Natural history of thoraco-abdominal aneurysm in high-risk patients.

INTRODUCTION: There is considerable interest in the role of novel endovascular techniques for the treatment of patients with complex aneurysms who are unsuitable for standard interventions. Knowledge of the natural history of these lesions, as well as other co-morbidities, is required in order that these techniques may be applied correctly in this high-risk group. METHOD: This study reviews the outcome of patients deemed to be unfit for surgery following assessment under the Scottish National Thoraco-abdominal aneurysm service (TAAA) service (2002-2008). RESULTS: Of 216 patients assessed, 89 (41%) patients were considered to be unfit for intervention. The median (interquartile range, IQR) age of patients was 75 (70-80) years and there were 39 men (44%). Median (IQR) aneurysm size was 6 (5.6-7.0) cm. The median (IQR) follow-up time was 12 (7-26) months. There were 49 (55%) deaths during the follow-up period of which 23 (47%) cases were due to ruptured TAAA and 26 (53%) were not aneurysm-related. Comparing patients with aneurysms <6 cm (33 patients) with those aneurysms > or =6 cm (56 patients) there was no difference in aneurysm-related death (p = 0.32) or all-cause mortality (p = 0.147). CONCLUSION: Aneurysm-related mortality amongst patients unsuitable for open TAAA surgery is considerable and evolving endovascular techniques may permit intervention in selected patients. However any intervention can only be justified if the patient's life expectancy is sufficient to allow benefit to accrue.

Contemporary results for open repair of suprarenal and type IV thoracoabdominal aortic aneurysms.

BACKGROUND: Endovascular and hybrid procedures are not yet widely established in the management of type IV thoracoabdominal aortic aneurysm (TAAA). Open surgery remains the treatment of choice until the long-term outcomes of these novel techniques are known. METHODS: This study reviewed a 10-year experience of open repair of non-ruptured type IV and suprarenal TAAA. All procedures were performed using a totally abdominal approach with supracoeliac clamping of the aorta. RESULTS: There were 53 patients (31 men; 58 per cent) of median age 69 (range 54-82) years. Forty-four patients had a type IV TAAA and nine a suprarenal aneurysm. Three patients (6 per cent) died within 30 days and the 12-month mortality rate for patients followed for at least 1 year was 6 per cent (three of 49). Ten patients (19 per cent) had a cardiac complication, 20 (38 percent) a respiratory complication, three (6 percent) required early reoperation, and one patient (2 percent) developed permanent paraplegia. There was one late death resulting from an aneurysm-related complication. CONCLUSION: Open repair of suprarenal aneurysms and type IV TAAA may be undertaken using a totally abdominal approach with acceptable levels of morbidity and mortality.

A transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in beta-cells.

Low levels of somatic mutations accumulate in mitochondrial DNA (mtDNA) as we age; however, the pathogenic nature of these mutations is unknown. In contrast, mutational loads of >30% of mtDNA are associated with electron transport chain defects that result in mitochondrial diseases such as mitochondrial encephalopathy lactic acidosis and stroke-like episodes. Pancreatic beta-cells may be extremely sensitive to the accumulation of mtDNA mutations, as insulin secretion requires the mitochondrial oxidation of glucose to CO(2). Type 2 diabetes arises when beta-cells fail to compensate for the increased demand for insulin, and many type 2 diabetics progress to insulin dependence because of a loss of beta-cell function or beta-cell death. This loss of beta-cell function/beta-cell death has been attributed to the toxic effects of elevated levels of lipids and glucose resulting in the enhanced production of free radicals in beta-cells. mtDNA, localized in close proximity to one of the major cellular sites of free radical production, comprises more than 95% coding sequences such that mutations result in changes in the coding sequence. It has long been known that mtDNA mutations accumulate with age; however, only recently have studies examined the influence of somatic mtDNA mutation accumulation on disease pathogenesis. This article will focus on the effects of low-level somatic mtDNA mutation accumulation on ageing, cardiovascular disease and diabetes.

