How much time is enough? Sentinel lymph node mapping time depends on the radiotracer agent.

BACKGROUND: In 2014, technetium-99m tilmanocept (TcTM) replaced technetium-99m sulfur colloid (TcSC) as the standard lymphoscintigraphy (LS) mapping agent in melanoma patients undergoing sentinel lymph node biopsy (SLNB). The aim of this study was to examine differences in mapping time, intra-operative identification of sentinel lymph node (SLN), and false negative rate (FNR) between patients who underwent SLNB with TcTM compared to TcSC. METHODS: Patients who underwent SLNB between 2010 and 2018 were retrospectively identified. Patient demographic, tumor, and imaging data was stratified by receipt of TcSC (n = 258) or TcTM (n = 133). Student's t test and χ2 test were used to compare characteristics and outcomes. RESULTS: Both cohorts were similar in demographic, primary tumor characteristics, and total number of SLN identified (TcTM 3.56 vs. TcSC 3.28, p = 0.244). TcTM was associated with significantly shorter LS mapping times (51.8 vs. 195.1 min, p < 0.01). There was no significant difference in the number of patients with positive SLN (TcTM 11.3 vs. TcSC 17.4%, p = 0.109) and the FNR was similar between both groups (TcTM 25% vs. TcSC 22%). CONCLUSION: TcTM was associated with significantly shorter LS mapping time while identifying similar numbers of SLN. Our results support further study to ensure similar FNR and oncologic outcomes between agents.

Repeatability of glomerular filtration rate studies performed using 99mTc-DTPA in a population including cancer patients.

OBJECTIVE: Glomerular filtration rate (GFR) measurement remains an integral investigation in clinical practice and is particularly important in the prediction and follow-up of renal side-effects of nephrotoxic chemotherapy in cancer patients. Knowing the coefficient of variation (CV) of a test is vital for the correct interpretation of serial studies. Recent difficulties with 51Cr-EDTA availability have renewed interest in 99mTc-DTPA, but there is a paucity of data on the test-retest variability of this radiopharmaceutical. Furthermore, the authors are unaware of published repeatability data in cancer patients. The aim of this study was to determine the CV of repeat 99mTc-DTPA GFR measurements in a clinical patient population that included cancer patients. METHODS: Patients who had undergone ≥2 GFR studies at our department between January 2009 and December 2019 were retrospectively identified. Patients with chronic kidney disease and those who had received chemotherapy, radiotherapy or surgery between measurements were excluded. The CV for each patient was calculated and the mean CVs of cancer and prospective renal donor groups were calculated and compared. RESULTS: Fifty-four patients were included in the final analysis. The mean CV in the cancer group (38 patients) was 8.5% [95% confidence interval (CI) 6.9-10.2%] and in the renal donor group (16 patients) 7.1% (95% CI 4.2-10.1%). These figures did not differ significantly (P = 0.37). The groups were combined to calculate the final overall mean CV of 8.1% (95% CI 6.7-9.6%). CONCLUSION: In both non-cancer and cancer patients the CV of GFR studies performed with 99mTc-DTPA was comparable with mostly 51Cr-EDTA figures presented in literature.

In vivo deposition study of a new generation nebuliser utilising hybrid resonant acoustic (HYDRA) technology.

Conventional nebulisation has the disadvantages of low aerosol output rate and potential damage to macromolecules due to high shear (jet nebulisation) or cavitation (ultrasonic nebulisation). HYDRA (HYbriD Resonant Acoustics) technology has been shown to overcome these problems by using a hybrid combination of surface and bulk sound waves to generate the aerosol droplets. We report the first in vivo human lung deposition study on such droplets. Twelve healthy adult subjects inhaled saline aerosols radiolabelled with technetium-99 m complexed with diethylene triamine penta-acetic acid (99mTc-DTPA). The distribution of the aerosolised droplets in the lungs was imaged by single photon emission computed tomography combined with low dose computed tomography (SPECT/CT). The volume median diameter and geometric standard deviation of the droplets were 1.32 ± 0.027 µm and 2.06 ± 0.040, respectively. The mean delivery efficiency from the nebuliser into the body was 51.2%. About 89.1 ± 4.3% and 2.3 ± 1.4% of the inhaled radiolabelled dose deposited in the lungs and oropharynx, respectively. The deposition was symmetrical and diffusive between the two lungs, with a mean penetration index of 0.82. Thus, the prototype HYDRA nebuliser showed excellent in vivo aerosol deposition performance, demonstrating its potential to be further developed for clinical applications.

