Microalbuminuria is a major determinant of elevated plasma retinol-binding protein 4 in type 2 diabetic patients.

Plasma retinol-binding protein 4 (RBP4) may be a new adipokine linked to obesity-induced insulin resistance and type 2 diabetes. The impact of diabetic nephropathy on plasma RBP4 levels, however, is not known. We tested the hypothesis that microalbuminuria is associated with elevated plasma concentrations of RBP4 in type 2 diabetic subjects. Retinol, its binding protein and transthyretin (TTR) were measured in the plasma and urine of 62 type 2 diabetic subjects, 26 of whom had microalbuminuria. The results were compared to 35 healthy control subjects. Despite no differences in plasma retinol, concentrations of the RBP4 were significantly elevated in plasma of diabetic patients and significantly higher in those with microalbuminuria. The higher plasma levels of the binding protein in subjects with microalbuminuria were accompanied by both significantly elevated plasma TTR and increased urinary levels of RBP4. There were no correlations of plasma-binding protein levels and parameters of insulin resistance. Our study suggests that plasma RBP4 levels in type 2 diabetic patients are affected by incipient nephropathy. Therefore, further studies evaluating RBP4 as a regulator of systemic insulin resistance and type 2 diabetes will need to take renal function into consideration.

Phase II trial of docetaxel and carboplatin in recurrent platinum-sensitive ovarian, peritoneal and tubal cancer.

OBJECTIVE: Docetaxel and carboplatin are active in relapsed ovarian, peritoneal and tubal cancer. Recently, two prospective-randomized trials showed an advantage of carboplatin combination regimen with paclitaxel or gemcitabine over carboplatinum alone in platinum-sensitive cases. The question on the most effective combination with the best tolerable side effects still needs to be answered. METHODS: Eligible patients had recurrent ovarian, peritoneal or tubal cancer (platinum-free interval >6 months), performance status 0-2 and normal bone marrow, renal and hepatic function. 25 patients (age 18-75 years) were enrolled into this phase II trial. Patients with debulking operation of recurrence were excluded from this study. Docetaxel 75 mg/m(2) via 30-min infusion was given on day 1 followed by carboplatin (area under curve [AUC] 5) on day 1. The administration was repeated every 3 weeks over 6 courses. Primary endpoint of this trial was the response rate; secondary endpoints were progression-free survival, overall survival and toxicity. RESULTS: In the intent-to-treat population, there were 16 (64.0%) complete and 2 (8.0%) partial responses resulting in an overall response rate of 72.0%. Three patients (12.0%) showed a stable disease and other 2 patients (8.0%) a progression of cancer. Two patients (8.0%) were not evaluable for response. Neutropenia was the most frequent G3/G4 hematologic toxicity in 15/25 patients (60.0%); but no neutropenic fever occurred in this trial. Diarrhea G3 was the most frequent G3/G4 non-hematologic toxicity in only 3/25 patients (12.0%). Dose-limiting toxicities were hypersensitivity reaction in one and depressive mood alteration requiring therapy in another case. CONCLUSION: Carboplatin in combination with docetaxel is highly active and well tolerated in patients with recurrent platinum-sensitive ovarian, peritoneal and tubal cancer. Prospective-randomized trials comparing this with other carboplatin therapeutic doublets in patients with recurrent ovarian cancer are a possible option for the future to answer the question on the best combination regimen.

Energy-related metabolites during and after induced myocardial infarction with special emphasis on the reperfusion injury after extracorporeal circulation.

In the clinical setting great efforts have been made with contradictory results to operate upon acutely myocardial ischaemic patients. The reasons for the absence of clear-cut results are not well understood nor are they scientifically explored. To resolve this problem further, we attempted to design an experimental in vivo model to mimic acute myocardial ischaemia followed by extracorporeal circulation (ECC) and reperfusion. One of the main targets of our protocol was monitoring of myocardial energy metabolism by microdialysis (MCD) during the periods of coronary occlusion (60 min), hypothermic (30 degrees C) ECC and cardioplegia (45 min), followed by reperfusion with (30 min) and without (60 min) ECC. In eight anaesthetized, open-chest pigs, myocardial lactate, pyruvate, adenosine, taurine, inosine, hypoxanthine and guanosine were sampled with MCD in both ischaemic and non-ischaemic areas. Myocardial area at risk and infarct size were quantified with the modified topographical evaluation methods. The principal finding with this experimental setup was a biphasic release pattern of lactate, adenosine, taurine, inosine, hypoxanthine and guanosine from ischaemic myocardium. Lactate levels were equally high in reperfused ischaemic and non-ischaemic myocardial tissue. Pyruvate demonstrated consistently higher values in non-ischaemic myocardium throughout the experiment. A pattern was discernible, lactate being a marker of compromised cell energy metabolism, and taurine being a marker of disturbed cell integrity. Of special interest was the increased level of pyruvate in microdialysates of non-ischaemic myocardium as compared with its ischaemic counterpart. In conclusion, we found disturbances in energy metabolism and cell integrity not only in ischaemic but also in non-ischaemic tissue during reperfusion implying that non-ischaemic myocardium demonstrated an unexpected accumulation of lactate and pyruvate. These new findings could at least partly be explicatory to the increased risk of heart surgery in connection with acute myocardial infarction.