Disruption of Sur2-containing K(ATP) channels enhances insulin-stimulated glucose uptake in skeletal muscle.

ATP-sensitive potassium channels (K(ATP)) are involved in a diverse array of physiologic functions including protection of tissue against ischemic insult, regulation of vascular tone, and modulation of insulin secretion. To improve our understanding of the role of K(ATP) in these processes, we used a gene-targeting strategy to generate mice with a disruption in the muscle-specific K(ATP) regulatory subunit, SUR2. Insertional mutagenesis of the Sur2 locus generated homozygous null (Sur2(-/-)) mice and heterozygote (Sur2(+/-)) mice that are viable and phenotypically similar to their wild-type littermates to 6 weeks of age despite, respectively, half or no SUR2 mRNA expression or channel activity in skeletal muscle or heart. Sur2(-/-) animals had lower fasting and fed serum glucose, exhibited improved glucose tolerance during a glucose tolerance test, and demonstrated a more rapid and severe hypoglycemia after administration of insulin. Enhanced glucose use was also observed during in vivo hyperinsulinemic euglycemic clamp studies during which Sur2(-/-) mice required a greater glucose infusion rate to maintain a target blood glucose level. Enhanced insulin action was intrinsic to the skeletal muscle, as in vitro insulin-stimulated glucose transport was 1.5-fold greater in Sur2(-/-) muscle than in wild type. Thus, membrane excitability and K(ATP) activity, to our knowledge, seem to be new components of the insulin-stimulated glucose uptake mechanism, suggesting possible future therapeutic approaches for individuals suffering from diabetes mellitus.

Predictable success with resin bonded fixed partial dentures.

The conservative nature of the resin bonded fixed partial denture is the reason it is used. The ability to replace a missing tooth while avoiding aggressive preparation of the abutment teeth is a desirable concept. The use of conservative preparation forms will aid in the long term predictable success of the resin bonded fixed partial denture.

Calpains play a role in insulin secretion and action.

Studies of the genetic basis of type 2 diabetes suggest that variation in the calpain-10 gene affects susceptibility to this common disorder, raising the possibility that calpain-sensitive pathways may play a role in regulating insulin secretion and/or action. Calpains are ubiquitously expressed cysteine proteases that are thought to regulate a variety of normal cellular functions. Here, we report that short-term (4-h) exposure to the cell-permeable calpain inhibitors calpain inhibitor II and E-64-d increases the insulin secretory response to glucose in mouse pancreatic islets. This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors. Enhancement of insulin secretion with short-term exposure to calpain inhibitors is not mediated by increased responses in intracellular Ca2+ or increased glucose metabolism in islets but by accelerated exocytosis of insulin granules. In muscle strips and adipocytes, exposure to both calpain inhibitor II and E-64-d reduced insulin-mediated glucose transport. Incorporation of glucose into glycogen in muscle also was reduced. These results are consistent with a role for calpains in the regulation of insulin secretion and insulin action.

Mechanisms underlying impaired GLUT-4 translocation in glycogen-supercompensated muscles of exercised rats.

Exercise training induces an increase in GLUT-4 in muscle. We previously found that feeding rats a high-carbohydrate diet after exercise, with muscle glycogen supercompensation, results in a decrease in insulin responsiveness so severe that it masks the effect of a training-induced twofold increase in GLUT-4 on insulin-stimulated muscle glucose transport. One purpose of this study was to determine whether insulin signaling is impaired. Maximally insulin-stimulated phosphatidylinositol (PI) 3-kinase activity was not significantly reduced, whereas protein kinase B (PKB) phosphorylation was approximately 50% lower (P < 0.01) in muscles of chow-fed, than in those of fasted, exercise-trained rats. Our second purpose was to determine whether contraction-stimulated glucose transport is also impaired. The stimulation of glucose transport and the increase in cell surface GLUT-4 induced by contractions were both decreased by approximately 65% in glycogen-supercompensated muscles of trained rats. The contraction-stimulated increase in AMP kinase activity, which has been implicated in the activation of glucose transport by contractions, was approximately 80% lower in the muscles of the fed compared with the fasted rats 18 h after exercise. These results show that both the insulin- and contraction-stimulated pathways for muscle glucose transport activation are impaired in glycogen-supercompensated muscles and provide insight regarding possible mechanisms.

