Distribution of extravascular fluid volumes in isolated perfused lungs measured with H215O.

The distributions per unit volume of extravascular water (EVLW), blood volume, and blood flow were measured in isolated perfused vertical dog lungs. A steady-state tracer technique was employed using oxygen-15, carbon-11, and nitrogen-13 isotopes and external scintillation counting of the 511-KeV annihilation radiation common to all three radionuclides. EVLW, and blood volume and flow increased from apex to base in all preparations, but the gradient of increasing flow exceeded that for blood and EVLW volumes. The regional distributions of EVLW and blood volume were almost identical. With increasing edema, lower-zone EVLW increased slightly relative to that in the upper zone. There was no change in the distribution of blood volume or flow until gross edema (100% wt gain) occurred when lower zone values were reduced. In four lungs the distribution of EVLW was compared with wet-to-dry ratios from lung biopsies taken immediately afterwards. Whereas the isotopically measured EVLW increased from apex to base, the wet-to-dry weight ratios remained essentially uniform. We concluded that isotopic methods measure only an "exchangeable" water pool whose volume is dependent on regional blood flow and capillary recruitment. Second, the isolated perfused lung can accommodate up to 60% wt gain without much change in the regional distribution of EVLW, volume, or flow.

Porous inverse vulcanised polymers for mercury capture.

Supercritical carbon dioxide is used to generate macroporosity in an inverse vulcanised polymer, which shows excellent promise for enhanced mercury capture and filtration from water.

Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography.

BACKGROUND: Atherosclerotic plaque rupture is usually a consequence of inflammatory cell activity within the plaque. Current imaging techniques provide anatomic data but no indication of plaque inflammation. The glucose analogue [18F]-fluorodeoxyglucose (18FDG) can be used to image inflammatory cell activity non-invasively by PET. In this study we tested whether 18FDG-PET imaging can identify inflammation within carotid artery atherosclerotic plaques. METHODS AND RESULTS: Eight patients with symptomatic carotid atherosclerosis were imaged using 18FDG-PET and co-registered CT. Symptomatic carotid plaques were visible in 18FDG-PET images acquired 3 hours post-18FDG injection. The estimated net 18FDG accumulation rate (plaque/integral plasma) in symptomatic lesions was 27% higher than in contralateral asymptomatic lesions. There was no measurable 18FDG uptake into normal carotid arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas of the plaque. CONCLUSIONS: This study demonstrates that atherosclerotic plaque inflammation can be imaged with 18FDG-PET, and that symptomatic, unstable plaques accumulate more 18FDG than asymptomatic lesions.

Recruitment of patients into an internet-based clinical trials database: the experience of OncoLink and the National Colorectal Cancer Research Alliance.

PURPOSE: In March 2001, the National Colorectal Cancer Research Alliance (NCCRA) and OncoLink (http://www.oncolink.org) established a database to facilitate patient enrollment onto clinical trials. This study describes the population registering with the database and identifies discrepancies between individuals registering through the Internet and those registering through a telephone call center. METHODS: Participants registered with the NCCRA/OncoLink database through the Internet or a telephone call center. All participants entering the database completed a questionnaire regarding basic demographics, colon cancer risk factors, and indicated how they became aware of the database. Comparisons were made between individuals registering through the Internet and those registering through the telephone call center. RESULTS: A total of 2,162 participants registered during the first 16 months of the database. Most patients registered through the Internet rather than the telephone call center (88% v 12%; P < .001). More females than males registered (73% v 27%; P < .001). The majority (89%) were white. Participants registering through the Internet were younger than those registering through the call center (mean, 48.8 v 55.0 years; P < .001). There was no difference between the two groups with regard to sex or ethnicity. CONCLUSION: The Internet has the potential to increase the likelihood that interested individuals find appropriate clinical trials. Some of the discrepancies that are known to exist for access to the Internet were also seen for those registering with the database through the Internet. Despite these differences, the potential to increase clinical trial enrollment with this type of Internet-based database is high.

Comparison of estimates of cardiac output by indicator dilution and freon 22 uptake during gas mixing in dogs.

