Corticomedullary shunting after ischaemia and reperfusion in the porcine kidney?

BACKGROUND: Renal perfusion may redistribute from cortex to medulla during systemic hypovolaemia and after renal ischaemia for other reasons, but there is no consensus on this matter. We studied renal perfusion after renal ischaemia and reperfusion. METHODS: Renal perfusion distribution was examined by use of 153Gadolinium-labeled microspheres (MS) after 2 h (hrs) and 4 h ischaemia of the pig kidney followed by 4 h of reperfusion. Intra-arterial injected MS are trapped in the glomeruli in renal cortex, which means that MS are not present in the medulla under normal physiological conditions. RESULTS: Visual evaluation after reperfusion demonstrated that MS redistributed from the renal cortex to the medulla in 6 out of 16 pigs (38%) subjected to 4 h ischaemia and in one out of 18 pigs subjected to 2 h ischaemia. Central renal uptake of MS covering the medullary/total renal uptake was significantly higher in kidneys subjected to 4 h ischaemia compared with pigs subjected to 2 h ischaemia (69 ± 5% vs. 63 ± 1%, p < 0.001), and also significantly higher than in the contralateral kidney (69 ± 5% vs. 63 ± 2%, p < 0.001). Analysis of blood and urine demonstrated no presence of radioactivity. CONCLUSION: The study demonstrated the presence of MS in the renal medulla in response to renal ischaemia and reperfusion suggesting that severe ischaemia and reperfusion of the pig kidney leads to opening of functional shunts bypassing glomeruli.

Imaging the myocardium at risk with 99mTc-lactadherin administered after reperfusion in a porcine model.

INTRODUCTION: Phosphatidylserine is translocated from the inner to the outer leaflet of the plasma membrane in the early stages of apoptosis and necrosis and in reversibly injured cells. In rabbit hearts, ischemia followed by reperfusion results in exposure of phosphatidylserine on myocytes unaffected by apoptosis or necrosis. Lactadherin was recently introduced as a highly sensitive phosphatidylserine ligand. We hypothesized that ischemic myocardial cell damage can be identified by radio-labeled lactadherin and that the ischemic area at risk (AAR) can be visualized retrospectively after reperfusion. METHODS: Left anterior descending coronary artery in pigs was occluded for 20 minutes, 45 minutes or 45 minutes preceded by ischemic preconditioning. In all three groups, (99m)Tc-lactadherin was injected intravenously 30 minutes after reperfusion. The AAR was demarcated by Evans blue and the infarct size by 2,3,5,-triphenyltetrazodium chloride staining. RESULTS: The regional myocardial uptake of (99m)Tc-lactadherin closely correlated with the AAR (r=.83, P = .001). The area of (99m)Tc-lactadherin uptake was unaltered by a shorter duration of ischemia and ischemic preconditioning (P=.23) despite significantly different infarct development (P=.001). CONCLUSION: The results suggest that (99m)Tc-lactadherin can be used as a sensitive marker for AAR imaging when injected 30 minutes after reperfusion following acute ischemia.

Mediastinal staging in Non-Small-Cell Lung Carcinoma: computed tomography versus F-18-fluorodeoxyglucose positron-emission tomography and computed tomography.

BACKGROUND: After the diagnosis Non-Small-Cell Lung Carcinoma (NSCLC) has been established, consideration must turn toward the stage of disease, because this will impact directly on management and prognosis. Staging is used to predict survival and to guide the patient toward the most appropriate treatment regimen or clinical trial. Distinguishing malignant involvement of the mediastinal lymph nodes (N2 or N3) from the hilar lymph nodes, or no lymph nodes (N0 or N1) is critical, because malignant involvement of N2 or N3 lymph nodes usually indicates non-surgically resectable disease. The purpose of this study was to examine and compare CT versus integrated F18-FDG PET/low dose CT (FDG PET/CT) for mediastinal staging in NSCLC, and the desire was to safely distinguish between malignant and benign lesions without the need for invasive procedures. All results were controlled for reproducibility. METHODS: 114 participants with NSCLC were included in a prospective cohort study. Blinded CT and FDG PET/CT images were reviewed. The participants' mediastinums were staged based on lymph node sizes (CT), or on FDG uptake (FDG PET/CT). Reference standard was tissue sampling. RESULTS: We found that there was no measureable difference between CT and FDG PET/CT mediastinal staging results; overall two-thirds of the participants in the study were correctly staged, and almost one-third of the participants were falsely staged. CONCLUSION: Neither CT nor FDG PET/CT could obviate the need for further invasive staging prior to thoracotomy in patients with NSCLC; for that purpose, the results of both modalities were too meagre. Therefore, these patients still depend on invasive staging methods. In our study, invasive staging was accomplished by mediastinoscopy. However, today this is increasingly replaced by EBUS or EUS.

