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Background: Stereotactic body radiotherapy (SBRT) can achieve high tumour control with limited toxicity for inoperable early stage non-small-cell lung cancer (NSCLC) patients. Patients and methods: The German Epidemiologic Cancer Registries from the Robert-Koch Institute were assessed. Periods according to the availability of SBRT were: (1) 2000–2003 (pre-SBRT); (2) 2004–2007 (interim); and (3) 2007–2014 (broad availability of SBRT). To assess the association of cancer-related parameters with mortality, hazard ratios (HR) from Cox proportional hazards models were computed. To evaluate the change of treatment-related mortality, we performed interaction analyses and the relative excess risk due to interaction (RERI, additive scale) was computed. Results: A total of 16,292 patients with UICC stage I NSCLC diagnosed between 2000 and 2014 were analysed. Radiotherapy utilization increased from 5% in pre-SBRT era to 8.8% after 2007. In univariate analyses, survival in the whole cohort improved only marginally when 2000–2003 is compared to 2004–2007 (HR 0.92, 95% CI 0.85–1.01) or 2008–2014 (HR 0.93, 95% CI 0.86–1.01). Comparing surgery/radiotherapy, mortality in the radiotherapy group started from a 3.5-fold risk in 2000–2003 to 2.6 after 2007. The interaction analysis revealed a stronger improvement for radiotherapy (multiplicative scale for 2000–2003 vs. > 2007: 0.74, 95% CI 0.58–0.94). On an additive scale, treatment × period interaction revealed an RERI for 2000–2003 vs. > 2007 of − 1.18 (95% CI − 1.8, − 0.55). Conclusions: Using population-based data, we observed a survival improvement in stage I lung cancer over time. With an increasing utilization of radiotherapy, a stronger improvement occurred in patients treated with radiotherapy when compared to surgery. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Uncoupling protein‐2 (UCP‐2) can induce mitochondrial uncoupling in the diabetic kidney. Although mitochondrial uncoupling reduces oxidative stress originating from the mitochondria and can be regarded as a protective mechanism, the increased oxygen consumption occurring secondarily to increased mitochondria uncoupling, that is leak respiration, may contribute to kidney tissue hypoxia. Using UCP‐2−/− mice, we tested the hypothesis that UCP‐2‐mediated leak respiration is important for the development of diabetes‐induced intrarenal hypoxia and proteinuria. Methods: Kidney function, in vivo oxygen metabolism, urinary protein leakage and mitochondrial function were determined in wild‐type and UCP‐2−/− mice during normoglycaemia and 2 weeks after diabetes induction. Results: Diabetic wild‐type mice displayed mitochondrial leak respiration, pronounced intrarenal hypoxia, proteinuria and increased urinary KIM‐1 excretion. However, diabetic UCP‐2−/− mice did not develop increased mitochondrial leak respiration and presented with normal intrarenal oxygen levels, urinary protein and KIM‐1 excretion. Conclusion: Although functioning as an antioxidant system, mitochondria uncoupling is always in co‐occurrence with increased oxygen consumption, that is leak respiration; a potentially detrimental side effect as it can result in kidney tissue hypoxia; an acknowledged unifying pathway to nephropathy. Indeed, this study demonstrates a novel mechanism in which UCP‐2‐mediated mitochondrial leak respiration is necessary for the development of diabetes‐induced intrarenal tissue hypoxia and proteinuria. [ABSTRACT FROM AUTHOR]

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Aim Diabetic patients are at increased risk for kidney disease. There is presently no clinical treatment available that effectively protects kidney function in diabetics. This study investigates whether chronic stimulation of the adenosine A2a receptor (A2a AR) protects kidney function in insulinopenic diabetic rats. Methods Streptozotocin-induced diabetic rats and corresponding controls were chronically treated with the adenosine A2a AR agonist CGS21680 throughout the four-week diabetes duration. Kidney function was thereafter investigated, and urine and plasma samples were collected for analysis of protein, oxidative stress and inflammatory markers. Results Glomerular filtration rate, renal blood flow, filtration fraction and diabetes-induced kidney hypoxia were all unaffected by chronic A2a AR stimulation. Furthermore, diabetic rats had increased oxidative stress, which was further increased by chronic A2a AR stimulation. However, the 10-fold increased urinary protein excretion observed in the diabetic rats was completely prevented by chronic A2a AR stimulation. These beneficial effects were accompanied by reduced levels of the pro-inflammatory TNF- α and increased levels of the anti-inflammatory IL-10 as well as decreased infiltration of macrophages, glomerular damage and basement membrane thickness. Conclusion Chronic A2a AR stimulation prevents proteinuria and glomerular damage in experimental diabetes via an anti-inflammatory mechanism independent of oxidative stress and kidney hypoxia. [ABSTRACT FROM AUTHOR]

