Health-economic evaluation of three imaging strategies in patients with suspected colorectal liver metastases: Gd-EOB-DTPA-enhanced MRI vs. extracellular contrast media-enhanced MRI and 3-phase MDCT in Germany, Italy and Sweden.

The purpose of this study was to perform an economic evaluation of hepatocyte-specific Gd-EOB-DTPA enhanced MRI (PV-MRI) compared to extracellular contrast-media-enhanced MRI (ECCM-MRI) and three-phase-MDCT as initial modalities in the work-up of patients with metachronous colorectal liver metastases. The economic evaluation was performed with a decision-tree model designed to estimate all aggregated costs depending on the initial investigation. Probabilities on the need for further imaging to come to a treatment decision were collected through interviews with 13 pairs of each a radiologist and a liver surgeon in Germany, Italy and Sweden. The rate of further imaging needed was 8.6% after initial PV-MRI, 18.5% after ECCM-MRI and 23.5% after MDCT. Considering the cost of all diagnostic work-up, intra-operative treatment changes and unnecessary surgery, a strategy starting with PV-MRI with 959 Euro was cost-saving compared to ECCM-MRI (1,123 Euro) and MDCT (1,044 Euro) in Sweden. In Italy and Germany, PV-MRI was cost-saving compared to ECCM-MRI and had total costs similar to MDCT. In conclusion, our results indicate that PV-MRI can lead to cost savings by improving pre-operative planning and decreasing intra-operative changes. The higher cost of imaging with PV-MRI is offset in such a scenario by lower costs for additional imaging and less intra-operative changes.

Increasing incidence of hypoglycemic coma in children with IDDM.

OBJECTIVE: To examine the incidence of hypoglycemic coma in children with insulin-dependent diabetes mellitus (IDDM) over 8 yr from 1981 to 1988 and to investigate the importance of residual beta-cell function of HbA1 levels and other variables as risk factors for hypoglycemic coma. RESEARCH DESIGN AND METHODS: The study consisted of 155 children with IDDM aged less than 16 yr at study entry. Mean age at onset of diabetes was 7.9 yr (range 1.1-15.6 yr). We made a prospective assessment of hypoglycemic coma episodes, with a standardized questionnaire, over a total observation time of 816.6 person-yr. Three monthly clinical and laboratory examinations, which included determinations of C-peptide and HbA1 levels, were conducted. We compared children with hypoglycemic coma (cases) with children without hypoglycemic coma (controls) in a case-control analysis matched for diabetes duration. Yearly incidence of hypoglycemic coma, calculated as the number of subjects having an attack in 1 yr divided by the cumulative number of person-years for that year, was measured. Univariate and multivariate odds ratios were calculated from logistic regression. RESULTS: Over the first 4 yr, the average yearly incidence was 4.4/100 person-yr compared with 7.4/100 person-yr during the later 4 yr (P less than 0.0001). This tendency was accompanied by intensification of insulin treatment with an increase in the mean number of daily injections and a decrease in mean HbA1 levels. In the case-control analysis, absent residual beta-cell function was the most important risk factor for hypoglycemic coma (adjusted odds ratio 7.8, 95% confidence intervals 2.0-31.2), followed by near-normal HbA1 levels (adjusted odds ratio 4.5, 95% confidence intervals 1.9-10.5). CONCLUSIONS: In this group of children, improvement of glycemic control apparently led to an increase in the incidence of severe hypoglycemia. In children with recurrent hypoglycemic coma and undetectable C-peptide levels, it may be safer to aim for somewhat less tight glycemic control.

Myogenic constriction is increased in mesenteric resistance arteries from rats with chronic heart failure: instantaneous counteraction by acute AT1 receptor blockade.