Cell injury after ischemia and reperfusion in the porcine kidney evaluated by radiolabelled microspheres, sestamibi, and lactadherin.

BACKGROUND: The purpose of the present study was to quantify renal cell injury after ischemia and reperfusion in a pig model using (99m)Tc-lactadherin as a marker of apoptosis and (99m)Tc-sestamibi as a marker of mitochondrial dysfunction. METHODS: Thirty-four pigs were randomized into unilateral renal warm ischemia of 120 (WI120) or 240 min (WI240). The glomerular filtration rate (GFR) was calculated by renal clearance of (51)Cr-ethylenediaminetetraacetic acid, and apoptosis was quantified by immunohistochemical detection of caspase-3. After 240 min of reperfusion, intravenous (99m)Tc-lactadherin or (99m)Tc-sestamibi was injected simultaneously with (153)Gd microspheres into the aorta. Ex-vivo static planar images of the kidneys were acquired for determination of the differential renal function of tracer distribution using a gamma camera. RESULTS: In WI120, there was no significant difference in the uptake of microspheres in the ischemic and contralateral normal kidney indicating adequate perfusion (uptake in ischemic kidney relative to the sum of uptake in both kidneys; 46% ± 12% and 51% ± 5%). In WI240, the uptake of microspheres was severely reduced in both groups (17% ± 11% and 27% ± 17%). GFR was severely reduced in the post ischemic kidney in both groups. In both groups, the uptake of lactadherin was reduced (41% ± 8%, 17% ± 13%) but not different from the uptake of (153)Gd microspheres. Caspase-3-positive cell profiles were increased in the post-ischemic kidneys (p < 0.001) and increased as the length of ischemia increased (p = 0.003). In both WI120 and WI240, the amount of (99m)Tc-sestamibi in the ischemic kidney was significantly lower than the amount of (153)Gd microspheres (40 ± 5 versus 51 ± 5 and 20 ± 11 versus 27 ± 17; p < 0.05). CONCLUSIONS: In an established pig model with unilateral renal warm ischemia, we found significantly reduced (99m)Tc-sestamibi uptake relative to perfusion in the kidneys exposed to ischemia indicating a potential ability to detect renal ischemic and reperfusion injuries. However, apoptosis was not detected using (99m)Tc-lactadherin in the post-ischemic kidneys despite increased number of caspase-3-positive cell profiles. TRIAL REGISTRATION: This study is approved by the Danish Inspectorate of Animal Experiments (2010/561-1837).

Reliability of endogenous markers for estimation of residual renal function in haemodialysis patients.

BACKGROUND: Residual renal function in haemodialysis patients is of increasing interest. However, reproducibility and agreement between methods to measure and estimate glomerular filtration rate (GFR) require further elucidation. The aim of this study was to evaluate the accuracy and reproducibility of GFR estimates based on endogenous markers in haemodialysis patients. METHODS: Twelve patients were examined twice. GFR was estimated by (i) urine clearances of creatinine, urea and the average of creatinine and urea clearance [U-Cl(crea-urea)]; (ii) an equation based on serum concentration of cystatin C [eGFR(CysC)]. These were compared to (51) Cr-EDTA clearance in plasma [P-Cl(EDTA)] and urine [U-Cl(EDTA)]. RESULTS: U-Cl(crea-urea) produced results similar to U-Cl(EDTA). eGFR(CysC) had a low week-to-week variability. Visually, eGFR(CysC) differed from y = x when compared to the other methods indicating bias, probably due to extrarenal elimination of cystatin C. Coefficients of variation were significantly different, P<0·001: P-Cl(EDTA), 10%; U-Cl(EDTA), 13%; and U-Cl(crea-urea), 13%. P-Cl(EDTA) was 2·1 ml min(-1) 1·73 m(-2) higher than U-Cl(EDTA) (mean). CONCLUSIONS: Glomerular filtration rate in haemodialysis patients can be estimated from U-Cl(crea-urea) when complete urine collection is performed. The available eGFR(CysC) in haemodialysis patients seemed to be biased, and further development and validation is desirable. P-Cl(EDTA) was the most reproducible method and might be useful in special situations.