[99mTc]Tilmanocept Lymphscintigraphy after inconclusive [99mTc]Nanocolloid Scan in Breast Cancer.

Lymphatic mapping for identification and subsequent removal of the sentinel lymph node (SLN) is an established procedure in breast cancer and cutaneous melanoma to minimize the extent of surgery (and thus, associated morbidity), simplify histopathological processing and subsequently provide prognostic information and help choose the optimal patient management. Established methods for SLN mapping include visual identification of nodal staining after peritumoral injection of a (blue) dye or the use of lymphoscintigraphy with technetium-labelled nanocolloid. In experienced hands, success rates for both methods exceed 95 %, nonetheless in some patients they fail despite correct application and imaging techniques. Potential reasons for false-negative SLN detection rates -beyond poor tracer injection technique or imaging of the wrong nodal basin- include inadequate pathologic examination of the SLN or complete replacement of the SLN with neoplastic disease, causing the injected tracer to completely bypass the infiltrated node 1.Beyond colloid particles, the more specific receptor-targeting small molecule [99mTc]Tilmanocept has recently been approved for scintigraphic SLN detection. Tilmanocept, or mannosyl diethylene-triamine-pentaacetate (DTPA) dextran, has a small molecular size of approximately 7 nm and works via specific binding to the mannose receptor (CD206) 2. The mannose receptor is particularly overexpressed on macrophages and dendritic precursor cells within lymph nodes, thus uptake in lymph nodes is not dependent on particle size 2, 3. In pilot studies scintigraphic SLN detection with [99mTc]Tilmanocept was superior to dye staining 4. Given its beneficial properties, [99mTc]Tilmanocept might offer advantages over the alternatively used radiocolloids. We present four cases of [99mTc]Tilmanocept application after inconclusive or unsuccessful attempts of SLN detection using [99mTc]nanocolloid lymphoscintigraphy.

Physiological uptake and retention of radiolabeled resveratrol loaded gold nanoparticles (99mTc-Res-AuNP) in colon cancer tissue.

When tagged with a suitable radionuclide, the cancer targeting properties of trans-resveratrol could be utilized to locate cancerous sites in the body using radionuclide imaging technique. However, the polyphenol due to its rapid and extensive metabolism exhibits low bioavailability in vivo. The study was designed to enhance the cancer targeting efficacy of radiolabeled resveratrol using nano-based technology. Technetium-99m labeled resveratrol loaded gold nanoparticles (Res-AuNP) were synthesized, characterized and evaluated for their cancer targeting efficacy in HT29 colon cancer cells and in animal cancer model. Results of various investigations were compared to corresponding results obtained for 99mTc-AuNP and 99mTc-resveratrol. Cancer cell internalization observed for 99mTc-Res-AuNP was significantly higher than that of 99mTc-AuNP and 99mTc-resveratrol. Also, a gradual rise in target to nontarget uptake with time was observed following i.v. administration of 99mTc-Res-AuNP to colon tumor bearing rats, demonstrating better in vivo targeting of colon adenocarcinoma with 99mTc-Res-AuNP when compared to 99mTc-resveratrol.

