analysis. We conclude that adding VH-CDT analysis to ordinary alcohol tests may become useful in forensic medicine for establishing the so-called 'alcoholic state', which may provide a tool in research dealing with the relation between alcohol withdrawal and various causes of death in alcoholics.
Academic credit for experiential learning.
If the formal education process is to be relevant to adult nursing students, their life experience should be acknowledged. Of particular significance is determining how prior life experiences have produced outcomes in the adult nursing student equivalent to what is expected in the nursing education program. The author discusses how to assess experiential learning for academic credit.