(1) Increased vascular resistance in chronic heart failure (CHF) has been attributed to stimulated neurohumoral systems. However, local mechanisms may also importantly contribute to set arterial tone. Our aim, therefore, was to test whether pressure-induced myogenic constriction of resistance arteries in vitro--devoid of acute effects of circulating factors--is increased in CHF and to explore underlying mechanisms. (2) At 12 weeks after coronary ligation-induced myocardial infarction or SHAM-operations in rats, we studied isolated mesenteric arteries for myogenic constriction, determined as the active constriction (% of passive diameter) in response to stepwise increase in intraluminal pressure (20 - 160 mmHg), in the absence and presence of inhibitors of potentially involved modulators of myogenic constriction. (3) We found that myogenic constriction in mesenteric arteries from CHF rats was markedly increased compared to SHAM over the whole pressure range, the difference being most pronounced at 60 mmHg (24+/-2 versus 4+/-3%, respectively, P<0.001). (4) Both removal of the endothelium as well as inhibition of NO production (L-N(G)-monomethylarginine, 100 micro M) significantly increased myogenic constriction (+16 and +25%, respectively), the increase being similar in CHF- and SHAM-arteries (P=NS). Neither endothelin type A (ET(A))-receptor blockade (BQ123, 1 micro M) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin, 100 nM) affected the myogenic response in either group. (5) Interestingly, increased myogenic constriction in CHF was fully reversed after angiotensin II type I (AT(1))-receptor blockade (candesartan, 100 nM; losartan, 10 micro M), which was without effect in SHAM. In contrast, neither angiotensin-converting enzyme (ACE) inhibition (lisinopril, 1 micro M; captopril, 10 micro M) or AT(2)-receptor blockade (PD123319, 1 micro M), nor inhibition of superoxide production (superoxide dismutase, 50 U ml(-1)), TXA(2)-receptor blockade (SQ29,548, 1 micro M) or inhibition of cyclooxygenase-derived prostaglandins (indomethacin, 10 micro M) affected myogenic constriction. (6) Sensitivity of mesenteric arteries to angiotensin II (10 nM - 100 micro M) was increased (P<0.05) in CHF (pD(2) 7.1+/-0.4) compared to SHAM (pD(2) 6.2+/-0.3), while the sensitivity to KCl and phenylephrine was not different. (7) Our results demonstrate increased myogenic constriction in small mesenteric arteries of rats with CHF, potentially making it an important target for therapy in counteracting increased vascular resistance in CHF. Our results further suggest active and instantaneous participation of AT(1)-receptors in increased myogenic constriction in CHF, involving increased sensitivity of AT(1)-receptors rather than apparent ACE-mediated local angiotensin II production.

[Identification and clinical use of the Metabolic Syndrome]. / Wird das Metabolische Syndrom in der Klinik erkannt und die Diagnose aktiv verwendet?

The Metabolic Syndrome is characterised by the following components: atherogenic dyslipidemia, elevated blood pressure, elevated glucose and abdominal obesity. 22% of 415 patients of an outpatient clinic in internal medicine fulfilled the criteria of a Metabolic Syndrome. The most common components were abdominal obesity, elevated blood pressure and elevated triglyceride. Only one in five treating physicians diagnosed a Metabolic Syndrome. Our data show that the concept of the Metabolic Syndrome has limited utility in clinical practice.

[Ethanol, sugar, acid and coma]. / Alkohol, Zucker, Säure und Koma.

We report on a 46-year-old female patient with chronic alcoholism, who presented with a severe metabolic acidosis and an increased anion gap despite repeated vomiting. In face of a dramatically increased serum-beta-hydroxybutyrate and after ruling out more common causes of acidosis, we were able to diagnose an alcoholic ketoacidosis. The epidemiology, pathophysiology, clinics and treatment of this often forgotten and misunderstood disorder of acid-base balance are discussed.

Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: experience of the PedPump Study in 17 countries.