Preoperative maximal removal rate of technetium-99m-galactosyl-human serum albumin of the remnant liver is associated with postoperative tumor relapse in hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND: Prognosis in patients with hepatocellular carcinoma (HCC) is not only influenced by tumor-related factors but also by the background liver functions. The maximal removal rate of technetium-99m-galactosyl human serum albumin (GSA-Rmax) of the remnant liver (rGSA-Rmax) is a useful candidate for predicting the liver function and clarifying the relationship between the remnant liver functional reserve and tumor-free survival in patients who have undergone hepatectomy. PATIENTS AND METHODS: One hundred and sixty-five patients with HCC who underwent curative hepatectomy were divided into three groups of hepatitis B virus (B-HCC; n=42), hepatitis C virus (C-HCC, n=58), and non-B, non-C (NBNC-HCC, n=65). The relationship between rGSA-Rmax and survival was examined by univariate and multivariate analyses. RESULTS: In the C-HCC group, the albumin, or LHL15, level was significantly lower, and alanine aminotransferase, ICGR15, and the prevalence of grade B liver damage were significantly higher than other two groups (P<0.05). GSA-Rmax or rGSA-Rmax was not different between the three groups. Lower GSA-Rmax and rGSA-Rmax were only significantly associated with lower tumor-free survival in the C-HCC group by the univariate analysis (P<0.05) but not significantly by the multivariate analysis. CONCLUSION: GSA-Rmax and rGSA-Rmax reflect the severity of liver dysfunction and furthermore, the lower rGSA-Rmax is useful as a complementary factor to predict the early HCC recurrence after hepatectomy.

SPECT-CT Comparison of Lung Deposition using a System combining a Vibrating-mesh Nebulizer with a Valved Holding Chamber and a Conventional Jet Nebulizer: a Randomized Cross-over Study.

PURPOSE: To compare in vivo the total and regional pulmonary deposition of aerosol particles generated by a new system combining a vibrating-mesh nebulizer with a specific valved holding chamber and constant-output jet nebulizer connected to a corrugated tube. METHODS: Cross-over study comparing aerosol delivery to the lungs using two nebulizers in 6 healthy male subjects: a vibrating-mesh nebulizer combined with a valved holding chamber (Aerogen Ultra®, Aerogen Ltd., Galway, Ireland) and a jet nebulizer connected to a corrugated tube (Opti-Mist Plus Nebulizer®, ConvaTec, Bridgewater, NJ). Nebulizers were filled with diethylenetriaminepentaacetic acid labelled with technetium-99 m (99mTc-DTPA, 2 mCi/4 mL). Pulmonary deposition of 99mTc-DTPA was measured by single-photon emission computed tomography combined with a low dose CT-scan (SPECT-CT). RESULTS: Pulmonary aerosol deposition from SPECT-CT analysis was six times increased with the vibrating-mesh nebulizer as compared to the jet nebulizer (34.1 ± 6.0% versus 5.2 ± 1.1%, p < 0.001). However, aerosol penetration expressed as the three-dimensional normalized ratio of the outer and the inner regions of the lungs was similar between both nebulizers. CONCLUSIONS: This study demonstrated the high superiority of the new system combining a vibrating-mesh nebulizer with a valved holding chamber to deliver nebulized particles into the lungs as comparted to a constant-output jet nebulizer with a corrugated tube.

γ-Tilmanocept, a New Radiopharmaceutical Tracer for Cancer Sentinel Lymph Nodes, Binds to the Mannose Receptor (CD206).

γ-Tilmanocept ((99m)Tc-labeled-tilmanocept or [(99m)Tc]-tilmanocept) is the first mannose-containing, receptor-directed, radiolabeled tracer for the highly sensitive imaging of sentinel lymph nodes in solid tumor staging. To elucidate the mannose-binding receptor that retains tilmanocept in this microenvironment, human macrophages were used that have high expression of the C-type lectin mannose receptor (MR; CD206). Cy3-labeled tilmanocept exhibited high specificity binding to macrophages that was nearly abolished in competitive inhibition experiments. Furthermore, Cy3-tilmanocept binding was markedly reduced on macrophages deficient in the MR by small interfering RNA treatment and was increased on MR-transfected HEK 293 cells. Finally, confocal microscopy revealed colocalization of Cy3-tilmanocept with the macrophage membrane MR and binding of labeled tilmanocept to MR(+) cells (macrophages and/or dendritic cells) in human sentinel lymph node tissues. Together these data provide strong evidence that CD206 is a major binding receptor for γ-tilmanocept. Identification of CD206 as the γ-tilmanocept-binding receptor enables opportunities for designing receptor-targeted advanced imaging agents and therapeutics for cancer and other diseases.

Delayed renal tissue tracer transit in Tc-99m-DTPA renography correlates with postoperative renal function improvement in UPJO patients.