Despite data showing that inhibitors of the renin-angiotensin system increase the risks of fetal morbidity and dysfunctionality later in life, their use during pregnancy has increased. The fetopathy induced by angiotensin converting enzyme ( ACE) inhibitors is characterized by anuria, hypotension and growth restriction, but can also be associated with pulmonary hypoplasia. In the kidney, this fetopathy includes atrophy of the medulla, reduced number of glomeruli, developmental lesions of tubules and vessels, tubulointerstitial inflammation and extracellular matrix accumulation. Although angiotensin II (Ang II) inhibition during nephrogenesis interferes with normal growth and development, this review will focus on effects of the heavily accumulated matrix component hyaluronan ( HA). An important mechanism of HA accumulation during nephrogenesis is disruption of its normal reduction as a consequence of lack of Ang II activation of hyaluronidase. Hyaluronan has very large water-attracting properties and is pro-inflammatory when fragmented. The ensuing inflammation and interstitial oedema affect kidney function. Hyaluronan is colocalized with CD44 overexpression and infiltrating immune cells. These properties make HA a plausible contributor to the observed structural and functional kidney defects associated with the fetopathy. Available data support an involvement of HA in kidney dysfunction of the foetus and during adulthood due to the physico-chemical characteristics of HA. No clinical treatment for HA accumulation exists. Treatment with the HA-degrading enzyme hyaluronidase and an HA synthesis inhibitor has been tested successfully in experimental models in the kidney, heart and pancreas. Reduced HA accumulation to reduce interstitial oedema and inflammation may improve organ function, but this concept needs to be tested in a controlled study before causal relationships can be established. [ABSTRACT FROM AUTHOR]

Aim Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. Sustained hyperglycaemia is also closely associated with kidney hypertrophy and increased electrolyte and glucose reabsorption in the proximal tubule. In this study, we investigated the role of the increased tubular sodium/glucose cotransport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback ( TGF) mechanism, we used adenosine A1-receptor deficient (A1 AR−/−) mice known to lack a functional TGF mechanism and compared the results to corresponding wild-type animals (A1 AR+/+). Methods Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate ( GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose cotransporters were inhibited by phlorizin 30 min prior to GFR measurements. Results Normoglycaemic animals had a similar GFR independent of genotype (A1 AR+/+ 233 ± 11 vs. A1 AR−/− 241 ± 25 μL min−1), and induction of diabetes resulted in glomerular hyperfiltration in both groups (A1 AR+/+ 380 ± 25 vs. A1 AR−/− 336 ± 35 μL min−1; both P < 0.05). Phlorizin had no effect on GFR in normoglycaemic mice, whereas it reduced GFR in both genotypes during diabetes (A1 AR+/+ 365 ± 18 to 295 ± 19, A1 AR−/− 354 ± 38 to 199 ± 15 μL min−1; both P < 0.05). Notably, the reduction was more pronounced in the A1 AR−/− ( P < 0.05). Conclusion This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point. [ABSTRACT FROM AUTHOR]

Data on incidence of intracerebral haemorrhage (ICH) vary widely. Population-based data on predictors of ICH survival and functional outcome are rare. The Ludwigshafen Stroke Study is a prospective, population-based stroke registry which started in January 2006. All residents of the city of Ludwigshafen, Germany, who suffer from acute stroke or transient ischaemic attack are registered. Patients with first-ever primary intracerebral haemorrhage (FE-pICH) between 2006 and 2010 were included in the present analysis. Between January 1st, 2006 and December 31st, 2010, 152 patients suffered a FE-pICH. Crude and age-adjusted incidence rates per 100,000 for FE-pICH were 18.7 (95 % CI 15.9-21.9) and 11.9 (95 % CI 10.2-14.0), respectively, and remained stable over time. Case-fatality rates for FE-pICH were 27.0, 34.9 and 44.1 % at days 28, 90 and 365, respectively. In 21 patients, an (21.3 %) early do-not resuscitate-order was documented. Excluding these patients from multivariate analyses, National Institute of Health Stroke Scale (NIHSS) (OR 1.22, 95 % CI 1.08-1.36), hypercholesterolemia (OR 0.16, 95 % CI 0.05-0.55) and modified Rankin Scale (mRS) prior to stroke (OR 1.56, 95 % CI 1.06-2.3) were independently associated with risk of 1-year mortality, whereas NIHSS (OR 1.41, 95 % CI 1.20-1.66) and leukocyte count on admission (OR 1.48, 95 % CI 1.16-1.89) were independently associated with good or moderate functional outcome (mRS ≤ 3) after 1 year. Incidence of FE-ICH is in the lower range of those reported from other registries and remained stable over the observation period. Higher treatment rates for hypertension might partly account for this. Stroke severity as indicated by NIHSS was independently associated with mortality and functional outcome after 1 year. We found no association between aetiology and outcome in ICH patients. [ABSTRACT FROM AUTHOR]