AIMS/HYPOTHESIS: To assess the use of paediatric continuous subcutaneous infusion (CSII) under real-life conditions by analysing data recorded for up to 90 days and relating them to outcome. METHODS: Pump programming data from patients aged 0-18 years treated with CSII in 30 centres from 16 European countries and Israel were recorded during routine clinical visits. HbA(1c) was measured centrally. RESULTS: A total of 1,041 patients (age: 11.8 +/- 4.2 years; diabetes duration: 6.0 +/- 3.6 years; average CSII duration: 2.0 +/- 1.3 years; HbA(1c): 8.0 +/- 1.3% [means +/- SD]) participated. Glycaemic control was better in preschool (n = 142; 7.5 +/- 0.9%) and pre-adolescent (6-11 years, n = 321; 7.7 +/- 1.0%) children than in adolescent patients (12-18 years, n = 578; 8.3 +/- 1.4%). There was a significant negative correlation between HbA(1c) and daily bolus number, but not between HbA(1c) and total daily insulin dose. The use of <6.7 daily boluses was a significant predictor of an HbA(1c) level >7.5%. The incidence of severe hypoglycaemia and ketoacidosis was 6.63 and 6.26 events per 100 patient-years, respectively. CONCLUSIONS/INTERPRETATION: This large paediatric survey of CSII shows that glycaemic targets can be frequently achieved, particularly in young children, and the incidence of acute complications is low. Adequate substitution of basal and prandial insulin is associated with a better HbA(1c).

Effects of acute hyperglycemia on mental efficiency and counterregulatory hormones in adolescents with insulin-dependent diabetes mellitus.

OBJECTIVE: To determine whether acute hyperglycemia adversely affects mental efficiency to the same extent as acute mild hypoglycemia. STUDY DESIGN: We administered a battery of cognitive tests to adolescents studied at hyperglycemic (20 mmol/L (360 mg/dl)), hypoglycemic (3.3 mmol/L (60 mg/dl)), or euglycemic (5.5 mmol/L (100 mg/dl)) targets, which were maintained by an insulin-glucose clamp. The study included 36 children, 9 to 19 years of age (mean = 14.7 years), with diabetes duration more than 2 years (mean = 6.9 years). RESULTS: Cognitive test performance did not deteriorate during hyperglycemia. In contrast, there was a significant decline in performance on all cognitive tests during mild hypoglycemia. Autonomic symptoms did not change significantly during hyperglycemia or during the rapid return from hyperglycemia to euglycemia. Although significant increments in epinephrine and pancreatic polypeptide levels occurred during mild hypoglycemia, no changes in counterregulatory hormones occurred during hyperglycemia. An exploratory regression analysis demonstrated that changes in mental efficiency were best predicted by increases in pancreatic polypeptide, a marker of autonomic activation. CONCLUSION: These results confirm our previous finding that mild hypoglycemia causes transient decrements in cognitive function. In contrast, neither hyperglycemia, nor the rapid drop from acute hyperglycemia to euglycemia, affected symptoms, cognitive function, or counterregulatory hormone secretion.

[Anti-angina effect of amiodarone in therapy-resistant angina pectoris]. / Antianginöse Wirksamkeit von Amiodarone bei therapierefraktärer Angina pectoris.

In a double-blind randomized trial 63 patients on the waiting list for coronary artery bypass grafting, with stable angina NYHA III and a positive stress test on triple (nitrates, beta- and calcium entry blockers) combination therapy, were studied for an additional antianginal effect of amiodarone over a period of 2 months. In the treatment group an increase in exercise duration and a decrease of the double product and of ST-depression were noted. Thus, amiodarone is an effective antianginal agent in patients with limiting angina pectoris on conventional triple therapy.

A general-purpose implantable multichannel telemetry system for physiological research.