Pharmacokinetics of the phosphatidylserine tracers 99mTc-lactadherin and 99mTc-annexin V in pigs.

BACKGROUND: Phosphatidylserine (PS) is a phospholipid normally located in the inner leaflet of the cell membrane. PS is translocated from the inner to the outer leaflet of the plasma membrane during the early stages of apoptosis and in necrosis. In cell and animal studies, reversible PS externalisation to the outer membrane leaflet has been observed in viable cells. Hence, PS markers have been proposed as markers of both reversibly and irreversibly damaged cells. The purpose of this experimental study in pigs was to investigate the kinetics of the newly introduced PS marker technetium-99m-labelled lactadherin (99mTc-lactadherin) in comparison with the well-known PS tracer 99mTc-annexin V with special reference to the renal handling of the tracers. The effective dose for humans was estimated from the biodistribution in 24 mice. METHODS: Nine anaesthetised pigs randomly allocated into two treatment groups were administered a single injection of either 99mTc-lactadherin or 99mTc-annexin V. Renal perfusion was assessed by simultaneous injection of 51Cr-EDTA. Throughout the examinations, planar, dynamic scintigraphy of the trunk was performed, urine was collected and arterial and renal vein blood was sampled. The effective dose was estimated using the adult male phantom from the RADAR website. RESULTS: 99mTc-lactadherin was cleared four times faster from plasma than 99mTc-annexin V, 57 ± 13 ml/min (mean ± SD) versus 14 ± 2 ml/min. 99mTc-lactadherin had a predominant uptake in the liver, whereas 99mTc-annexin V was primarily taken up by the kidneys. The estimated effective human dose after single injection of 99mTc-lactadherin and 99mTc-annexin V was 5.8 and 11 µSv/MBq, respectively. CONCLUSIONS: The high hepatic uptake of 99mTc-lactadherin compromises the use of 99mTc-lactadherin for imaging PS externalisation in the liver. Due to scatter from the liver, the use of in vivo visualisation of PS externalisation in the lower thorax and upper abdomen by 99mTc-lactadherin is challenged, but not precluded. In contrast to 99mTc-annexin, 99mTc-lactadherin has a low renal uptake and may be the preferred tracer for imaging PS externalisation in the kidneys. The effective dose after injection of 99mTc-lactadherin and 99mTc-annexin was low. Recommendations regarding the clinical use of 99mTc-lactadherin must await tracer kinetic studies in patients.

Endogenous markers for estimation of renal function in peritoneal dialysis patients.

OBJECTIVE: This method comparison study, conducted at the peritoneal dialysis (PD) outpatient clinic of the Department of Renal Medicine, Aarhus University Hospital, Denmark, set out to evaluate the accuracy and reproducibility of methods for estimating glomerular filtration rate (GFR) based on endogenous markers in PD patients. PATIENTS: The 12 consecutive patients included in the study were examined twice while in a stable condition. All patients finished the study. Inclusion criteria were age 18 years or older, ability to collect 24-hour urine, and urine production greater than 300 mL in 24 hours. MAIN OUTCOME MEASURES: The methods for estimating GFR using endogenous markers included the average of urinary clearances of creatinine and urea [U-Cl(crea-urea)] and two equations using the serum concentration of cystatin C [eGFR(CysC)]. The resulting GFR estimates were compared with those obtained using urinary and corrected plasma clearances of (51)Cr-EDTA [U-Cl(EDTA) and cP-Cl(EDTA)], the corrected plasma clearance being plasma clearance minus dialysate clearance. RESULTS: Compared with the U-Cl(EDTA), the U-Cl(crea-urea) GFR estimate was 12% higher [95% confidence limits (CL): 3%, 21%]. Although significantly different (p = 0.01), the latter two methods showed the best agreement. The estimates obtained using the eGFR(CysC) methods were skewed from y = x compared with the estimates obtained using other methods, indicating strong bias, probably because of extrarenal elimination. The cP-Cl(EDTA) estimate was 34% (95% CL: 26%, 42%), higher than the U-Cl(EDTA) estimate (p < 0.001). The reproducibility (coefficients of variation) differed significantly between methods: cP-Cl(EDTA), 7%; U-Cl(EDTA), 14%; U-Cl(crea-urea), 18%; and both eGFR(CysC) methods, 3%. CONCLUSIONS: In PD patients, GFR may be estimated as U-Cl(crea-urea) when complete urine collection is performed, taking into account an overestimation of approximately 12%. The available equations for eGFR(CysC) seem to be inaccurate; further development and validation is desirable. Omitting the eGFR(CysC) methods, cP-Cl(EDTA) was the most reproducible method and might be useful in certain situations.