Background and purpose Atrial fibrillation (AF) is amongst the most important etiologies of ischaemic stroke. In a population-based stroke registry, we tested the hypothesis of low adherence to current guidelines as a main cause of high rates of AF-associated stroke. Methods Within the Ludwigshafen Stroke Study (LuSSt), a prospective ongoing population-based stroke register, we analyzed all patients with a first-ever ischaemic stroke (FEIS) owing to AF in 2006 and 2007. We determined whether AF was diagnosed before stroke and assessed pre-stroke CHADS2 and CHA2DS2-VASc scores. Results In total, 187 of 626 patients with FEIS suffered from cardioembolic stroke owing to AF, which was newly diagnosed in 57 (31%) patients. Retrospective pre-stroke risk stratification according to CHADS2 score indicated low/intermediate risk in 34 patients (18%) and high risk (CHADS2 ≥ 2) in 153 patients (82%). Application of CHA2DS2-VASc score reduced number of patients at low/intermediate risk (CHA2DS2-VASc score 0-1) to five patients (2.7%). In patients with a CHADS2 score ≥ 2 and known AF (n = 106) before stroke, 38 (36%) were on treatment with vitamin K antagonists on admission whilst only in 16 patients (15%) treatment was in therapeutic range. Conclusions Our study strongly supports the hypothesis that underuse of oral anticoagulants in high-risk patients importantly contributes to AF-associated stroke. CHA2DS2-VASc score appears to be a more valuable risk stratification tool than CHADS2 score. Preventive measures should focus on optimizing pre-stroke detection of AF and better implementation of present AF-guidelines with respect to anticoagulation therapy. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes. Methods: Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment. Results: Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 ± 0.1 vs 0.2 ± 0.1 pmol O s [mg protein]), glomerular hyperfiltration (502 ± 26 vs 385 ± 3 μl/min), increased proteinuria (21 ± 2 vs 14 ± 1, μg/24 h), mitochondrial fragmentation (fragmentation score 2.4 ± 0.3 vs 0.7 ± 0.1) and size (1.6 ± 0.1 vs 1 ± 0.0 μm) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (−1.1 ± 0.1 pmol O s [mg protein]). UCP-2 protein levels were similar in untreated control and db/db mice (67 ± 9 vs 67 ± 4 optical density; OD) but were reduced in CoQ10 treated groups (43 ± 2 and 38 ± 7 OD). Conclusions/interpretation: db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress. [ABSTRACT FROM AUTHOR]

Purpose. A transient painless monocular visual loss due to a decrease in retinal circulation--also known as "amaurosis fugax"-- often precedes acute territorial cerebral ischaemia. The case we present underlines the importance of a comprehensive diagnostic workup in patients with amaurosis fugax. Case Report. A 44-year-old man who had suffered from a dissection of the ascending aorta (Stanford Type A) five months ago presented with recurrent monocular vision problems. Episodes with sectional vision loss mainly occurred in combination with low blood pressure levels. Furthermore, the haemoglobin level was chronically low (Hb 9.7mg/dL), and the patient was by mistake on a simultaneous therapy with phenprocoumon and unfractionated heparin. Carotid artery duplex scanning revealed a high-grade stenosis of the proximal right common carotid artery. MR imaging corroborated hypoperfusion in brain area corresponding to the right MCA. Conclusion. Our patient is an example in whom transient retinal ischaemic attacks may originate from haemodynamic reasons. [ABSTRACT FROM AUTHOR]

