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.

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.

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.

Removal of adenosine decreases the responsiveness of muscle glucose transport to insulin and contractions.

Adenosine in the extracellular space modulates stimulated glucose transport in striated muscle. In the heart and in adipocytes, adenosine potentiates insulin-stimulated glucose transport. There is controversy regarding the effect of adenosine in skeletal muscle, with reports of both an inhibitory effect and no effect, on insulin-stimulated glucose transport. We found that, in rat epitrochlearis and soleus muscles, removing adenosine with adenosine deaminase or blocking its action with the adenosine receptor blocker CPDPX markedly reduces the responsiveness of glucose transport to stimulation by 1) insulin alone, 2) contractions alone, and 3) insulin and contractions in combination. Measurement of the increase in GLUT4 at the cell surface in response to a maximally effective insulin stimulus in the epitrochlearis muscle, using the exofacial label ATB-[3H]BMPA, showed that adenosine deaminase treatment markedly reduces cell-surface GLUT4 labeling. The reduction in cell-surface GLUT4 labeling was similar in magnitude to the decrease in maximally insulin-stimulated glucose transport activity in adenosine deaminase-treated muscles. These results show that adenosine potentiates insulin- and contraction-stimulated glucose transport in skeletal muscle by enhancing the increase in GLUT4 at the cell surface and raise the possibility that decreased adenosine production or action could play a causative role in insulin resistance.

Short-term exposure to tumor necrosis factor-alpha does not affect insulin-stimulated glucose uptake in skeletal muscle.

It has been hypothesized that increased production of tumor necrosis factor-alpha (TNF-alpha) plays a role in causing the insulin resistance associated with obesity. Obesity with insulin resistance is associated with increased production of TNF-alpha by fat cells. Exposure of 3T3-L1 adipocytes to TNF-alpha for 3-4 days makes them insulin resistant. TNF-alpha has also been reported to rapidly (15-60 min) cause insulin resistance, with a decrease in insulin-stimulated tyrosine phosphorylation, in a number of cultured cell lines. Because skeletal muscle is the major tissue responsible for insulin-stimulated glucose disposal, we performed the present study to determine if acute exposure to TNF-alpha causes insulin resistance in muscle. We found that exposure of soleus muscles to 6 nmol/l TNF-alpha for 45 min in vitro had no inhibitory effect on insulin-stimulated tyrosine phosphorylation of the insulin receptor or insulin receptor substrate 1 (IRS-1) or on phosphatidylinositol 3-kinase association with IRS-1. Incubation of epitrochlearis and soleus muscles with 6 nmol/l TNF-alpha for 45 min or 4 h had no effect on insulin-stimulated 2-deoxyglucose (2-DG) uptake. Treatment of epitrochlearis muscles with 2 nmol/l TNF-alpha for 8 h also had no effect on insulin-stimulated 2-DG uptake. We conclude that in contrast to Fao hepatoma cells and 3T3-L1 fibroblasts, skeletal muscle does not become insulin resistant in response to short-term exposure to TNF-alpha.

Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle.

beta-Adrenergic stimulation has been reported to inhibit insulin-stimulated glucose transport in adipocytes. This effect has been attributed to a decrease in the intrinsic activity of the GLUT-4 isoform of the glucose transporter that is mediated by phosphorylation of GLUT-4. Early studies showed no inhibition of insulin-stimulated glucose transport by epinephrine in skeletal muscle. The purpose of this study was to determine the effect of epinephrine on GLUT-4 phosphorylation, and reevaluate the effect of beta-adrenergic stimulation on insulin-activated glucose transport, in skeletal muscle. We found that 1 microM epinephrine, which raised adenosine 3',5'-cyclic monophosphate approximately ninefold, resulted in GLUT-4 phosphorylation in rat skeletal muscle but had no inhibitory effect on insulin-stimulated 3-O-methyl-D-glucose (3-MG) transport. In contrast to 3-MG transport, the uptakes of 2-deoxyglucose and glucose were markedly inhibited by epinephrine treatment. This inhibitory effect was presumably mediated by stimulation of glycogenolysis, which resulted in an increase in glucose 6-phosphate concentration to levels known to severely inhibit hexokinase. We conclude that 1) beta-adrenergic stimulation decreases glucose uptake by raising glucose 6-phosphate concentration, thus inhibiting hexokinase, but does not inhibit insulin-stimulated glucose transport and 2) phosphorylation of GLUT-4 has no effect on glucose transport in skeletal muscle.

Effects of ovariectomy and exercise training on muscle GLUT-4 content and glucose metabolism in rats.

The present study examined the effects of 6 wk of ovarian endocrine deficiency on skeletal muscle GLUT-4 glucose transporter protein and glucose transport activity in sedentary and endurance-trained rats. Female Wistar rats (10 wk old) underwent bilateral ovariectomy (OVX) or sham surgery followed by a 5-wk swim-training protocol. OVX resulted in no significant changes in glycogen or GLUT-4 glucose transporter concentration in the soleus, epitrochlearis, or flexor digitorum brevis (FDB) muscles or in basal and maximally insulin-stimulated 2-deoxy-D-[1,2-3H]glucose (2-[3H]DG) transport in the soleus or epitrochlearis, suggesting that moderate-duration ovarian hormone deficiency does not significantly impair insulin action in skeletal muscle. In contrast, OVX decreased the maximal activation of 2-[3H]DG transport in the FDB by in vitro electrical stimulation. OVX had no significant effect on the training-induced changes in oxidative enzyme activities, GLUT-4 protein expression, glycogen content, or insulin-stimulated 2-[3H]DG transport in the soleus or epitrochlearis. These findings provide the first evidence that ovarian hormone deficiency decreases contraction-stimulated glucose transport in skeletal muscle.