Nucleoside transport inhibition in ischemic myocardium results in enhanced taurine efflux.

We measured with the microdialysis technique energy-related metabolites in ischemic myocardium over time in an experimental pig model. Emphasis was put on the dipyridamole effect when administered in the microdialysis probe inserted in ischemic myocardium. Not only adenosine but also taurine and pyruvate concentrations were significantly higher in the microdialysate during the periods of ischemia and extracorporeal circulation with cardioplegia. The enhanced efflux of taurine in ischemic myocardium induced by dipyridamole is a new finding. A mechanistic role of taurine in the prevention of Ca(2+) overload in ischemic myocytes is discussed. Also, taurine may have stimulatory effects on glycolysis in ischemic heart.

Discrepant outcome between myocardial energy-related metabolites and infarct size limitation during retroperfusion of the coronary sinus.

The basic idea of retroperfusion of the coronary sinus (RCS) is to ameliorate detrimental consequences of myocardial ischaemia. Several experimental models of RCS have been introduced, most with an emphasis on functional myocardial status. Since only few studies have been devoted to energy metabolic considerations and none to continuous monitoring of energy-related metabolites of myocardium during RCS, we here present such a study using microdialysis. This study comprised the following components: Coronary occlusion and drainage on the beating heart with RCS-assist (60 min), hypothermic (30 degrees C) extracorporeal circulation (ECC) and cardioplegia (45 min), reperfusion and rewarming to 38 degrees C on ECC (30 min). The microdialysis analytical outcome mainly reflected anaerobic energy metabolism in potentially ischaemic myocardium. Additionally, a pronounced increase of microdialysate content of lactate, pyruvate and guanosine was observed in non-ischaemic myocardium especially during the reperfusion phase. The planimetric calculation revealed an infarct size reduction from 69% to 19% and was not correlated to clear-cut improvements of potentially ischaemic myocardial energy metabolism. We conclude that prolonged (60 min) anaerobic energy metabolism does not pose an immediate threat to cell viability but could even sustain myocyte survival.

Inflammatory response during simulated extracorporeal circulation with addition of nitric oxide.

BACKGROUND: Heart operations performed with extracorporeal circulation (ECC) are associated with an inflammatory response. This response is partially due to granulocyte activation. Leukocyte derived free radicals are involved in tissue injury. The purpose of this study was to observe whether nitric oxide influence the inflammatory response during simulated ECC. METHODS: In a model of simulated extracorporeal circulation, fresh whole human blood mixed with Ringer's solution was circulated through a heart-lung machine for three hours. In five circuits NO was added to oxygen/air mixture (group N), while five other circuits were ventilated with oxygen/air mixture (group C). The methods for estimating the inflammatory response were determination of oxygen free radicals production capacity, using chemiluminescence, and measurements of concentration of granulocyte derived proteins (myeloperoxidase and human neutrophil lipocalin). RESULTS: All measured parameters were similarly independent of additional supply of nitric oxide almost throughout extracorporeal circulation time. The sole significant difference between the two groups was found at an early stage of extracorporeal circulation, when luminol-enhanced chemiluminescence in whole blood was higher in the N group (1,500, 1,470-1,950 vs 1,038, 750-1,050 in the control group; medians with quartiles). A similar tendency was observed in lucigenin-enhanced chemiluminescence at 60 min of extracorporeal circulation (625, 560-875 in the N group vs 400, 360-525 in the control group; medians with quartiles). CONCLUSIONS: Nitric oxide supply does not influence inflammatory response during three hours long extracorporeal circulation, although some protective effect on hydrogen peroxide production in whole blood was detected in the initial phase of extracorporeal circulation.