OBJECTIVE: The aim of the study was to explore the potential parameters for evaluating the improvement in relative renal function (RRF) in patients with unilateral ureteropelvic junction obstruction (UPJO) who underwent surgery. In this regard we observed the RRF expressed as the obstructed kidney's percentage contribution to overall renal function in technetium-99m diethylenetriaminepentaacetic acid (Tc-99m-DTPA) diuretic renography. MATERIALS AND METHODS: Data on 47 patients, who underwent Anderson-Hynes pyeloplasty for diagnosed unilateral UPJO during the period of February 2003 to October 2014, were retrospectively collected. Tc-99m-DTPA diuretic renography was performed on all patients before and after surgery, and no morphological or functional abnormalities were detected on the contralateral kidney. Several parameters, especially renal tissue tracer transit (TTT), the response to furosemide stimulation, and RRF, were evaluated. All data were analyzed with the statistical software SPSS, 17.0, and a value of P less than 0.05 was considered statistically significant. RESULTS: Data on 42 patients were eventually retained for further analysis; five patients were excluded because of indeterminate TTT. All patients showed obstructive response to furosemide stimulation with a preoperative RRF of 41±12%. Postoperative RRF of the obstructed kidneys was 47±11%, significantly higher than the preoperative RRF (P<0.05). Postoperative RRF improvement (absolute increment≥5%) was seen in 18/42 (43%) patients, and 24/42 (57%) of them manifested with postoperative drainage improvement. After surgery, both the RRF increment and the percentage of patients with postoperative RRF improvement in the preoperative delayed TTT group were significantly higher than those in the normal TTT group (12±7 vs. 2±4%, and 81 vs. 19%, respectively; P<0.05), but no significant difference in postoperative drainage improvement was detected between the two groups (56 vs. 54%, P>0.05). None of the other factors, including the preoperative RRF, obstructed kidney location, surgical method, sex, and age, had a significant influence on postoperative RRF improvement (P>0.05). CONCLUSION: Preoperatively delayed TTT of Tc-99m-DTPA diuretic renography was an independent factor that correlated with RRF improvement of unilaterally hydronephrotic kidneys, and might provide valuable information for surgical decisions pertaining to UPJO patients.

Removal of body surface area normalisation improves raw-measured glomerular filtration rate estimation by the Chronic Kidney Disease Epidemiology Collaboration equation and drug dosing in the obese.

BACKGROUND/AIM: We aimed to compared estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), with (mL/min/1.73 m(2) ) and without body surface area (BSA) normalisation (CKD-EPI_noBSA, mL/min) against measured (99m) Technetium - diethylenepentaacetic acid (Tc-DTPA GFR) (mL/min) in 222 individuals, including 80 with malignancy. METHODS: BSA was calculated for each individual using the Du Bois equation. The CKD-EPI and CKD-EPI_noBSA equations were compared with measured Tc-DTPA GFR with respect to bias, proportion within 30% of GFR (P30) and root mean square error for predicting levels of GFR, and concordance in relation to carboplatin dosing. RESULTS: The mean (SD) for BSA and measured GFR for the entire group was 1.99 (0.25) m(2) and 127 (41) mL/min respectively. The P30 for Tc-DTPA GFR was significantly higher with the CKD-EPI_noBSA (80%) than with the CKD-EPI equation (63%, P = 0.0001). In those with body mass index (BMI) > 30 kg/m(2) , the P30 values for the CKD-EPI_noBSA and CKD-EPI were 74% and 42% respectively (P < 0.0001). Carboplatin dosing concordance for the cancer patients using the CKD-EPI and CKD-EPI_noBSA equation was 71% and 56% respectively (P = 0.07). In 78 individuals with BMI > 30 kg/m(2) , concordance in relation to carboplatin dosing using CKD-EPI_noBSA was 65% compared with 26% with the CKD-EPI (P < 0.0001). CONCLUSION: The CKD-EPI without normalisation (CKD-EPI_noBSA) equation was superior to the CKD-EPI equation in estimating raw-measured Tc-DTPA GFR (mL/min).

[Assessment of hepatic reserve function of cirrhosis liver using dynamic SPECT (99m)Tc-galactosyl human serum albumin scintigraphy].