Renal uptake of 99mTc-dimercaptosuccinic acid is dependent on normal proximal tubule receptor-mediated endocytosis.

UNLABELLED: (99m)Tc-labeled dimercaptosuccinic acid ((99m)Tc-DMSA) accumulates in the kidney cortex and is widely used for imaging of the renal parenchyma. Despite its extensive clinical use, the mechanism for renal targeting of the tracer is unresolved. Megalin and cubilin are cooperating receptors essential to the proximal tubule endocytic uptake of proteins from the glomerular ultrafiltrate. We have used megalin/cubilin-deficient mice produced by gene knockout to determine whether receptor-mediated endocytosis is responsible for the renal uptake of (99m)Tc-DMSA. METHODS: Control or megalin/cubilin-deficient mice were injected intravenously with 0.5 MBq of (99m)Tc-DMSA or (99m)Tc-mercaptoacetyltriglycine (MAG3). Whole-body scintigrams and the activity in plasma, urine, and the kidneys were examined 6 h after injection. The size and identity of (99m)Tc-DMSA-bound proteins in urine were analyzed by fractionation by centrifugation and separation by sodium dodecyl sulfate polyacrylamide gel electrophoresis, followed by autoradiography and mass spectrometry. RESULTS: No renal accumulation of (99m)Tc-DMSA was identified in scintigrams of megalin/cubilin-deficient mice. The renal accumulated activity of the tracer was reduced to 11.4% (± 2.5%, n = 7) of the normal uptake in control mice, correlating with a reduction in renal megalin/cubilin expression in knockout mice to about 10% of normal. The reduced renal uptake in megalin/cubilin-deficient mice was accompanied by an increase in the urinary excretion of (99m)Tc-DMSA. Size separation of the urine by ultracentrifugation and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that in megalin/cubilin-deficient mice an increased amount of (99m)Tc-DMSA was excreted in an approximately 27-kDa form, which by mass spectrometry was identified as the plasma protein α1-microglobulin, an established megalin/cubilin ligand. CONCLUSION: (99m)Tc-DMSA is filtered bound to α1-microglobulin and accumulates in the kidneys by megalin/cubilin-mediated endocytosis of the (99m)Tc-DMSA protein complex. Renal accumulation of (99m)Tc-DMSA is thus critically dependent on megalin/cubilin receptor function and therefore is a marker of proximal tubule endocytic activity.

Characterization of pulmonary lesions in patients with suspected lung cancer: computed tomography versus [¹8F] fluorodeoxyglucose-positron emission tomography/computed tomography.

Pulmonary nodules are of high clinical importance, given they may prove to be an early manifestation of lung cancer. Pulmonary nodules are small, focal, radiographic opacities that may be solitary or multiple. A solitary pulmonary nodule is a single, small (<-30 mm in diameter) opacity. Larger opacities are called masses and are often malignant. As imaging techniques improve and more nodules are detected, the optimal management of pulmonary nodules remains unclear. However, the question of malignancy of any given nodule remains the same. A standard contrast-enhanced computed tomography (CT) scan is often the first examination, followed by a number of other examinations. The purpose of this study was to examine the clinical feasibility of CT versus integrated [18F]fluorodeoxyglucose-positron emission tomography (PET)/low-dose CT scan in patients with suspected lung cancer and pulmonary lesions on CT. All results were controlled for reproducibility. We found that when used early in the work-up of the lesions, CT raised the prevalence of lung cancer in the population to the point where further diagnostic imaging examination could be considered futile. We also found that the overall diagnostic accuracy, as well as the classification probabilities and predictive values of the two modalities were not significantly different; the reproducibility of these results was substantial.