Heparin-coated cardiopulmonary bypass circuits reduce circulating complement factors and interleukin-6 in paediatric heart surgery.

Children are sensitive to the inflammatory side effects of cardiopulmonary bypass (CPB). Our intention was to investigate if the biocompatibility benefits of heparin-coated CPB circuits apply to children. In 20 operations, 19 children were randomized to heparin-coated (group HC, n = 10) or standard (group C, n = 10) bypass circuits. Plasma levels of acute phase reactants, interleukins, granulocytic proteins and complement factors were measured. All were significantly elevated after CPB. Levels of complement factor C3a (851 (791-959)ng/ml [median with quartiles] in group C, 497 (476-573)ng/ml in group HC, p < 0.001), Terminal Complement Complex (114 (71-130) AU/ml in group C, 35.5 (28.9-51.4) AU/ml in group HC, p < 0.001), and interleukin-6 (570 (203-743) pg/ml in group C, 168 (111-206)pg/ml in group HC, p = 0.005), were significantly reduced in group HC. Heparin-coated CPB circuits improve the biocompatibility of CPB during heart surgery in the paediatric patient population, as reflected by significantly reduced levels of circulating complement factors and interleukin-6.

Influence of two blood conservation techniques (cardiotomy reservoir versus cell-saver) on biocompatibility of the heparin coated cardiopulmonary bypass circuit during coronary revascularization surgery.

Blood conservation during cardiac surgery is critically important because of the inherent risks in homologous blood transfusions. Two techniques for the intraoperative conservation of blood--retransfusion of the red cells using a cell-saver (CS), or retransfusion of the blood using a cardiotomy suction (CTR) system--were compared using biocompatibility markers, granulocyte activation, and production of oxygen-free radicals (OFR). In the CTR group, heparin coated circuits with an uncoated cardiotomy reservoir were used. For the CS group, identical heparin coated cardiopulmonary bypass (CPB) sets, without a cardiotomy reservoir but with a CS, were used. In each group, eight patients had coronary artery bypass grafting performed. The capacity of the whole blood and the granulocytes to produce OFR was estimated by a chemiluminescence, and granulocyte activation was measured as release of the granulocyte granule proteins myeloperoxidase (MPO) and lactoferrin. A significantly reduced capacity to produce OFR by the whole blood was noted at 45 minutes of CPB in the CTR group (68% +/- 17% vs 94% +/- 16% in the CS group). MPO release was higher after 3 hours (p = 0.05) and 20 hours (p < 0.05), postoperatively, in the CTR group (417 +/- 77 micrograms/L and 257 +/- 31 micrograms/L vs 246 +/- 25 micrograms/L and 164 +/- 12 micrograms/L, respectively, in the CS group). We conclude that the heparin coated CPB circuit with the uncoated cardiotomy reservoir may be less biocompatible than the identical CPB set used together with the CS.

Biomaterial-dependent blood activation during simulated extracorporeal circulation: a study of heparin-coated and uncoated circuits.

OBJECTIVE: Blood activation during extracorporeal circulation is associated with morbidity and mortality in cardiac surgery. This activation can be diminished by usage of heparin-coated circuits. Nitric oxide has also been reported to influence humoral and cellular components of blood. This study was performed to determine biomaterial-dependent part of blood activation. DESIGN: Fresh, whole human blood mixed with Ringer's solution was circulated through a heart-lung machine for two and half hours. Five circuits were heparin-coated (group HC), whilst five other circuits were uncoated (group NC). During the last half hour NO was added to the oxygen/air mixture. METHODS: Blood activation was estimated by measuring following parameters: interluekin 6, complement activation products C3a and terminal complement complex, and oxygen free radicals (OFR) production capacity, which was determined using chemiluminescence enhanced by serum opsonized zymosan (SOZ) and phorbol myristate acetate (PMA). Granulocyte activation was measured as release of myeloperoxidase (MPO) and human neutrophil lipocalin (HNL). RESULTS: OFR in granulocyte suspension stimulated by SOZ and PMA were significantly lower in the NC group, mostly later during ECC. Similarly, lower neutrophil and monocyte counts were observed in this group. NO increased superoxide production in the whole blood in heparin-coated circuits, but did not change OFR in isolated granulocytes. MPO was also affected by heparin-coating. NO supply seemed to increase release of MPO and HNL. It is concluded that heparin-coating contributed to reduction of biomaterial-dependent blood activation. An addition of NO at late stage of ECC tended to influence this activation.