High-fat diet-induced muscle insulin resistance: relationship to visceral fat mass.

It has been variously hypothesized that the insulin resistance induced in rodents by a high-fat diet is due to increased visceral fat accumulation, to an increase in muscle triglyceride (TG) content, or to an effect of diet composition. In this study we used a number of interventions: fish oil, leptin, caloric restriction, and shorter duration of fat feeding, to try to disassociate an increase in visceral fat from muscle insulin resistance. Substituting fish oil (18% of calories) for corn oil in the high-fat diet partially protected against both the increase in visceral fat and muscle insulin resistance without affecting muscle TG content. Injections of leptin during the last 4 days of a 4-wk period on the high-fat diet partially reversed the increase in visceral fat and the muscle insulin resistance, while completely normalizing muscle TG. Restricting intake of the high-fat diet to 75% of ad libitum completely prevented the increase in visceral fat and muscle insulin resistance. Maximally insulin-stimulated glucose transport was negatively correlated with visceral fat mass (P < 0.001) in both the soleus and epitrochlearis muscles and with muscle TG concentration in the soleus (P < 0.05) but not in the epitrochlearis. Thus we were unable to dissociate the increase in visceral fat from muscle insulin resistance using a variety of approaches. These results support the hypothesis that an increase in visceral fat is associated with development of muscle insulin resistance.

Scholarship in teaching: an imperative for the 21st century.

At some medical schools broader definitions of scholarship have emerged along with corresponding changes in their academic reward systems. Such situations are not common, however. The definition of scholarship generally applied by medical schools is unnecessarily narrow and excludes areas of legitimate academic activity and productivity that are vital to the fulfillment of the school's educational mission. The authors maintain that creative teaching with effectiveness that is rigorously substantiated, educational leadership with results that are demonstrable and broadly felt, and educational methods that advance learners' knowledge are consistent with the traditional definition of scholarship. Faculty whose educational activities fulfill the criteria above are scholars and must be recognized by promotion. The authors specifically address scholarship in education, focusing on teaching and other learning-related activities rather than on educational research, which may be assessed and rewarded using the same forms of evidence as basic science or clinical research. They build on Boyer's work, which provides a vocabulary for discussing the assumptions and values that underlie the roles of faculty as academicians. Next, they apply Glassick et al.'s criteria for judging scholarly work to faculty members' educational activities to establish a basis for recognition and reward consistent with those given for other forms of scholarship. Finally, the authors outline the organizational infrastructure needed to support scholars in education.

Transgenic overexpression of hexokinase II in skeletal muscle does not increase glucose disposal in wild-type or Glut1-overexpressing mice.

Glut1 transgenic mice were bred with transgenic mice that overexpress hexokinase II in skeletal muscle in order to determine whether whole-body glucose disposal could be further augmented in mice overexpressing glucose transporters. Overexpression of hexokinase alone in skeletal muscle had no effect on glucose transport or metabolism in isolated muscles, nor did it alter blood glucose levels or the rate of whole-body glucose disposal. Expression of the hexokinase transgene in the context of the Glut1 transgenic background did not alter glucose transport in isolated muscles but did cause additional increases in steady-state glucose 6-phosphate (3.2-fold) and glycogen (7.5-fold) levels compared with muscles that overexpress the Glut1 transporter alone. Surprisingly, however, these increases were not accompanied by a change in basal or insulin-stimulated whole-body glucose disposal in the doubly transgenic mice compared with Glut1 transgenic mice, probably due to an inhibition of de novo glycogen synthesis as a result of the high levels of steady-state glycogen in the muscles of doubly transgenic mice (430 micromol/g versus 10 micromol/g in wild-type mice). We conclude that the hexokinase gene may not be a good target for therapies designed to counteract insulin resistance or hyperglycemia.