STUDY OBJECTIVE: The aim was to measure cardiac output while rebreathing tidal volumes, by correction of soluble gas uptake for gaseous mixing. DESIGN: Simultaneous measurements of cardiac output by indocyanin green and freon 22 uptake during rebreathing were made. Mixing for a hypothetical gas of identical gaseous diffusivity to freon 22 was calculated by interpolation between concentrations of two insoluble gases, helium and sulphur hexafluoride. Mixing efficiency was estimated by the number of breaths for helium to become 99% equilibrated with lung gas (n99-He). EXPERIMENTAL MATERIAL: Five anaesthetised dogs rebreathed at intervals with 300 ml of test gas. MEASUREMENTS AND MAIN RESULTS: 63 comparisons of cardiac output using indocyanin green and freon 22 uptake (over breaths 7-13 using the mean mixed volume of distribution), gave a mean (95% confidence interval) underestimation of 0.345 (0.093-0.597) litre.min-1 (14%). Exclusion of 12 points in which n99-He was greater than 15 resulted in a mean underestimation of 0.052(-0.163-0.267) litre.min-1 (2%). Without correction for gaseous mixing, freon 22 uptake for these data overestimated blood flow by a mean of 1.31 litre.min-1 (overestimation = 2.7 over breaths 5-11). Use of the equilibrium volume of distribution resulted in an overestimation of blood flow relative to green dye of 1.2 litre.min-1 (breaths 5-11) and 0.76 litre.min-1 (breaths 7-13). CONCLUSIONS: Estimates of cardiac output by soluble gas uptake are optimal when correction is made for mixing of gas of identical diffusivity. The mean mixed gas volume gives the best correlation with the reference method, implying a selective distribution of blood flow to the better ventilated areas.

Ras inhibitors and radiation therapy.

Local recurrence after a definitive course of radiation therapy remains a significant clinical problem and represents a common pattern of failure for many solid tumors. The sensitivity of tumor cells to the cytotoxicity of ionizing radiation is thought to be one of the major determinants of local control for tumors in patients treated with radiation therapy. There is substantial experimental evidence to demonstrate that increased radiation resistance is associated with the expression of activated oncogenes, including Ras. Mutated forms of Ras are found in 30% of human cancers including a substantial proportion of pancreatic and colon adenocarcinomas. Mutated Ras produces proteins that remain locked in a constitutively active state, thereby relaying uncontrolled signals. Ras proteins are guanosine triphosphate-binding proteins that play a pivotal role in the control of many cellular processes, including growth and differentiation. Preclinical studies have shown that expression of mutant Ras increases cellular radioresistance. Ras function is dependent on its localization to the plasma membrane. This is achieved by posttranslational modifications, including the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). This enzyme has become an important target for the design of new agents that target Ras. FTase inhibitors (FTIs) block the farnesylation of Ras and reverse Ras-mediated radioresistance in human cell lines. FTIs have been well tolerated in animal studies and appear not to cause generalized cytotoxicity. There are ongoing clinical trials to determine the optimal therapeutic schedules and dose for FTIs. A phase 1 trial of the FTI L778-123 and radiotherapy has recently been completed.

A rapid rebreathing method for measurement of pulmonary gas volume in humans.

We have developed a rapid gas-dilution technique, with which pulmonary gas volume can be measured in only 20 s, even in the presence of maldistribution of ventilation. The subject rebreathes from a 0.75-liter anesthetic bag filled with 10% He and 30% O2 in argon. Breath-by-breath flow-weighted inspired concentrations of all gases present are calculated from continuous measurement by mass spectrometry. Insoluble gas concentrations are corrected continuously for shrinkage of the system volume. By use of these corrected values a mathematical extrapolation predicts the equilibrium concentration for He in the absence of complete mixing. Validation of the technique was carried out by comparing volumes calculated from the predicted equilibrium value with those obtained by whole-body plethysmography in 7 normal subjects and 12 patients with lung disease. In normal subjects equilibrium was usually attained within the 20 breaths and no extrapolation was required. In most of the patients, however, equilibrium was not reached and the use of the extrapolation technique increased the proportion of the lung volume measured by gas dilution from 0.82 +/- 0.16 (SD) to 0.95 +/- 0.12 of that measured by plethysmography.