Background: Stroke etiology in ischemic stroke guides preventive measures and etiological stroke subgroups may show considerable differences between both sexes. In a population-based stroke registry we analyzed etiological subgroups of ischemic stroke and calculated sex-specific incidence and mortality rates. Methods: The Ludwigshafen Stroke Study is a prospective ongoing population-based stroke registry. Multiple overlapping methods of case ascertainment were used to identify all patients with incident stroke or transient ischemic attack. Modified TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria were applied for subgroup analysis in ischemic stroke. Results: Out of 626 patients with first-ever ischemic stroke in 2006 and 2007, women (n = 327) were older (73.5 ± 12.6 years) than men (n = 299; 69.7 ± 11.5 years; p < 0.001). The age-adjusted incidence rate of ischemic stroke was significantly higher in men (1.37; 95% CI 1.20-1.56) than in women (1.12; 95% CI 0.97-1.29; p = 0.04). Cardioembolism (n = 219; 35.0%), small-artery occlusion (n = 164; 26.2%), large-artery atherosclerosis (n = 98; 15.7%) and 'probable atherothrombotic stroke' (n = 84; 13.4%) were common subgroups of ischemic stroke. Stroke due to large-artery atherosclerosis (p = 0.025), current smoking (p = 0.008), history of smoking (p < 0.001), coronary artery disease (p = 0.0015) and peripheral artery disease (p = 0.024) was significantly more common in men than in women. Overall, 1-year survival was not different between both sexes; however, a significant age-sex interaction with higher mortality in elderly women (>85 years) was detected. Conclusions: Cardioembolism is the main source for ischemic stroke in our population. Etiology of ischemic stroke differs between sexes, with large-artery atherosclerotic stroke and associated diseases (coronary artery disease and peripheral artery disease) being more common in men. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Elevated glomerular filtration rate (GFR) is a common observation in early diabetes mellitus and closely correlates with the progression of diabetic nephropathy. Hyperfiltration has been explained to be the result of a reduced load of sodium and chloride passing macula densa, secondarily to an increased proximal reabsorption of glucose and sodium by the sodium-glucose co-transporters. This results in an inactivation of the tubuloglomerular feedback (TGF), leading to a reduced afferent arteriolar vasoconstriction and subsequently an increase in GFR. This hypothesis has recently been questioned due to the observation that adenosine A1-receptor knockout mice, previously shown to lack a functional TGF mechanism, still display a pronounced hyperfiltration when diabetes is induced. Leyssac demonstrated in the 1960s ( Acta Physiol Scand 58, 1963:236) that GFR and proximal reabsorption can work independently of each other. Furthermore, by the use of micropuncture technique a reduced hydrostatic pressure in Bowman’s space or in the proximal tubule of diabetic rats has been observed. A reduced pressure in Bowman’s space will increase the pressure gradient over the filtration barrier and can contribute to the development of diabetic hyperfiltration. When inhibiting proximal reabsorption with a carbonic anhydrase inhibitor, GFR decreases and proximal tubular pressure increases. Measuring intratubular pressure allows a sufficient time resolution to reveal that net filtration pressure decreases before TGF is activated which highlights the importance of intratubular pressure as a regulator of GFR. Taken together, these results imply that the reduced intratubular pressure observed in diabetes might be crucial for the development of glomerular hyperfiltration. [ABSTRACT FROM AUTHOR]

Objective:Mice deficient of the serotonin transporter (5-HTT ko) mice have a reduced brain serotonin content and develop late-onset obesity. To elucidate the pathophysiology of this obesity, we analyzed the expression of the interrelated weight-regulatory molecules: brain-derived neurotrophic factor (BDNF) and leptin receptor (LR) in brain areas associated with nutrition and activity.Research Design and Methods:We investigated feeding behavior, physical activity and metabolic parameters of 5-HTT ko and wild-type mice and measured the expression of BDNF and LR in brain areas associated with nutrition and activity using quantitative real-time PCR. The influence of age, gender and fasting was analyzed.Results:Male 5-HTT ko mice developed obesity without hyperphagia from the age of 5 months. Physical activity was reduced in old male, but not old female, 5-HTT ko mice. The BDNF gene expression in frontal cortex was elevated in young, but reduced in old 5-HTT ko mice. Fasting failed to increase the BDNF gene expression in frontal cortex of young 5 HTT ko mice and in the hypothalamus in old 5-HTT ko mice. The fasting-induced hypothalamic increase of LR was absent in both young and old 5-HTT ko mice.Conclusions:We propose that low brain serotonin level due to the 5-HTT ko genotype leads to reduced physical activity and low BDNF, which together with the lack of fasting-induced hypothalamic BDNF and LR production results in late-onset obesity. Although lack of the 5-HTT is a genetic vulnerability factor for obesity, female gender is protective. [ABSTRACT FROM AUTHOR]

Background: Leukocyte-platelet aggregates appear to be a stable and sensitive marker of platelet activation as suggested by studies in coronary heart disease. We tested the hypothesis that leukocyte-platelet aggregates are increased after ischemic stroke and investigated the contribution of different leukocyte subtypes to such increase. Methods: We serially determined granulocyte-, lymphocyte- and monocyte-platelet aggregates, using flow cytometry at days 1, 2, 3, 5, 7, 10, and 90 in patients with ischemic stroke (n = 45) and in age- and sex-matched healthy control subjects (n = 30). Results: Granulocyte-platelet aggregates (granulocytes with ≥1 platelet/μl) were more common in patients than control subjects from day 1 through day 10 (p < 0.04, respectively), but not on day 90 after stroke. The percentage of granulocytes forming aggregates was increased on days 1–3 after stroke but not at other time points. Lymphocyte-platelet aggregates were not more common at any time point after stroke. Total numbers and percentages of monocytes forming platelet aggregates were significantly increased on day 2 (p = 0.003), but not at other time points after stroke. Conclusion: The 3 leukocyte subtypes showed different kinetics regarding aggregate formation with platelets after ischemic stroke. Increase of monocyte-platelet aggregates is short-lived and may reflect an acute reaction to cerebral ischemia, whereas granulocyte-platelet aggregate formation persists into the subacute phase, suggesting that they are a particularly sensitive parameter reflecting both prothrombotic and inflammatory processes after stroke. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In this paper we examine the importance of financial and other obstacles to innovation in the Netherlands using statistical information from the CIS 3.5 innovation survey. We report results on the effect of these obstacles on the firms’ decision to abandon, prematurely stop, seriously slow down, or not to start an innovative project. These results are compared with those from other studies in the Netherlands and other countries. We end with a discussion of policy measures that have been taken to overcome, or at least attenuate these obstacles, such as R&D tax incentives, venture capital financing and policy mix packages. [ABSTRACT FROM AUTHOR]