The majority of physiologically significant parameters can be accurately measured with relatively simple transducers and with a minimum of sophisticated electronics; such parameters include temperature, pressure, and electrical activity and generally require less than a 200 Hz bandwidth. In most experiments, however, measurements at multiple sites are needed to characterize fully a particular response, and the use of totally implantable telemetry systems becomes attractive as the problems of percutaneous leads in conscious animals are compounded in proportion to the number of sensors. These systems have been produced in limited quantities because a large number of components and long assembly times are necessary to provide simple amplifications and signal processing in a small implantable package. A new six-channel system incorporates all signal processing on a single integrated circuit, and only one CMOS divider chain and an integrated telemetry transmitter are required for support. This high level of integration accelerates assembly time and increases reliability by minimizing the interconnections. Such advancements are essential before the full potential of implantable telemetry can be realized. This paper details the performance of this system during initial applications requiring pressure, bioelectrical, or temperature telemetry.

Influence of sustained mechanical stress on Egr-1 mRNA expression in cultured human endothelial cells.

Restenosis after initially successful balloon angioplasty of coronary artery stenosis remains a major problem in clinical cardiology. Previous studies have identified pathogenetic factors which trigger cell proliferation and vascular remodeling ultimately leading to restenosis. Since there is evidence that endothelial cells adjacent to the angioplasty wound area synthesize factors which may initiate this process, we investigated the effects of mechanical stimulation on endothelial gene expression in vitro and focussed on the influence of sustained mechanical stress on expression of immediate early genes which have previously been shown to be induced in the vascular wall in vivo. Primary cultured human umbilical vein endothelial cells (HUVEC) and the human endothelial cell line EA.hy 926 were plated on collagen-coated silicone membranes and subjected to constant longitudinal stress of approximately 20% for 10 min to 6 h. Total RNA was isolated and the expression of the immediate early genes c-Fos and Egr-1 was studied by Northern blot analysis. We found a rapid upregulation c-Fos and Egr-1 mRNA which started at 10 min and reached its maxima at 30 min. HUVEC lost most of their stretch response after the third passage whereas immediate early gene expression was constantly in EA.hy 926 cells. Using specific inhibitors we investigated the contribution of several signal transduction pathways to stretch-activated Egr-1 mRNA expression. We found significant suppression of stretch-induced Egr-1 mRNA expression by protein kinase C (PKC) inhibition (p < 0.05) and by calcium depletion (EA.hy 926, p < 0.05; HUVEC, p = 0.063). No effect on stretch-activated Egr-1 mRNA expression was detected by inhibition of protein kinase A, blockade of stretch-activated cation channels or inhibition of microtubule synthesis. We conclude that sustained mechanical strain induces Egr-1 mRNA expression by PKC- and calcium-dependent mechanisms.

Does a low-salt diet exert a protective effect on endothelial function in normal rats?

Sodium restriction is often used as an adjunct in the treatment of conditions characterized by endothelial dysfunction, such as hypertension and heart or kidney disease. However, the effect of sodium restriction on endothelial function is not known. Therefore, male Wistar rats were studied after a fixed salt diet had been maintained (low-salt group: 0.05% NaCl, n = 10; normal-salt group: 0.3% NaCl, n = 10) for 6 weeks. Blood pressure and sodium excretion values were measured once a week. Subsequently the rats were killed, the aorta was removed, and rings were cut. Endothelium-independent (sodium nitrite [SN]) and endothelium-dependent (acetylcholine [ACh]) vasodilator responses were assessed in the presence of indomethacin (a cyclo-oxygenase inhibitor) and in the presence or absence of NG-monomethyl-L-arginine (L-NMMA; a competitive inhibitor of nitric oxide [NO] synthase). Endothelium-independent vasodilatation was not different for the two salt groups. Endothelium-dependent vasodilatation, on the other hand, was different. The response to ACh was almost completely abolished by L-NMMA in the normal-salt group, whereas vasodilatation was partially preserved during L-NMMA in the low-salt group. Accordingly, the L-NMMA-sensitive contribution to ACh-dependent vasodilatation was smaller in the low-salt group. Thus, salt restriction induced a non-NO and non-prostaglandin-dependent vasodilating pathway. By exclusion this could be endothelium-derived hyperpolarizing factor, a pathway of vasculoprotective potential. Accordingly, the relative contributions of the different vasoactive endothelial pathways were affected by salt intake. Further research will be needed to clarify the nature and importance of this non-NO, non-prostaglandin-dependent pathway in the clinical setting as well.