Dentin bonding agents and resin cements--current status.

Contemporary restorative dentistry is a rapidly evolving science which challenges the progressive clinician with a plethora of "new and improved" products. Sound product choices should be couched in the prudent consideration of well conducted in vitro and in vivo product research. This review shall list the most recent product developments in dentin bonding agents (fifth generation agents), resin-containing dental cements and the newest generation of dental cements i.e., resin-ionomer dental cements.

Hydroxyl radical generation during exercise increases mitochondrial protein oxidation and levels of urinary dityrosine.

Isolated mitochondria are well-established sources of oxidants in vitro. There is little direct evidence that mitochondria promote oxidative stress in vivo, however. Model system studies demonstrate that ortho-tyrosine, meta-tyrosine, and o,o'-dityrosine increase in proteins oxidized by hydroxyl radical. To determine whether mitochondria generate oxidants in vivo, we used isotope dilution gas chromatography mass spectrometry to quantify levels of these markers in the heart muscle of control and exercised rats. Exercise led to a 50% increase in ortho-tyrosine, metatyrosine, and o,o'-dityrosine in the mitochondrial proteins but not cytosolic proteins of heart muscle. This increase was transient, and levels returned to normal when exercised animals were allowed to rest. There also was a transient increase in the level of o,o'-dityrosine in the urine of exercised rats. This relationship between mitochondrial and urine levels of o,o'-dityrosine suggests that urine assays of this oxidized amino acid may serve as noninvasive measures of oxidative stress. These observations also provide direct evidence that heart muscle mitochondria produce an intermediate resembling the hydroxyl radical that promotes protein oxidation in vivo.

Effects of endurance exercise training on muscle glycogen accumulation in humans.

The purpose of this investigation was to determine whether endurance exercise training increases the ability of human skeletal muscle to accumulate glycogen after exercise. Subjects (4 women and 2 men, 31 +/- 8 yr old) performed high-intensity stationary cycling 3 days/wk and continuous running 3 days/wk for 10 wk. Muscle glycogen concentration was measured after a glycogen-depleting exercise bout before and after endurance training. Muscle glycogen accumulation rate from 15 min to 6 h after exercise was twofold higher (P < 0.05) in the trained than in the untrained state: 10.5 +/- 0.2 and 4.5 +/- 1.3 mmol. kg wet wt(-1). h(-1), respectively. Muscle glycogen concentration was higher (P < 0.05) in the trained than in the untrained state at 15 min, 6 h, and 48 h after exercise. Muscle GLUT-4 content after exercise was twofold higher (P < 0.05) in the trained than in the untrained state (10.7 +/- 1.2 and 4.7 +/- 0.7 optical density units, respectively) and was correlated with muscle glycogen concentration 6 h after exercise (r = 0.64, P < 0.05). Total glycogen synthase activity and the percentage of glycogen synthase I were not significantly different before and after training at 15 min, 6 h, and 48 h after exercise. We conclude that endurance exercise training enhances the capacity of human skeletal muscle to accumulate glycogen after glycogen-depleting exercise.

Decreased insulin-stimulated GLUT-4 translocation in glycogen-supercompensated muscles of exercised rats.

It was recently found that the effect of an exercise-induced increase in muscle GLUT-4 on insulin-stimulated glucose transport is masked by a decreased responsiveness to insulin in glycogen-supercompensated muscle. We evaluated the role of hexosamines in this decrease in insulin responsiveness and found that UDP-N-acetyl hexosamine concentrations were not higher in glycogen-supercompensated muscles than in control muscles with a low glycogen content. We determined whether the smaller increase in glucose transport is due to translocation of fewer GLUT-4 to the cell surface with the 2-N-4-(1-azi-2,2,2-trifluroethyl)-benzoyl-1, 3-bis(D-mannose-4-yloxy)-2-propylamine (ATB-[2-3H]BMPA) photolabeling technique. The insulin-induced increase in GLUT-4 at the cell surface was no greater in glycogen-supercompensated exercised muscle than in muscles of sedentary controls and only 50% as great as in exercised muscles with a low glycogen content. We conclude that the decreased insulin responsiveness of glucose transport in glycogen-supercompensated muscle is not due to increased accumulation of hexosamine biosynthetic pathway end products and that the smaller increase in glucose transport is mediated by translocation of fewer GLUT-4 to the cell surface.