Right internal mammary artery for myocardial revascularization: early results and indications.

The right internal mammary artery (RIMA) was used for coronary artery bypass grafting in 258 patients from October 1985 to October 1991. The RIMA was inserted as the only graft in 8 patients and in combination with the left internal mammary artery (LIMA) in 231 patients, the right gastroepiploic artery in 19, and autologous vein in 184. The patients received a total of 1 to 8 distal anastomoses (mean number, 3.3). A total of 64% of the RIMAs were anastomosed to the left anterior descending coronary artery. The primary indication for use of the RIMA was small-vessel disease in 86 patients, repeat bypass grafting in 32, varicose or stripped saphenous veins in 61, and "selected routine case" in 79. The early (< or = 30 days postoperatively) mortality rate in these four groups was 8.1%, 6.3%, 0%, and 0%, respectively (p < 0.01). Independent risk factors (logistic regression analysis) for early mortality were small-vessel disease, insufficient grafting, repeat coronary artery bypass grafting, diabetes, history of smoking, age of 60 years or older, and family history of ischemic heart disease. Combined into a risk index, these risk factors identified six risk groups with early mortality of 0% in the four low-risk groups and 5.6% and 58.3% in groups V and VI, respectively (p < 0.0001). No RIMA-related variables were risk factors for significant postoperative myocardial enzyme release. Intraoperative electromagnetic flow measurements revealed no differences between the RIMA and LIMA. Early angiographic patency in 50 patients was 98% for the RIMA and 93% for the LIMA.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiarterial coronary artery bypass grafting with special reference to small vessel disease and results in women.

From 1985 to 1991 a total of 220 patients underwent coronary artery bypass grafting (CABG) with at least two native pedicled artery grafts. Bilateral internal mammary artery (IMA) grafting was performed in 201 patients, IMA combined with gastro-epiploic artery (GEA) grafting in five, and double IMA plus GEA grafting in 14; in addition 156 patients received 1-3 vein grafts. The primary indication for elective multi-arterial CABG was coronary arteries of small calibre (small vessel disease) in 77 patients, repeat CABG in 17 (without small vessel disease), varicose/stripped saphenous veins in 57 (without small vessel disease), while the remaining 69 were routine cases; the distribution differed between women (42, 0, 47, and 11%, respectively) and men (33, 10, 19, and 38%, respectively; P < 0.0001). The women also were older (62 +/- 7 vs 56 +/- 9 years; P < 0.001), and had higher prevalences of systemic hypertension, diabetes mellitus, and hypercholesterolaemia. The number of artery grafts and total number of grafts were, however, similar for women and men. Early mortality (< or = 30 days) was 5.6% in women and 2.4% in men (ns). Early mortalities in relation to primary indications were: 7.8% for small vessel disease, 5.9% for repeat CABG, and 0% for both varicose/stripped saphenous veins and routine cases (P < 0.05). Logistic regression analysis identified small vessel disease, insufficient grafting, age of > = 60 years, a history of smoking, a family history of ischaemic heart disease, and female gender as independent risk factors for early mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgery for chronic left ventricular aneurysm. Benefits and side effects.

Seventy patients who underwent elective resection of symptomatic postinfarction apico-anterior left ventricular (LV) aneurysm with or without coronary revascularization are reviewed. The early (< or = 30 day) mortality was 5.7%. Mural thrombosis occurred in 29 cases (41.4%), unrelated to the degree of preoperative LV impairment and predictable from preoperative LV angiography in only seven cases. The response to surgery comprised significant overall improvement of global LV ejection fraction (LVEF) during rest and of all variables in stress testing. This LVEF recovery correlated significantly with that of peak ejections rate, a variable of myocardial contractility. Contrastingly, right ventricular ejection fraction (RVEF) at rest decreased slightly but significantly without correlation to preoperative RVEF or LVEF. In comparisons between patients with congestive heart failure or angina at rest as dominant symptom, the former group showed greater depression of preoperative watt and LVEF but better postoperative recovery of these variables, while right ventricular deterioration was significant only in the latter. Postoperative recovery was best in patients with poor preoperative LV function (LVEF < or = 20%), even when surgery comprised only aneurysmectomy in isolated but ungraftable LAD disease (5 cases). The observed RV deterioration may be 'nonspecific', but it must be kept in mind as a side effect of the operation, as it detracts unpredictably from postoperative ventricular recovery. Patients with well preserved preoperative LVEF, small LV aneurysm and marginal expected post-aneurysmectomy changes according to LaPlace's law are probably at risk, and surgery should then instead be directed towards preserving the remaining viable myocardium by direct revascularization.