Interaction of the renin-angiotensin system and the endothelin system in cardiac hypertrophy.

It has been suggested that the renin-angiotensin system (RAS) interacts with the endothelin system in the pathogenesis of cardiac remodeling. We examined endothelin system regulation in a model of chronic RAS dysfunction, which is believed to be an important factor in cardiac remodeling. We used the transgenic rat line TGR(mRen2)27, which overexpresses the mouse Renin-2 gene and shows hypertension and left ventricular hypertrophy compared to Sprague-Dawley (SD) rats. Ren-2 rats (n = 24) received either losartan (LOS), quniapril (QIN), or carvedilol (CARV) for 11 weeks, or no treatment. After 11 weeks left (LV) and right ventricular (RV) weights were determined and total RNA extracted. Ren-2 rats showed a mean systolic blood pressure of 190 mm (+/- SEM), which could be normalized to 110 +/- mm (+/- SEM) by treatment with LOS or QIN. CARV also reduced blood pressure but did not normalize it. LV end-diastolic pressure was normal in both SD and Ren-2 rats. LV weight was increased in the Ren-2 rats compared to SD rats, and was significantly reduced to normal in the LOS and QIN but not in the CARV group. RV weight was normal in all groups. Northern blot analysis of preproendothelin-1 (preproET-1) and endothelin-converting enzyme-1 (ECE-1) expression revealed a significant (p < 0.05) 20% decrease in preproET-1 mRNA in the mRen2 rats in the RV and in the LV, compared to SD rats. ECE-1 mRNA was unchanged. Treatment with LOS, but not with QIN or CARV, induced preproET-1 transcription by threefold (p < 0.01) over baseline in both the LV and RV. ECE-1 mRNA was unaltered in the CARV and LOS group and was decreased by 20% in the QIN group. Similar changes in LV and RV indicated a direct influence of a dysregulated RAS on the endothelin system. In conclusion, the activated RAS downregulates the endothelin system in this model of cardiac hypertrophy. This suggests that in chronic RAS activated, the endothelin system may have a different pathophysiologic impact as a co-factor leading to cardiac hypertrophy.

Epidemiology of type I diabetes mellitus in Switzerland: steep rise in incidence in under 5 year old children in the past decade.

AIMS/HYPOTHESIS: In this nationwide prospective study we wanted to verify the trend of increasing diabetes incidence data from our earlier retrospective analysis of the military registry of Swiss men. SUBJECTS AND METHODS: The data collection of newly diagnosed children in Switzerland at an age younger than 15 years started in 1991. The countrywide survey used a small questionnaire which was sent back to the study centre. The questionnaire was anonymous and contained: hospital of diagnosis, initials, sex, birth date, date of diagnosis, residence, country of citizenship, and responsible physician. General data on the population were taken from publications of the Swiss Federal Statistical Office. RESULTS: A total of 941 children below the age of 15 years with newly diagnosed Type I (insulin-dependent) diabetes mellitus were collected (434 girls, 507 boys). The incidence in children aged 0 to 14 years rose significantly between 1991 and 1999 with a yearly average increase of 5.1%. In the age group 0 to 4 years a more than four-fold increase in incidence from 2.4/100,000 per year to 10.5/100,000 per year (p = 0.0002) was recorded, whereas the age-specific incidence in the 5 to 9-year-old and 10 to 14-year-old children did not change during the data collection period. The incidence was significantly higher in boys than in girls, whereas no difference was found between rural and urban populations. CONCLUSION/INTERPRETATION: The incidence of Type I diabetes is rising in children living in Switzerland but only the youngest age group of under 5 years of age is affected showing a large annual average increase of 23.8%.