Insulin resistance of muscle glucose transport in male and female rats fed a high-sucrose diet.

It has been reported that, unlike high-fat diets, high-sucrose diets cause insulin resistance in the absence of an increase in visceral fat and that the insulin resistance develops only in male rats. This study was done to 1) determine if isolated muscles of rats fed a high-sucrose diet are resistant to stimulation of glucose transport when studied in vitro and 2) obtain information regarding how the effects of high-sucrose and high-fat diets on muscle insulin resistance differ. We found that, compared with rat chow, semipurified high-sucrose and high-starch diets both caused increased visceral fat accumulation and insulin resistance of skeletal muscle glucose transport. Insulin responsiveness of 2-deoxyglucose (2-DG) transport measured in epitrochlearis and soleus muscles in vitro was decreased approximately 40% (P < 0.01) in both male and female rats fed a high-sucrose compared with a chow diet. The high-sucrose diet also caused resistance of muscle glucose transport to stimulation by contractions. There was a highly significant negative correlation between stimulated muscle 2-DG transport and visceral fat mass. In view of these results, the differences in insulin action in vivo observed by others in rats fed isocaloric high-sucrose and high-starch diets must be due to additional, specific effects of sucrose that do not carry over in muscles studied in vitro. We conclude that, compared with rat chow, semipurified high-sucrose and high-cornstarch diets, like high-fat diets, cause increased visceral fat accumulation and severe resistance of skeletal muscle glucose transport to stimulation by insulin and contractions.

GLUT-1 or GLUT-4 transgenes in obese mice improve glucose tolerance but do not prevent insulin resistance.

Insulin-stimulated glucose uptake is defective in patients with type 2 diabetes. To determine whether transgenic glucose transporter overexpression in muscle can prevent diabetes induced by a high-fat, high-sugar diet, singly (GLUT-1, GLUT-4) and doubly (GLUT-1 and -4) transgenic mice were placed on a high-fat, high-sugar diet or a standard chow diet. On the high-fat, high-sugar diet, wild-type but not transgenic mice developed fasting hyperglycemia and glucose intolerance (peak glucose of 337 +/- 19 vs. 185-209 mg/dl in the same groups on the high-fat, high-sugar diet and 293 +/- 13 vs. 166-194 mg/dl on standard chow). Hyperinsulinemic clamps showed that transporter overexpression elevated insulin-stimulated glucose utilization on standard chow (49 +/- 4 mg. kg-1. min-1 in wild-type vs. 61 +/- 4, 67 +/- 5, and 63 +/- 6 mg. kg-1. min-1 in GLUT-1, GLUT-4, and GLUT-1 and -4 transgenic mice given 20 mU. kg-1. min-1 insulin, and 54 +/- 7, 85 +/- 4, and 98 +/- 11 in wild-type, GLUT-1, and GLUT-4 mice given 60-80 mU. kg-1. min-1 insulin). On the high-fat, high-sugar diet, wild-type and GLUT-1 mice developed marked insulin resistance, but GLUT-4 and GLUT-1 and -4 mice were somewhat protected (glucose utilization during hyperinsulinemic clamp of 28.5 +/- 3.4 vs. 42.4 +/- 5.9, 51.2 +/- 8.1, and 55.9 +/- 4. 9 mg. kg-1. min-1 in wild type, GLUT-1, GLUT-4, GLUT-1 and -4 mice). These data demonstrate that overexpression of GLUT-1 and/or GLUT-4 enhances whole body glucose utilization and prevents the development of fasting hyperglycemia and glucose intolerance induced by a high-fat, high-sugar diet. GLUT-4 overexpression improves the insulin resistance induced by the diet. We conclude that upregulation of glucose transporters in skeletal muscle may be an effective therapeutic approach to the treatment of human type 2 diabetes.