OBJECTIVE: To evaluate the effectiveness of dynamic SPECT (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy on the assessment of reserve function of cirrhosis liver. METHODS: From January 2010 to December 2011, 55 patients with cirrhosis liver were enrolled in this study. The case numbers of male and female were 43 and 12 respectively and the age was (51 ± 9) years (ranging from 35 to 69 years). After routine biochemistry test, CT scan and (99m)Tc-GSA dynamic SPECT scan were performed in turn using a juxtaposed SPECT/CT system. Then the morphologic volume of liver parenchyma (MLV), functional liver volume (FLV) and the hepatic cell absorption rate constant (GSA-K) were calculated. The correlations between GSA-K and routine biochemistry test, Child-Pugh score, indocyanine green clearance rate (ICG-K) were analyzed. The patients were further divided into 3 groups according to whether there was occlusion or stenosis in the main branch of left portal vein (group 1, n = 5), right portal vein (group 2, n = 13) or not (group 3, n = 37) and the regional hepatic functions index of the 3 groups were compared. RESULTS: The value of FLV of the whole, left and right liver was (594 ± 152) ml, (244 ± 119) ml and (356 ± 171) ml, respectively. There were correlations between GSA-K and total bilirubin, prothrombintime, Child-Pugh score and ICG-K (r = -0.730--0.298, P < 0.05). The FLV and MLV ratios of involved hemiliver to uninvolved hemiliver were 0.09 ± 0.06 and 0.30 ± 0.14 in group 1, 0.57 ± 0.43 and 1.08 ± 0.63 in group 2, 0.71 ± 0.30 and 0.71 ± 0.48 in group 3. The difference in MLV-FLV ratio was signifcant between group 1 and group 3, between group 2 and group 3 (P = 0.000). CONCLUSIONS: The dynamic SPCECT (99m)Tc-GSA scintigraphy can not only assess the whole liver function of cirrhosis liver effectively, but also evaluate the variation of regional liver function accurately.

Correlation of various published radionuclide glomerular filtration rate estimation techniques and proposed paediatric normative data.

OBJECTIVE: The aim of this study is to assess the comparability and interchangeability of the radionuclide glomerular filtration rate (GFR) using different published techniques, and propose normative data for paediatrics. METHODS: A total of 476 paediatric oncology patients aged 2-17 years, referred between January 2001 and December 2008 for GFR estimation, were reviewed for any potential cause of renal impairment. Sixty-nine patients met the stringent inclusion criteria, and were included in the study. GFR estimation was carried out using either technetium-99m diethylene triamine penta-acetic acid (99mTc-DTPA) or chromium-51 EDTA (5¹Cr-EDTA). Multiple GFR results were calculated from the same blood sample data (counts/min/ml), according to previously published GFR estimation techniques using one to three blood samples. These techniques were slope-intercept, slope-only and half life. For slope-intercept techniques, GFR was normalized to body surface area or extracellular fluid volume. RESULTS: The GFR values obtained using different techniques were highly variant. The intraclass correlation (ICC) for different methods was moderate (ICC=0.56-0.66). A reliable empiric formula to allow conversion of GFR values from one technique to another could not be derived because of this variability, with some exceptions. 5¹Cr-EDTA yielded the same or lower variability than 99mTc-DTPA. The British Nuclear Medicine Society-recommended method had the lowest coefficient of variation, with a mean value of 116 (SD 22) normalized to 1.73 m² for 5¹Cr-EDTA using two samples. CONCLUSION: The GFR values obtained from different calculation techniques are not readily interchangeable or comparable, with some exceptions. For both 99mTc-DTPA and 5¹Cr-EDTA, the British Nuclear Medicine Society-recommended technique appears to be the most robust, with the least coefficient of variation.

[Role of single-photon emission computer tomography in dynamic evaluation of combined treatment of malignant cerebral glioma].