Objective: The nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) is generated by protein arginine N-methyltransferase (PRMT)-1 and is metabolized by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH). We tested the hypothesis that increased serum ADMA (S(ADMA)) in the streptozotocin (STZ)-induced diabetic rat model of diabetes is mediated by an angiotensin receptor blocker-sensitive change in DDAH or PRMT expression.Research Design and Methods: Data were compared from four groups of rats: sham-injected controls, untreated STZ-induced diabetic rats at 4 weeks, STZ-induced diabetic rats administered the angiotensin II (Ang II) receptor blocker telmisartan for 2 weeks, and control rats administered telmisartan for 2 weeks.Results: Immunostaining and Western blotting of microdissected nephron segments localized DDAH I in the proximal tubules and DDAH II in the glomeruli, afferent arterioles, macula densa, and distal nephron. Renal Ang II and S(ADMA) increased with diabetes but were normalized by 2 weeks of telmisartan. DDAH I expression was decreased in diabetic kidneys, while DDAH II expression was increased. These changes were reversed by telmisartan, which also reduced expression of PRMT-1 and -5. Telmisartan increased expressions of DDAH I but decreased DDAH II in Ang II-stimulated kidney slices ex vivo.Conclusions: Renal Ang II and S(ADMA) are increased in insulinopenic diabetes. They are normalized by an Ang II receptor blocker, which increases the renal expression of DDAH I, decreases PRMT-1, and increases renal NO metabolites. [ABSTRACT FROM AUTHOR]