Effect of brushing with sonic and counterrotational toothbrushes on the bond strength of orthodontic brackets.

The purpose of this study was to evaluate the effect of brushing with both a sonic and mechanical counter rotary power toothbrush on the bond strength of orthodontic brackets. Forty-five extracted teeth were divided into three random groups and had orthodontic brackets bonded to them. One group was brushed with a counterrotational toothbrush, the Interplak, one group with a sonic toothbrush, the Sonicare, and a third group was not brushed and was held as a control. After the equivalent of 2 years brushing, the teeth were placed in an Instron machine and the shear force to remove the brackets was recorded. Group 1, the counter rotary power brush, had a mean of 107.5 kg/cm2, the second group, the sonic brush, had a mean of 79.7 kg/cm2, and the control group had a mean of 125. 4 kg/cm2. Single factor analysis of variance followed by the Fisher-Hayter Multiple Comparison Procedure showed a statistically significant difference between the sonic power brush and the control (P <.01), but no significant difference between the counter rotary and the control (P >.05). There was no significant difference between the two power brushes (P >.05).

Oxidized amino acids in the urine of aging rats: potential markers for assessing oxidative stress in vivo.

Oxidative damage of proteins has been implicated in disease and aging. In vitro studies demonstrate that two unnatural amino acids, o,o'-dityrosine and o-tyrosine, are stable markers of protein oxidation. We have investigated the possibility that assaying these compounds in urine could provide a noninvasive way to determine levels of protein oxidation in vivo. Isotope dilution gas chromatography-mass spectrometry was used to quantify levels of o,o'-dityrosine and o-tyrosine in skeletal muscle and urine of aging rats subjected to two interventions: 1) dietary antioxidant supplementation and 2) exercise training. In both sedentary rats and exercise-trained rats, antioxidant therapy reduced levels of protein-bound o,o'-dityrosine in skeletal muscle. In contrast, antioxidant therapy or exercise training minimally affected o-tyrosine levels in this tissue. Levels of the oxidized amino acids in urine samples mirrored those of skeletal muscle proteins. Quantification of the levels of oxidized amino acids in urine may thus serve as a noninvasive measure of oxidative stress in vivo because they change in parallel with levels of protein-bound oxidized amino acids in skeletal muscle.

Current methods of finish-line exposure by practicing prosthodontists.

PURPOSE: The purpose of this study was to survey members of The American College of Prosthodontists to evaluate current methods of finish-line exposure. In addition, frequency of use of epinephrine compounds and observed side effects were assessed. MATERIALS AND METHODS: A questionnaire was mailed to the 2,436 members of The American College of Prosthodontists. Group differences were evaluated using chi 2 analysis. RESULTS: Completed questionnaires were returned by 1,246 prosthodontists, which is a return rate of 51%. Ninety-eight percent of respondent prosthodontists use retraction cord, and 48% use a double-cord technique. Plain cord is the most commonly used cord (44%), followed by aluminum chloride-impregnated cord (18%), and epinephrine-impregnated cord (14%). Nine hundred one respondents (81%) soak the cord before placing it in the gingival sulcus. The most common medicament for soaking the cords is buffered aluminum chloride (55%). Side effects to epinephrine were reported by 387 respondents (33%), with the most common side effect reported being increased pulse rate, followed by anxiety. Approximately one quarter (24%) of the prosthodontists surveyed had observed side effects to chemical agents other than epinephrine. CONCLUSIONS: Prosthodontists throughout the country use many different techniques and agents to expose finish lines. No statistically significant differences (p > .05) were found between year of specialty training completion groups with respect to retraction cord use. Copper bands are used significantly more frequently (p < .05) in the northwest region of the United States than elsewhere.