Thirty-nine patients with malignant glioma of the brain were examined at the Center's Clinic. Tumor volume ranged 0.8-175.1 cu cm. Radionuclide diagnosis was obtained with the aid of single-photon emission tomography (E.Cam, Siemens). 99mTc-DTPA, 3-6 MBc/body, was injected intravenously. Smaller size of tumor and lower ratio of differentiated marker accumulation focus/contralateral area were registered in 34%. Simultaneously, a high index of the marker accumulation in the brain was reported, thus suggesting hyperimpermeability of the blood brain barrier. Another 26% revealed larger size of tumor and higher ratio of differentiated 99mTc-DTPA accumulation, likely due to lower impermeability of the blood brain barrier. Hence, use of single-photon emission tomography in diagnosis of malignant cerebral glioma provides a means of evaluating the level of the marker in a tumor node.

Usefulness of Tc-99m-GSA scintigraphy for liver surgery.

Postoperative mortality remains high after hepatectomy compared with other types of surgery in patients who have cirrhosis or chronic hepatitis. Although there are several useful perioperative indicators of liver dysfunction, no standard markers are available to predict postoperative liver failure in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. The best preoperative method for evaluating the hepatic functional reserve of patients with HCC remains unclear, but technetium-99m diethylenetriamine pentaacetic acid galactosyl human serum albumin ((99m)Tc-GSA) scintigraphy is a candidate. (99m)Tc-GSA is a liver scintigraphy agent that binds to the asialoglycoprotein receptor, and can be used to assess the functional hepatocyte mass and thus determine the hepatic functional reserve in various physiological and pathological states. The maximum removal rate of (99m) Tc-GSA (GSA-Rmax) calculated by using a radiopharmacokinetic model is correlated with the severity of liver disease. There is also a significant difference of GSA-Rmax between patients with chronic hepatitis and persons with normal liver function. Regeneration of the remnant liver and recurrence of hepatitis C virus infection in the donor organ after living donor liver transplantation have also been investigated by (99m)Tc-GSA scintigraphy. This review discusses the usefulness of (99m)Tc-GSA scintigraphy for liver surgery.

Cystatin C is a reliable marker for estimation of glomerular filtration rate in renal transplantation: validation of a new turbidimetric assay using monospecific sheep antibodies.

BACKGROUND: The potential use of cystatin C was recently assessed in kidney transplantation. A new particle-enhanced turbidimetric immunoassay (PETIA) that uses sheep antibodies (Binding Site human cystatin C immunoassay) has been developed. Analytical performance of this new assay was evaluated. Clinical relevance was determined by comparison with a reference method in a cohort of kidney transplant patients. METHODS: First, the analytical performance of the Binding Site cystatin C kit was tested on SPA(PLUS)® and Hitachi® analyzers. Second, a comparison study was performed using SPA(PLUS)® analyzer against two other cystatin C methods (the Siemens-PENIA method on BNII® and the Dako-PETIA application on Olympus AU640®). Third, the glomerular filtration rate (GFR) was estimated using several predictive cystatin C- and creatinine-based equations and compared to GFR measured by an isotopic method (99(m)Tc-DTPA). These predictive algorithms were analyzed with respect to bias, precision and accuracy. RESULTS: Total intra-assay and inter-assay coefficients of variation were below 5%. Values obtained with the SPA(PLUS)® correlated with the Siemens-PENIA and the Dako-PETIA methods. The creatinine and cystatin C-based equation allowed reliable assessment of GFR in our population of renal transplantation. CONCLUSIONS: The use of algorithms based on cystatin C and creatinine could provide a reliable estimate of GFR in kidney transplantation.

Lung epithelial permeability and inhaled furosemide: added dimensions in asthmatics.