Aims: Glomerular hyperfiltration is commonly found in diabetic patients early after the onset of disease. This is one of the first indications of the development of progressive diabetic nephropathy. It has been proposed that glomerular hyperfiltration is caused by decreased delivery of electrolytes to the macula densa due to the increased sodium and glucose reabsorption in the proximal tubule, which would increase the glomerular filtration rate (GFR) via the tubuloglomerular feedback (TGF) mechanism. In this study, we investigated the role of TGF in diabetes-induced glomerular hyperfiltration by inducing diabetes in adenosine A1-receptor knockout (A1AR−/−) mice known to lack a functional TGF mechanism. Methods: Diabetes was induced by alloxan (75 mg kg−1 bw) injected into the tail vein. The 24-hour urinary electrolyte excretion was measured in metabolic cages, the GFR determined by inulin clearance under isoflurane-anaesthesia, and histological changes evaluated. Results: All alloxan-treated animals developed hyperglycaemia (≥20 mm). Normoglycaemic animals had a similar GFR independent of genotype (A1AR+/+ 9.3 ± 0.5 vs. A1AR−/− 10.1 ± 0.8 μL min−1g−1 bw) and diabetes resulted in similar glomerular hyperfiltration in both groups (A1AR+/+ 14.0 ± 1.7, n = 9 vs. A1AR−/− 15.3 ± 1.9 μL min−1g−1 bw). Diabetic animals had a similar tendency to develop interstitial fibrosis, whereas the glomerular volume was similar in both genotypes, and unaltered by diabetes. Conclusions: This study shows that the A1AR−/− mice develop diabetes-induced glomerular hyperfiltration, demonstrating that the TGF mechanism is not the major cause of the development of hyperfiltration. Furthermore, the hyperfiltration in the present study was not related to alterations in the glomerular filtration area. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate controversial results regarding the effect of the contrast medium (CM) iothalamate on renal medullary blood flow by applying two different methods simultaneously. Material and Methods: The outer medullary blood flow (OMBF) response was estimated using laser-Doppler flowmetry and hydrogen gas wash-out (microelectrodes) simultaneously. Outer medullary oxygen tension (P O2 ) was measured using Clark type microelectrodes. Iothalamate was injected i.v. at 1600 mg I/kg body weight for 2 min. Results: CM induced a transient 28% decrease in OMBF as measured with the laser Doppler. The hydrogen gas wash-out rate was reduced by 50%, indicating a reduced perfusion. CM induced a transient 60% reduction in P O2 , while renal fluid and electrolyte excretion increased several fold. Conclusion: The CM iothalamate reduces outer medullary perfusion as estimated by two different techniques applied simultaneously. The P O2 in the same region was also reduced. Previous controversies regarding the effect of iothalamate on OMBF can be explained by extreme dosage and injection rates greatly exceeding clinical relevance. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess whether signal changes can be detected in the neurovascular bundle of the mandibular canal after the extraction of a third molar. We retrospectively analyzed MRI scans of 30 test subjects with healthy mandibles and 41 patients who had had a wisdom tooth extracted. Signal intensities were measured at particular sites in the neurovascular bundle, which were defined as regions of interest (ROI) in the sagittal T1-weighted images before and after intravenous administration of a paramagnetic contrast agent. On the basis of the signal intensity increases that were measured after contrast agent administration, we compared the signal increases obtained for the patients who had received surgical treatment with the results obtained for the population of test subjects with unremarkable mandibles ( t-test, P<0.05). Compared with the healthy test subjects, patients who had received surgical treatment showed significantly higher signal intensity increases at two measurement sites, i.e., the second molar and the second premolar ( P<0.05). We found no significant differences when the measurements were performed at the first molar ( P=0.06), the third molar ( P=0.47) and in the area of the ascending mandibular ramus ( P=0.79). Compared with a population of healthy test subjects, patients who had their third molars surgically removed show higher signal intensity increases in the neurovascular bundle after intravenous contrast agent administration. The underlying cause may be the higher blood flow in the arteries and veins and the perineural plexus, which may give evidence of the pathophysiological mechanism of nerve damage in the narrow canal as a result of osteotomy. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether it is possible to measure tooth vitality using magnetic resonance imaging (MRI). Methods: Signal intensity measurements were conducted using T1 and T2 sequences at the region of interest in 211 teeth (35 patients). Results: Clinical findings showed that 17.3% of the teeth were avital, whereas 82.7% were found to be vital. Neither the T2 sequence nor the non-contrast-enhanced T1 sequence showed significant differences between vital and avital teeth. However, the contrast-enhanced sequence and, in particular, a comparison of signal intensities between the non-contrast-enhanced T1 sequence and the contrast-enhanced sequence showed a significant difference between vital and avital teeth. Conclusion: Contrast-enhanced MRI enables us to draw conclusions on pulpal perfusion in vivo. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. The renal medullary region is particularly vulnerable to reduced oxygen concentration because of its low blood perfusion and high basal oxygen consumption. This study investigated renal metabolic changes in relation to the previously observed decreased oxygen tension in streptozotocin-induced diabetic rats. Methods. Blood perfusion, oxygen tension and consumption, interstitial pH, and glycolytic and purine-based metabolites were determined in the renal cortex and the medulla of non-diabetic and diabetic animals by, respectively, laser Doppler flowmetry, oxygen and pH microelectrodes, and microdialysis. The importance of increased polyol pathway activity for the observed alterations was investigated by daily treatment with the aldose reductase inhibitor AL-1576 throughout the course of diabetes. Results. The diabetes-induced decrease in renal oxygen tension, due to augmented oxygen consumption, did not result in manifest hypoxia in either the cortical or the medullary region, as evaluated by microdialysis measurements of purine-based metabolites. The profound alterations in medullary oxygen metabolism were, however, associated with an increased lactate : pyruvate ratio and a concomitantly decreased pH. Notably, the renal medullary changes in oxygen tension, oxygen consumption, lactate : pyruvate ratio and pH were preventable by inhibition of aldose reductase. Conclusions/interpretation. Substantial metabolic changes were observed in the renal medulla in diabetic animals. These disturbances seemed to be mediated by increased polyol pathway activity and could be prevented by inhibition of aldose reductase. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Augmented formation of reactive oxygen species (ROS) induced by hyperglycaemia has been suggested to contribute to the development of diabetic nephropathy. This study was designed to evaluate the influence of streptozotocin (STZ)-induced diabetes mellitus, as well as the effects of preventing excessive ROS formation by α-tocopherol treatment, on regional renal blood flow, oxygen tension and oxygen consumption in anaesthetized Wistar Furth rats. Methods. Non-diabetic and STZ-diabetic rats were investigated after 4 weeks with or without dietary treatment with the radical scavenger DL-α-tocopherol (vitamin E, 5%). A laser-Doppler technique was used to measure regional renal blood flow, whilst oxygen tension and consumption were measured using Clark-type microelectrodes. Results. Renal oxygen tension, but not renal blood flow, was lower throughout the renal parenchyma of diabetic rats when compared to non-diabetic control rats. The decrease in oxygen tension was most pronounced in the renal medulla. Renal cellular oxygen consumption was markedly increased in diabetic rats, predominantly in the medullary region. Diabetes increased lipid peroxidation and protein carbonylation in the renal medulla. Treatment with α-tocopherol throughout the course of diabetes prevented diabetes-induced disturbances in oxidative stress, oxygen tension and consumption. The diabetic animals had a renal hypertrophy and a glomerular hyperfiltration, which were unaffected by α-tocopherol treatment. Conclusions/interpretation. We conclude that oxidative stress occurs in kidneys of diabetic rats predominantly in the medullary region and relates to augmented oxygen consumption and impaired oxygen tension in the tissue. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of the contrast medium (CM) iopromide on renal microcirculation and oxygen tension in non-diabetic control and streptozotocin-diabetic Wistar Furth rats.Materials and Methods: Oxygen tension was measured with Clark-type microelectrodes and blood flow with laser-Doppler flow probes. In order to differentiate between an acutely increased blood glucose concentration and a long-term diabetic state, some of the non-diabetic control rats were intravenously infused with glucose.Results: CM decreased the medullary oxygen tension in control (non-diabetic normoglycemic) rats ( approximately 35%) but not in diabetic rats. Medullary blood flow in control rats increased after CM administration and remained elevated, while it was unchanged in the diabetic rats. In response to CM, glucose-infused control rats responded similarly to control animals in medullary oxygen tension, but similarly to diabetic rats in medullary blood flow. Contrary to in control rats, medullary oxygen tension was unchanged in diabetic animals after CM administration.Conclusion: Streptozotocin-diabetic rats have an altered response to intravenous injection of the CM iopromide compared to non-diabetic rats. The unaltered medullary oxygen tension, seen in the diabetic group after injection of CM, suggests that non-hemodynamic mechanisms are responsible for the increased frequency of renal failure commonly seen among diabetic patients. [ABSTRACT FROM AUTHOR]