Modification of pulmonary gas mixing by postural changes.

Mixing for two gases of markedly different gaseous diffusivity, helium (He) (mol wt = 4) and sulfur hexafluoride (SF6) (mol wt = 146) has been studied by a rebreathing method in different postures. In nine normal subjects duplicate measurements were made in the erect (seated), supine, and lateral decubitus posture, at a constant tidal volume (700 ml) and frequency (1 Hz) starting from functional residual capacity (FRC). Additional measurements were made on four of the subjects, rebreathing seated erect at a volume similar to the relaxed FRC supine and supine at a volume similar to the relaxed FRC seated. In the supine posture the mean breath number to reach 99% equilibrium (n99), was not significantly different for the two gases, 8.9 for He and 9.8 for SF6. There was a difference (P less than 0.01) when erect; n99 (He) = 8.2 and n99 (SF6) = 10.9. The greatest He-SF6 difference (P less than 0.001) was in the lateral decubitus position n99 (He) = 10.1 and n99 (SF6) = 15.9. The mean relaxed FRC as percent of seated was 71% supine and 75% in lateral decubitus posture. Rebreathing seated at a lower volume did not abolish the He-SF6 mixing difference nor did rebreathing at a higher volume when supine induce a He-SF6 mixing difference. Thus the effect of posture on gas mixing cannot be due solely to lung volume and must represent a convective and diffusive dependent change in the distribution of ventilation per unit lung volume.

Cardiopulmonary response to exercise in patients with intrapulmonary vascular shunts.

The majority of patients with intrapulmonary right-to-left shunting due to pulmonary arteriovenous malformations-exhibit good maximum exercise capacity (> 70% predicted) despite profound arterial oxygen desaturation. We studied seven such patients to assess tissue oxygen delivery during steady-state exercise. From rest to exercise [50 +/- 7 (SE) W] arterial saturation fell from 80 +/- 3 to 74 +/- 3%, and mean right-to-left shunt increased slightly from 31 +/- 4 to 34 +/- 5% (P = NS). Minute ventilation was high for oxygen uptake, and the ventilatory equivalent was raised (174 +/- 19% predicted) and was correlated with shunt size (r = 0.93). The majority of the patients maintained pulmonary alveolar blood flow within the predicted range for their power output, but total cardiac output was increased to 142 +/- 11% predicted due to flow through the shunt. Consequently, on exercise, oxygen delivery per unit oxygen consumption [2.3-3.3 (normal range 1.6-2.4)] and calculated mixed venous oxygen tension (27.0 +/- 0.8 Torr) were preserved. Arterial PCO2 rose on exercise by 2.8 +/- 1.2 Torr, in proportion to the ratio of flow through the shunt to total cardiac output (r = 0.73), but remained low (33.1 +/- 1.4 Torr) in absolute terms. The high cardiac output on exercise may be facilitated by a low pulmonary vascular resistance (0.33 +/- 0.08 mmHg.1-1.min, measured at rest), which may explain why exercise performance is better in these patients than in patients with equivalent hypoxemia from other causes.

Glassy cell carcinoma of the cervix: report of three cases.

Glassy cell carcinoma is a poorly differentiated adenosquamous carcinoma of the cervix, hallmarked by aggressive behavior, occurrence in association with pregnancy, and a poor patient survival rate. Three of these very rare cervical, primary malignancies are reported. At the time of this writing, only one patient has survived.

A comparison of the dual lumen and coaxial catheters for temporary hemodialysis access.

Percutaneous central venous catheterization can provide reliable temporary hemodialysis access. The current study compared the hemodynamic performance of 28 coaxial catheters to 27 side by side catheters. A total of 675 dialysis sessions were evaluated to assess the flow characteristics of these two designs. The results demonstrated that the side by side catheter provided greater cumulative blood flow with more favorable venous and arterial pressures. Nevertheless, the coaxial catheter performed satisfactorily and met the minimum standards for these devices.

Measurement of functional residual capacity and pulmonary carbon monoxide uptake in conscious Greyhounds.