OBJECTIVE: Lung clearance rates of inhaled (99m)Tc-DTPA aerosols constitute a sensitive index to evaluate the permeability changes characteristic of airway epithelial damage. It was thought that edema of the airway wall which is reported in asthma could be relieved with a diuretic like furosemide, helping to relieve the symptoms. We intended to study the effect of inhaled furosemide on lung epithelial permeability in asthmatics and smokers with the help of (99m)Tc-DTPA lung clearance test (LCT). METHODS: The study included three groups (n = 15), viz. normal healthy controls, asymptomatic chronic smokers, and chronic persistent asthmatics. Each subject underwent the LCT twice, baseline and post-furosemide (Lasix) study, within a week's interval. The post-furosemide study was carried out 15 min after inhalation of 10 mg of lasix. Lung epithelial permeability was determined in terms of clearance half-life (T (1/2)). RESULTS: The baseline mean T (1/2) values for controls, smokers, and asthmatics were 50.95 +/- 16.58, 20.81 +/- 5.47, 24.06 +/- 6.19 min, respectively. Post-lasix T (1/2) values were 50.83 +/- 15.84, 20.70 +/- 5.65, 41.27 +/- 15.07 min, respectively. There was a significant difference (P < 0.001) in baseline and post-lasix clearance values in asthmatics only. CONCLUSION: Baseline lung epithelial permeability was altered in smokers and asthmatics compared to the controls. Furosemide was effective only in asthmatics in reverting the permeability almost back to the normal range. Inhaled furosemide was effective even in moderate and severe asthmatics. Furosemide has multiple mechanisms of action. It possibly acts at bronchial level in view of the pathology in asthmatics lying in the airways.

Effects of ambient air particulate exposure on blood-gas barrier permeability and lung function.

Particulate air pollution is associated with increased risk of pulmonary diseases and detrimental outcomes related to the cardiovascular system, including altered vessel functions. This study's objective was too evaluate the effects of ambient particle exposure on the blood-gas permeability, lung function and Clara cell 16 (CC16) protein release in healthy young subjects. Twenty-nine nonsmokers participated in a randomized, two-factor crossover study with or without biking exercise for 180 min and with 24-h exposure to particle-rich (6169-15,362 particles/cm(3); 7.0-11.6 microg/m(3) PM(2.5); 7.5-15.8 microg/m(3) PM(10-2.5)) or filtered (91-542 particles/cm(3)) air collected above a busy street. The clearance rate of aerosolized (99m)Tc-labeled diethylenetriamine pentaacetic acid ((99m)Tc-DTPA) was measured as an index for the alveolar epithelial membrane integrity and permeability of the lung blood-gas barrier after rush-hour exposure. Lung function was assessed using body plethysmography, flow-volume curves, and measurements of the diffusion capacity of carbon monoxide. CC16 was measured in plasma and urine as another marker of alveolar integrity. Particulate matter exposure had no significant effect on the epithelial membrane integrity using the methods available in this study. Exercise increased the clearance rate of (99m)Tc-DTPA indicated by a 6.8% (95% CI: 0.4-12.8%) shorter half-life and this was more pronounced in men than women. Neither particulate matter exposure nor exercise had an effect on the concentration of CC16 in plasma and urine or on the static and dynamic volumes or ventilation distribution of the lungs. The study thus demonstrates increased permeability of the alveolar blood-gas barrier following moderate exercise, whereas exposure to ambient levels of urban air particles has no detectable effects on the alveolar blood-gas barrier or lung function.

Molecular imaging of alpha v beta3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA.

AIMS: The integrin alpha v beta3 is highly expressed in atherosclerotic plaques by medial and intimal smooth muscle cells and by endothelial cells of angiogenic microvessels. In this study, we have assessed non-invasive molecular magnetic resonance imaging (MRI) of plaque-associated alpha v beta3 integrin expression on transgenic ApoE-/- mice with a low molecular weight peptidomimetic of Arg-Gly-Asp (mimRGD) grafted to gadolinium diethylenetriaminepentaacetate (Gd-DTPA-g-mimRGD). The analogous compound Eu-DTPA-g-mimRGD was employed for an in vivo competition experiment and to confirm the molecular targeting. The specific interaction of mimRGD conjugated to Gd-DTPA or to 99mTc-DTPA with alpha v beta3 integrin was furthermore confirmed on Jurkat T lymphocytes. METHODS AND RESULTS: The mimRGD was synthesized and conjugated to DTPA. DTPA-g-mimRGD was complexed with GdCl3.6H2O, EuCl3.6H2O, or with [99mTc(CO)3(H2O)3]+. MRI evaluation was performed on a 4.7 T Bruker imaging system. Blood pharmacokinetics of Gd-DTPA-g-mimRGD were assessed in Wistar rats and in c57bl/6j mice. The presence of angiogenic blood vessels and the expression of alpha v beta3 integrin were confirmed in aorta specimens by immunohistochemistry. Gd-DTPA-g-mimRGD produced a strong enhancement of the external structures of the aortic wall and of the more profound layers (possibly tunica media and intima). The aortic lumen seemed to be restrained and distorted. Pre-injection of Eu-DTPA-g-mimRGD diminished the Gd-DTPA-g-mimRGD binding to atherosclerotic plaque and confirmed the specific molecular targeting. A slower blood clearance was observed for Gd-DTPA-g-mimRGD, as indicated by a prolonged elimination half-life and a diminished total clearance. CONCLUSION: The new compound is potentially useful for the diagnosis of vulnerable atherosclerotic plaques and of other pathologies characterized by alpha v beta3 integrin expression, such as cancer and inflammation. The delayed blood clearance, the significant enhancement of the signal-to-noise ratio, and the low immunogenicity of the mimetic molecule highlight its potential for an industrial and clinical implementation.