Monitoring renal function during chemotherapy.

PURPOSE: Renal function is monitored during chemotherapy because chemotherapeutic drugs are excreted by the kidneys and are potentially nephrotoxic. Doses are adjusted according to the glomerular filtration rate (GFR), i.e. the more reduced the GFR, the lower the treatment dose. Plasma clearance of (51)Cr-EDTA is a reliable indicator of GFR before and during treatment with potentially nephrotoxic drugs, but its measurement is costly. GFR can also be estimated using an algorithm that converts plasma creatinine concentration to GFR, e.g. the MDRD equation. The aim of this investigation was to evaluate the reliability of estimated GFR (eGFR) in detecting changes in GFR as assessed by the MDRD equation in cancer patients treated with nephrotoxic chemotherapeutic drugs. METHODS: We included all patients from the Department of Oncology undergoing chemotherapy who were referred to the Department of Nuclear Medicine for measurement of GFR by the (51)Cr-EDTA plasma clearance technique at least four times during the study period of 12 months. The eGFR was calculated from plasma creatinine concentration and the MDRD formula. GFR was determined by the (51)Cr-EDTA plasma clearance method. RESULTS: In 48 patients with a mean age of 47 years, GFR decreased from 86 to 73 ml/min/1.73 m(2) (mean values, p < 0.002) from the first to the last measurement, whereas plasma creatinine concentration and eGFR remained unchanged. In 13 patients (27 %) the finding of a decreased GFR led to adjustment of the dose of the chemotherapy drug. Eight of the 13 patients with decreased GFR also had a reduced eGFR but five patients had a normal eGFR. These five patients would have been treated with the nephrotoxic drug at a dose that was too high. CONCLUSION: Neither creatinine plasma concentration nor eGFR (MDRD) can be recommended as a replacement for measurement of GFR with the (51)Cr-EDTA plasma clearance method in patients treated with nephrotoxic cytostatic drugs.

Estimating risk of pulmonary neoplastic embolism during vertebroplasty.

STUDY DESIGN: Vertebroplasty was simulated on a pig model. OBJECTIVE: To evaluate the risk of neoplastic tissue migration into lungs during vertebroplasty. SUMMARY OF BACKGROUND DATA: The application of vertebroplasty in spinal metastasis is not well documented. The risk of neoplastic tissue migration into the lungs during vertebroplasty remains unknown. METHODS: A cancer model was built in 11 Landrace pigs (50 kg) by injecting 99mTc-labeled albumin macroaggregates into the center of L5 and L6 prior to vertebroplasty. Continuous scintigraphic imaging was performed with 1-minute frames over the lungs and vertebrae before and after injection to ensure steady state and baseline. We surveyed free TcO4- in thyroid. Twenty minutes after the 99mTc injection, 2-level vertebroplasty was performed at L5 and L6 with 3 Jamshidi needles in each vertebra. Into each vertebra, on average, 2.8 ± 1.1 mL of poly(methyl methacrylate) cement (Depuy CMW, Blackpool, UK) was injected. Quantitative scintigrams were obtained within 90 minutes after vertebroplasty. X-rays and quantitative computed tomography scans quantified cement distribution. Means of 99mTc activity before and after vertebroplasty were compared in a paired t test. RESULTS: In this cancer model, we found an 80% risk of tissue migration to the lungs when performing vertebroplasty. In average, the study showed a significant amount of macroaggregate migration of 1.87% total range from 0% to 8% (CI: 0.05%-0.37%) with P = 0.045. There was no free TcO4- in the thyroid. Despite the standardized procedure, we found a large interindividual variation of pulmonary embolism. CONCLUSION: It is demonstrated that there exists a significant risk of exporting neoplastic disease or fatty tissue to the lungs when performing vertebroplasty. A similar adverse effect can be expected with balloon kyphoplasty. In patients with metastatic disease, vertebroplasty should be limited to those with short life expectancy.

Reliability of 5¹Cr-EDTA plasma and urinary clearance as a measure of residual renal function in dialysis patients.