Purpose: Renal vasoconstriction with resultant tissue hypoxia, especially in the renal medulla, has been suggested to play a role in contrast media (CM)-induced nephropathy. Endothelin (ET) is released into the blood stream following CM injection and has been proposed as a potential mediator through its vasoconstrictive properties. Material and Methods: To investigate the possible protective influence of ET-receptor antagonists against CM-induced reduction in renal function, we studied the effects of injection of iopromide with and without pretreatment with BQ123 (ET-A antagonist) or BQ788 (ET-B antagonist) on renal superficial cortical flow (CBF), outer medullary blood flow (OMBF) and outer medullary oxygen tension (pO2) in normal rats. Results: Administration of CM (1600 mg I/kg b.w.) did not affect CBF in any of the groups. However, a transient decrease in OMBF occurred, which was unaffected by both BQ123 and BQ788. Also a transient decrease in outer medullary pO2 was induced by CM administration. The pO2 reduction was significantly smaller after pretreatment with BQ123, than after injection of CM alone or together with BQ788, and pO2 returned more rapidly to the control level. Neither receptor antagonist had an effect on CM-mediated increases in electrolyte excretion. Conclusion: In the normal rat, activation of ET-A receptors is partly involved in the depression of outer medullary pO2 caused by injection of iopromide. However, the decrease in OMBF after iopromide injection is not mediated by ET receptors. The beneficial effects of the ET-A receptor antagonist on CM-induced changes in outer medullary pO2 seem therefore not primarily mediated on the hemodynamic level but may rather involve tubular transport mechanisms. [ABSTRACT FROM AUTHOR]

In this study, we syngeneically transplanted islets to three different implantation sites of diabetic and nondiabetic rats, then 9-12 weeks later we measured the blood perfusion and compared the tissue partial pressure of oxygen (PO2) levels of these transplanted islets to endogenous islets. Modified Clark microelectrodes (outer tip diameter 2-6 microm) were used for the oxygen tension measurements, and islet transplant blood perfusion was recorded by laser-Doppler flowmetry (probe diameter 0.45 mm). The islet graft blood perfusion was similar in all islet grafts, irrespective of the implantation site. In comparison, the three implantation organs (the kidney cortex, liver, and spleen) differed markedly in their blood perfusion. There were no differences in islet graft blood perfusion between diabetic and nondiabetic recipients. Within native pancreatic islets, the mean PO2 was approximately 40 mmHg; however, all transplanted islets had a mean PO2 of approximately 5 mmHg. The oxygen tension of the grafts did not differ among the implantation sites. In diabetic recipients, an even lower PO2 level was recorded in the islet transplants. We conclude that the choice of implantation site seems less important than intrinsic properties of the transplanted islets with regard to the degree of revascularization and concomitant blood perfusion. Furthermore, the mean PO2 level in islets implanted to the kidney, liver, and spleen was markedly decreased at all three implantation sites when compared with native islets, especially in diabetic recipients. These results are suggestive of an insufficient oxygenization of revascularized transplanted islets, irrespective of the implantation site. [ABSTRACT FROM AUTHOR]

The author discusses the study on renal oxygenation during haemorrhage which is not by angiotensin II (AngII). He mentions the discontinuation of pre-operative process of angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI) whic h is recommended prevent perioperative complications. It also mentions the increase of sympathetic nervous system activation in AngII and kidney renin.

Describes several studies about market dynamics and innovation. Relationship between market structure and innovation activity; Role of rivalry in fostering innovations; Role of market transparency in the competition between financial markets.