Indomethacin in controlling "normal perfusion pressure breakthrough" in a case of large cerebral arteriovenous malformation.

Control of "normal perfusion pressure breakthrough" is difficult and controversial. We describe a case in which indomethacin was used with success. We recommend extensive cerebral monitoring including regional cerebral oximetry when using indomethacin to detect impending cerebral ischemia.

A random trial comparing recovery after midazolam-alfentanil anesthesia with and without reversal with flumazenil, and standardized neurolept anesthesia for major gynecologic surgery.

STUDY OBJECTIVE: To compare the recovery characteristics of total intravenous anesthesia (TIVA) using midazolam-alfentanil, with or without reversal with flumazenil to a standardized neurolept anesthesia with nitrous oxide (N2O). DESIGN: Randomized, double-blinded clinical study. SETTING: University medical center. PATIENTS: 80 ASA physical status I and II women scheduled for major elective gynecologic surgery. INTERVENTIONS: Patients were anesthetized with one of three different anesthetic techniques. Patients in the TIVA group with reversal received midazolam-alfentanil reversed with flumazenil (Group 1), the TIVA group without reversal received midazolam-alfentanil reversed with placebo (Group 2), and patients in the neurolept group received anesthesia using thiopental sodium, droperidol, fentanyl, and N2O (Group 3). MEASUREMENTS AND MAIN RESULTS: Recovery was assessed by an observer blinded to the treatment allocation, using a Modified Steward Recovery Score and judgment of orientation and comprehension, collaboration and degree of sedation for the first 4 hours after extubation. Arterial blood gases were measured 30 minutes after extubation. A questionnaire regarding the degree of perioperative amnesia was presented to the patients 4 and 24 hours after surgery. The recovery scores were better in the TIVA group with reversal than in the other two groups from 0 to 30 minutes postoperatively. No difference between the groups could be found thereafter, although after 30 minutes some resedation occurred in the TIVA group with reversal. The median injected amount of flumazenil in Group 1 was 0.5 mg. Respiratory depression (breathing frequency below 10 breaths/min) was reversed with naloxone in one patient in the TIVA group with reversal, five patients in the TIVA group without reversal, and no patient in the neurolept group (p < 0.001). On blood gas analysis, there was no evidence of hypoxemia or carbon dioxide retention. No difference was seen between the groups regarding consumption of analgesics, degree of amnesia, or patient rating of the quality of anesthesia. One patient in Group 2, however, recorded awareness at skin incision when questioned 4 hours after the operation, but could not recall this 20 hours later. CONCLUSIONS: TIVA with midazolam and alfentanil can be used for major gynecologic surgery. Recovery in the neurolept group was equal to recovery in the TIVA group without reversal, and flumazenil improves the recovery after midazolam anesthesia. Overall, in comparison with the neurolept technique no major advantage could be demonstrated using TIVA with midazolam-alfentanil.

Iron-carbonyl bond geometries of carboxymyoglobin and carboxyhemoglobin in solution determined by picosecond time-resolved infrared spectroscopy.

The iron-carbonyl geometries in carboxymyoglobin (MbCO) and carboxyhemoglobin (HbCO) in ambient temperature solution have been investigated using picosecond time-resolved infrared spectroscopy. Polarized infrared and visible beams were used to monitor the change in infrared absorbance of the bound CO stretch bands on photodissociation of the ligand. The ratio of the change in absorbance for perpendicular and parallel relative polarizations of the photolysis and infrared probe beams is directly related to the angle between the ligand bond axis and the normal to the heme plane. Ratios, and hence the angles, have been obtained for the configurations giving rise to the principal CO stretch infrared absorption bands of HbCO and MbCO: 18 degrees for the 1951 cm-1 band of HbCO; 20 degrees and 35 degrees, respectively, for the 1944 cm-1 and 1933 cm-1 bands of MbCO. Structures consistent with x-ray diffraction and the picosecond experiments reported here are proposed for MbCO and HbCO in which the Fe-C bond tilts to the heme normal and the Fe-C-O angle differs significantly from 180 degrees.

Mediation of compensatory renal growth in the rat: cell culture demonstration of a serum factor.

1. The participation of a circulating growth factor in the mediation of compensatory renal growth has been hypothesized but not proven. Theoretical considerations predict that in vitro methods could be profitably used to resolve this question, since such methods would allow dissociation of the growth effects of the postulated factor from the complex physiological changes which accompany compensatory renal growth in vivo. 2. A culture system using epithelial cells obtained from the rat kidney is described which is suitable for testing serum from previously unilaterally nephrectomized or sham-operated rats for the presence of a factor mediating compensatory renal growth. The morphology of the cultured cells is compatible with that of proximal tubule epithelium, this being the cell type stimulated to divide in vivo after unilateral nephrectomy. 3. Treatment with serum from rats unilaterally nephrectomized 48 h previously results in consistent increase in uptake of tritiated thymidine by cultures, when compared with control serum from sham-operated rats. Serum from rats unilaterally nephrectomized 18--36 h previously is not consistently stimulatory. 4. There are indications that the differential effect of sera from unilaterally nephrectomized and control animals is due to the presence of a stimulatory factor in the former rather than an inhibitor in the latter. 5. Use of this culture system has confirmed the existence of a serum factor involved in compensatory renal growth.