PURPOSE: In dialysis patients, longer survival is associated with a higher residual renal function. Randomized controlled trials are conducted to clarify how residual renal function can be preserved. However, existing methods for measuring residual renal function are uncertain and there is a need for establishing a standard for measurements of glomerular filtration rate (GFR) in dialysis patients. METHODS: 5¹Cr-EDTA clearances in plasma, urine, and dialysate were evaluated in a sample of 12 hemodialysis and 12 peritoneal dialysis patients. The patients' condition was generally stable, and all patients were investigated twice within 4-10 days. RESULTS: Plasma clearances of 5¹Cr-EDTA for all patients ranged between 2.1 and 30.8 mL/min/1.73 m², whereas urinary 5¹Cr-EDTA clearances ranged from 0.7-20.0 mL/min/1.73 m². This difference was statistically significant (p < 0.001). Week-to-week reproducibility expressed as coefficients of variation were below or equal to 10% for plasma clearances and 13% for urinary clearances in hemodialysis patients and 14% in peritoneal dialysis patients. CONCLUSIONS: This study demonstrated a difference between 5¹Cr-EDTA plasma and urinary clearances in dialysis patients. Plasma clearance of 5¹Cr-EDTA had the best reproducibility. For repeated measurements as in clinical prospective trials, we recommend 5¹Cr-EDTA plasma clearance based on blood sampling at 5 + 24 hours with subtraction of 5¹Cr-EDTA dialysate clearance in peritoneal dialysis patients. Further studies are needed to corroborate our findings.

Postreperfusion myocardial technetium-99m-sestamibi defect corresponds to area at risk: experimental results from an ischemia-reperfusion porcine model.

INTRODUCTION: Technetium-99m-sestamibi (MIBI) is the most frequently used myocardial perfusion tracer in patients with ischemic heart disease. In patients with acute ST-elevation myocardial infarction, we previously found that the defect in myocardial MIBI uptake was the same in patients injected with MIBI before primary angioplasty and in patients injected immediately after successful treatment. Thus, reperfusion may not be followed by increased uptake of MIBI. Instead, the MIBI defect after reperfusion may reflect the area at risk (AAR) defined by MIBI injected before treatment. We intended to investigate whether myocardial imaging with MIBI administered after reperfusion reflects myocardial perfusion or rather the ischemic AAR. METHODS: In 12 pigs, left anterior descending coronary artery was totally occluded for 45 min with an angioplasty balloon. After a 2-h reperfusion, MIBI was injected intravenously, and (153)Gd-microspheres were injected in left atrium. AAR and infarct size (IS) were determined by histochemical staining. MIBI and microsphere distribution were evaluated by counting the sliced left ventricle on a gamma camera. Defects were defined as uptake less than 45% of maximum uptake. RESULTS: The mean±S.D. defect size as a fraction of left ventricle was for MIBI 21%±5.5%, AAR 25%±6.3%, IS 13%±3.9% and microspheres defect size 7.3%±5.5%. MIBI defect size overestimated IS (P=.0005) and microspheres defect size (P=.0001), but it was not significantly different from AAR (P=.30). CONCLUSION: In a porcine model of myocardial infarction after 45 min of ischemia, MIBI administered 120 min after reperfusion delineates AAR.

The α-MSH analogue AP214 attenuates rise in pulmonary pressure and fall in ejection fraction in lipopolysaccharide-induced systemic inflammatory response syndrome in pigs.

BACKGROUND: The effect of an α-melanocyte stimulating hormone (α-MSH) analogue (AP214) on experimentally endotoxin-induced systemic inflammatory response syndrome (SIRS) was studied, because α-MSH in rodent models has shown promise in attenuating inflammatory response markers and associated organ damage in SIRS. SIRS is associated with considerable morbidity and mortality. Consequently, new treatment modalities are still warranted to address the different aspects of the pathophysiological process. METHODS: SIRS was induced by lipopolysaccharide (LPS) (Escherichia coli endotoxin) infusion in anaesthetized Danish Landrace pigs (20-25 kg). The pigs received an α-MSH analogue (AP214) or saline as a bolus at the initiation of the LPS infusion. The hemodynamic response was registered as well as echocardiographic indices of left ventricular function. RESULTS: The cardiovascular response was recorded together with echocardiographic indices of left ventricular function in control and in intervention animals. AP214 reduced the early peak in pulmonary pressure and pulmonary vascular resistance by approximately 33%. Furthermore, AP214 prevented the decline in left ventricular fractional shortening as observed in the control group. Mean change and standard deviation in fractional shortening (ΔFS) in control group: - 7·3 (4·7), AP214 (low dose): 0·9 (8·2) and AP214 (high dose) 4·1 (6·0), P < 0·05 for both intervention groups versus control. CONCLUSIONS: In the porcine model, the peak increase in pulmonary pressure was attenuated, and the LPS-induced decline in left ventricular function was prevented.