Comments on the works of Alogoskoufis et al. (1997), McCauley and White (1997) and Pagano (1997) on the position of the euro in relationship with likely developments in European financial markets. Theoretical framework; Potential of the euro as an international currency; Competitions in European-based financial institutions; Brief account of similar studies and publications.

This study investigates the determinants of individual unemployment and jobsearch duration and the size and direction of duration dependence in a proportional hazard model. New insights into the shape of the time dependence of unemployment duration are obtained using a semi-parametric baseline hazard specification in combination with a parametric (gamma) heterogeneity correction or with a semi-parametric heterogeneity correction. Registration data on unemployed individuals in The Netherlands in the period April 1987-May 1987 are used. For both sexes, the hazard rate quickly rises during the first five months, but then after the fifth month rapidly declines until the end of the first year of unemployment, not showing any clear tendency thereafter. Commonly used parametric specifications for the baseline hazard prove to be too restrictive. For men we discuss the influences of the regressors. [ABSTRACT FROM AUTHOR]

We consider the dynamic regression model with lagged endogenous variables and moving average disturbances, when some observations on the endogenous variable are missing. The available data are assumed to be sampled at regular intervals of length m and can be linear combinations of the realizations of the variable over a finite number of periods. We discuss the identification of the parameters in the model. For some selected models, we evaluate the large sample variances of the maximum likelihood (ML) estimates for the incomplete data and complete data respectively. In this way, we get an indication of the loss of information when the data are incomplete. Finally, we give some results for the effects on the properties of the OLS estimator, when interpolated series are substituted for the missing observations and we briefly discuss ways to obtain ML estimates. Our general conclusion is that when the sample is incomplete it is very important to use all available reliable a priori information to analyze the model. [ABSTRACT FROM AUTHOR]

This article forecasts the growth rate of real output for eight European Economic Community countries and the U.S. using pooled international data. It has long been recognized that national economies are economically interdependent. Recognition of such interdependence raise the question of whether such interdependence can be exploited economically to produce improved forecasts of countries' macroeconomic variables such as rates of growth of output, and so forth. There are several alternative approaches to the problem of obtaining improved international macroeconomic forecasts. There is the approach of Project Link that attempts to link together elaborate structural models of national econometric model. Analysis of simple models for the rates of growth of output for various countries provides benchmark forecasting performance against which other models' performance can be judged. There are many different pooling models. The article is interested in finding the extent to which use of various pooling models result in improved forecasting performance relative to that of naive models and of single equation models implemented just with individual countries of European community.

We use a model-based approach to derive quarterly figures on several variables for the aggregate labor market in the Netherlands that are only observed annually. These approximations are conditional expectations derived from univariate and bivariate quarterly time series models for the series under consideration. They are subsequently used as proxies to estimate and analyze the structural labor market equations. Attention is given to the properties of estimation procedures based on proxy variables. [ABSTRACT FROM AUTHOR]

In this paper, we report some results on the exact significance level when the usual F-statistic is used in a linear regression model with autocorrelated disturbances. The exact tail area probabilities sometimes differ substantially from the nominal size used in an 'F-test' and from upper-bound probabilities derived by Kiviet (1979) which do not depend on the values of the regressors. A similar conclusion is also reached for the exact size of the significance tests for the spurious regressions considered by Granger and Newbold (1974, 1977). The results indicate once more that one has to be careful when using an algebraic F-test in the presence of autoregressive errors. However then too, the Durbin-Watson test is expected to indicate the presence of autocorrelation. [ABSTRACT FROM AUTHOR]

We present a numerically convenient procedure for computing Wald criteria for nested hypotheses. Similar to Szroeter's (1983) generalized Wald test, the suggested procedure does not require explicit derivation of the restrictions implied by the null hypothesis and hence its use might eliminate an intricate step in testing linear and nonlinear hypotheses. We show that the traditional Wald test, Szroeter's (1983) generalized Wald test and our procedure are asymptotically equivalent under H. A class of nonlinear transformations of the restrictions for which the Wald statistic is asymptotically invariant is discussed. Finally, we illustrate the use of our procedure for testing the common factor restrictions in a dynamic regression model. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging is not established in the preoperative diagnosis of mandibular cystic lesions; therefore, no attempts have been made thus far to evaluate the course of the mandibular neurovascular bundle along the process. However, the radiologist can detect the neurovascular bundle along the cystic lesion by high-resolution MR imaging and convey this information to the maxillofacial surgeon. This reduces the risk of intraoperative damage of the nerve. The examination of the neurovascular bundle can easily be integrated in a tumor MRI protocol of the jaw if the slice orientation is adapted to the course of the mandibular canal. [ABSTRACT FROM AUTHOR]

The autho reflects on the research conducted by J. B. Heimlich and colleagues which investigates the potential role of endothelin-1 (ET-1) to treat kidney diseases. Topics discussed include a description of the effect of high salt intake on the kidney, the limited effect of conventional treatment methods, and an assessment of the clinical trials involving the use of ET-1 to treat the disease.