A simplified rebreathing method was developed for measurement of functional residual capacity (FRC) and pulmonary diffusing capacity for CO in nonanesthetized standing Greyhounds. The FRC was related to body weight according to the equation: FRC = 0.04 (body weight in kg)1.22 whereas pulmonary diffusing capacity for CO in nonanesthetized standing Greyhounds (ml/min/mm of Hg) = 2.34 (body weight in kg).0.66 The large FRC per unit of body weight in the Greyhound emphasizes the need for breed specific prediction equations in veterinary respiratory physiologic studies and may reflect selection for exercise performance in the development of the Greyhound breed.

Comparative treatment planning between proton and X-ray therapy in pancreatic cancer.

With the utilization of new biologic agents and experimental chemotherapy in the treatment of pancreatic cancer, the issue of local-regional control will become increasingly important. This study was undertaken to determine the feasibility of dose escalation using proton therapy, as compared to conventional 3-dimensional conformal radiation, by minimizing the dose to normal tissues. The photon treatment plans of 4 patients with unresectable pancreatic cancer treated on a biologic therapy trial were utilized. Each patient was treated using a 3- or 4-field photon plan with 45 Gy to the clinical target volume (CTV), followed by a boost of 14.4 Gy to the gross target volume (GTV). Using a Helax treatment planning system, proton plans were generated to encompass the same CTV and GTV to the same prescribed dose. Dose-volume histograms (DVHs) were generated for the GTV, CTV, spinal cord, liver, and right and left kidneys. Each DVH was compared between the photon and proton plans. Proton plans utilized either a 2- or 3-field technique. Available energies included 130 or 180 MeV. Range modulators and bolus were used as needed to conform to the target volume. With the CTV and GTV receiving the same dose from the proton and photon plans, all individual proton plans were superior to the photon plans in reduction of normal tissue dose. For the 4 patients, the average dose reduction to 50% of the organ at risk was 78% to spinal cord (p = 0.003), 73% to left kidney (p = 0.025), 43% to right kidney (p = 0.059), and 55% to liver (p = 0.061). These comparative treatment plans show proton therapy results in significant reductions of dose to normal tissue compared to conventional photons while treating the same target volumes. This allows for the design of dose-escalation protocols using protons in combination with new biologic therapies and chemotherapy.

Genital clear cell adenocarcinoma.

Genital clear cell adenocarcinoma is a rare cancer in young women related to prenatal exposure to diethylstilbestrol (DES). From the Diethylstilbestrol Registry, an analysis of 57 cases of genital clear cell adenocarcinoma is presented from the state of California, the most populous state in the United States. Approximately two-thirds of these patients have positive histories of prenatal diethylstilbestrol exposure. The majority of patients had early-stage genital cancer. Generally, early-stage clear cell cancer is successfully treated with radical pelvic surgery. A carefully structured screening program of the DES exposed patient is advised.

Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthma.

BACKGROUND: Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory-tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. OBJECTIVE: To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. METHODS: Sputum cells were induced from steroid-naïve, allergen-challenged and allergen-naïve subjects (atopic asthmatics, atopic non-asthmatics and non-atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. RESULTS: hRTDC stained HLA-DR(+) (negative for markers of other cell lineages) were predominantly myeloid and comprised approximately 0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4(+) naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC-dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05-P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c(-)CD123(high) hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. CONCLUSION: Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.

Effect of posture on inter-regional distribution of pulmonary ventilation in man.

Regional ventilation per unit alveolar volume (V/VA) and regional lung expansion (FRCR/TLCR) were measured in twelve normal male human subjects in seated, supine, lateral decubitus and prone postures using a gamma camera and inhalation of the radioactive gases 81Krm (half-life 13 sec) and 85Krm (half-life 4.4 h). FRCR/TLCR decreased from superior to inferior in all postures except prone where it was uniform; V/VA increased from superior to inferior except in the prone position where it was uniform. In the horizontal axis FRCR/TLCR and V/VA were uniformly distributed except for cranial to caudal gradients (with lower values caudally) in supine and lateral decubitus postures. In the prone posture V/VA tended to be higher in caudal lung zones.