Multiple intestinal duplications in a child with thoracic myelomeningocele and hydrocephalus.

An infant with thoracic spina bifida, myelomeningocele and hydrocephalus was found to have intrathoracic gastric duplication and noncontiguous tubular duplication along two-thirds of the small bowel. The myelomeningocele was closed and the hydrocephalus relieved with a shunt. The intrathoracic duplication was excised in toto and the intra-abdominal malformation successfully treated by stripping the entire mucosal tube from within the duplication.

A "new" intraabdominal artery. The pedicled right gastroepiploic artery for myocardial revascularization.

The right gastroepiploic artery (GEA) was used as a pedicled conduit for direct coronary artery revascularization in 20 patients presenting with more or less exhausted saphenous vein resources. The early angiographic patency of the GEA conduit appears to be satisfactory when it is connected to the right coronary artery system. A distinct disadvantage of GEA grafting is the necessity to enter the abdominal cavity, which may lead to probably rare and as yet unrecognized morbidity. Future abdominal surgery may injure the GEA conduit unless its topographic relations to the prepyloric antrum, liver and diaphragm are properly recognized. The surgeon must then be prepared to encounter antegastric, retrogastric, antehepatic, transhepatic and retrohepatic routes of the redirected intraabdominal artery. The present paper addresses this problem. Preoperative angiography of the celiac trunk and superior mesenteric artery may be helpful in decision-making when a patient reports or records show that a graft has been harvested from the abdominal cavity.

Left ventricular aneurysmectomy in patients with poor left ventricular function.

Physical performance and left ventricular (LV) function in the resting state were assessed in 22 patients with postinfarction anterior-apical left ventricular aneurysm (LVA) and global ejection fraction less than or equal to 20% who subsequently underwent radical LVA resection. The basic findings in the 20 survivors of surgery were significant improvement of global systolic LV function and more or less complete recovery of regional ejection fraction in the predominantly viable low and high lateral LV wall. This improvement was evident in patients with concomitant bypass grafting as well as in those with isolated and ungraftable lesions of the left anterior descending (LAD) coronary artery. We conclude that postinfarction anterior-apical LVA in a poorly functioning LV is suitable for surgical treatment, which can be accomplished with acceptable risk. All graftable stenotic major coronary arteries should be bypassed, in addition to the LVA resection, but a minority of patients with isolated, ungraftable LAD disease are likely to benefit from aneurysmectomy alone.

Flowmetric evaluation of internal mammary artery flap during repair of aortic coarctation.

Resection of the internal shelf through a longitudinal aortotomy and widening with the free end of the left in situ internal mammary artery (IMA) were steps in correction of aortic coarctation with isthmus hypoplasia in nine patients aged 9-14 (mean 10.5) years. Electromagnetic flowmetry was performed on the left IMA before and after the repair. The essential finding was considerably increased mean blood flow in the IMA flap during cross-clamping proximal to the completed repair, from 53 +/- 48 to 430 +/- 74 ml/min (378 +/- 78%). The IMA thus is a powerful conduit with extraordinary flow capacity when runoff is appropriate. Integration of IMA as a viable flap in the repair of aortic coarctation implies that this artery increases its collateral flow contribution to the distal aorta.

Left internal mammary artery flap aortoplasty.

In 14 consecutive 9- to 18-year-old patients with preductal aortic coarctation and isthmic hypoplasia, we resected the coarctation ridge through a longitudinal aortotomy and widened the aorta with an in situ left internal mammary artery flap. This technique resulted in no surgical complications. At 6-month follow-up examination, the average decrease in systolic pressure across the repair was 8.8 mmHg; all patients showed a clear reduction in arterial hypertension at rest and during exercise. Femoral pulses were easily palpable in all cases. Angiography and magnetic resonance imaging showed no aneurysm formation. The narrowest internal diameter of repair was 88% +/- 12% (mean +/- SD) of the diameter of the aortic arch. The internal mammary artery flap technique, which reflects the basic principle of autogenous arterial grafting in situ, allows appropriate circumferential widening of the aorta in many patients with coarctation and hypoplasia of the aortic isthmus involving delayed repair. This procedure should be considered when the internal mammary artery is of good caliber and quality and the anatomic conditions are not ideal for classic end-to-end anastomotic repair.