Visualizing the impact of prevalence on a diagnostic test.

The purpose of a diagnostic test is to confirm or rule out disease or to increase or decrease the probability of disease. Only a few tests can separate all patients into those with and without a disease (true positive and true negative test). Usually there will be some false test results (false positive and false negative). Traditionally, the four test results are given in a 2 by 2 table, and the terms sensitivity, specificity, and predictive values defined. The influence of the prevalence of the disease in question on the relative distribution of the four test results is not obvious. This technical note brings a new illustration of the relative distribution of the four test results at prevalence from 0-1. The figure facilitates the understanding of the impact prevalence has on the predictive values of a clinical test.

Biodistribution of 99mTc-HYNIC-lactadherin in mice--a potential tracer for visualizing apoptosis in vivo.

INTRODUCTION: The aim of this study was to establish a radio synthesis of (99m)Tc-HYNIC-lactadherin for in vivo studies and to perform biodistribution analysis studies in mice, comparing (99m)Tc-HYNIC-lactadherin to (99m)Tc-HYNIC-annexin V. METHODS: The radiochemical purity of (99m)Tc-HYNIC-lactadherin was optimized by varying the amount of SnCl(2) in the synthesis. Furthermore, the need for bovine serum albumin (BSA) as a stabilizing agent was evaluated by following the stability by radiochemical purity measurement with and without the addition of BSA. A total of 24 mice were assigned to groups of 15 and nine mice, respectively. The animals were sacrificed at different time points; 10 min, 60 min, and 180 min. RESULTS: The synthesis of (99m)Tc-HYNIC-lactadherin for in vivo studies has been optimized to give a stable product without addition of BSA and with a radiochemical purity of more than 95%. Approximately 60% of the injected dose of (99m)Tc-HYNIC-lactadherin was found in the liver and 4-5% could be assigned to kidneys. In contrast, (99m)Tc-HYNIC-annexin V distributes with around 13% and 45% of the injected dose in liver and kidneys, respectively. Over the experimental period (10-180 min) only small distributional changes were observed for both probes. CONCLUSION: In conclusion, the biodistribution of (99m)Tc-HYNIC-lactadherin, a potential new tracer for in vivo quantification of apoptosis, was evaluated. The small renal uptake of (99m)Tc-HYNIC-lactadherin makes it possible to image apoptosis in the kidneys, but the high liver clearance may be a disadvantage during myocardial perfusion.

Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial.

BACKGROUND: Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty. We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infarction, and done before primary percutaneous coronary intervention, increases myocardial salvage. METHODS: 333 consecutive adult patients with a suspected first acute myocardial infarction were randomly assigned in a 1:1 ratio by computerised block randomisation to receive primary percutaneous coronary intervention with (n=166 patients) versus without (n=167) remote conditioning (intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff). Allocation was concealed with opaque sealed envelopes. Patients received remote conditioning during transport to hospital, and primary percutaneous coronary intervention in hospital. The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment; analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00435266. FINDINGS: 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index. Median salvage index was 0.75 (IQR 0.50-0.93, n=73) in the remote conditioning group versus 0.55 (0.35-0.88, n=69) in the control group, with median difference of 0.10 (95% CI 0.01-0.22; p=0.0333); mean salvage index was 0.69 (SD 0.27) versus 0.57 (0.26), with mean difference of 0.12 (95% CI 0.01-0.21; p=0.0333). Major adverse coronary events were death (n=3 per group), reinfarction (n=1 per group), and heart failure (n=3 per group). INTERPRETATION: Remote ischaemic conditioning before hospital admission increases myocardial salvage, and has a favourable safety profile. Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes. FUNDING: Fondation Leducq.