Modulation of bronchial epithelial cell barrier function by in vitro jet propulsion fuel 8 exposure.

The loss of epithelial barrier integrity in bronchial and bronchiolar airways may be an initiating factor in the observed onset of toxicant-induced lung injuries. Acute 1-h inhalation exposures to aerosolized jet propulsion fuel 8 (JP-8) have been shown to induce cellular and morphological indications of pulmonary toxicity that was associated with increased respiratory permeability to 99mTc-DTPA. To address the hypothesis that JP-8 jet fuel-induced lung injury is initiated through a disruption in the airway epithelial barrier function, paracellular mannitol flux of BEAS-2B human bronchial epithelial cells was measured. Incubation of confluent cell cultures with non-cytotoxic concentrations of JP-8 or n-tetradecane (C14), a primary constituent of JP-8, for a 1-h exposure period resulted in dose-dependent increases of paracellular flux. Following exposures of 0.17, 0.33, 0.50, or 0.67 mg/ml, mannitol flux increased above vehicle controls by 10, 14, 29, and 52%, respectively, during a 2-h incubation period immediately after each JP-8 exposure. C14 caused greater mannitol flux increases of 37, 42, 63, and 78%, respectively, following identical exposure conditions. The effect on transepithelial mannitol flux reached a maximum at 12 h and spontaneously reversed to control values over a 48-h recovery period, for both JP-8 and C14 exposure. These data indicate that non-cytotoxic exposures to JP-8 or C14 exert a noxious effect on bronchial epithelial barrier function that may preclude pathological lung injury.

Effects of hydrogen peroxide on the guinea-pig tracheobronchial mucosa in vivo.

Lumenal entry of plasma (mucosal exudation) is a key feature of airway inflammation. In airways challenged with histamine-type mediators and allergen the mucosal exudation response occurs without causing epithelial derangement and without increased airway absorption. In contrast, reactive oxygen metabolites may cause mucosal damage. In this study, involving guinea-pig airways, we have examined effects of H2O2 on airway exudation and absorption in vivo. Vehicle or H2O2 (0.1 and 0.5 M) was superfused onto the tracheobronchial mucosal surface through an oro-tracheal catheter. 125I-albumin, given intravenously, was determined in tracheobronchial tissue and in lavage fluids 10 min after challenge as an index of mucosal exudation of plasma. The tracheobronchial mucosa was also examined by scanning electron microscopy. In separate animals, 99mTc-DTPA was superfused 20 min after vehicle or H2O2 (0.1 and 0.5 M) had been given. A gamma camera determined the disappearance rate of 99mTc-DTPA from the airways as an index of airway absorption. The high dose of H2O2 (0.5 M) produced epithelial damage, increased the absorption of 99mTc-DTPA (P < 0.001), and increased the exudation of plasma (P < 0.001). Notably, it appeared that all extravasated plasma had entered the airway lumen within 10 min. These data demonstrate that H2O2 differs from exudative autacoids such as histamine by causing both epithelial damage and plasma exudation responses. These data also agree with the view that the epithelial lining determines the rate of absorption and is responsible for the valve-like function that allows lumenal entry of extravasated bulk plasma without any increased inward perviousness.