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Abstract Background A method for assessing the model validity of randomised controlled trials of homeopathy is needed. To date, only conventional standards for assessing intrinsic bias (internal validity) of trials have been invoked, with little recognition of the special characteristics of homeopathy. We aimed to identify relevant judgmental domains to use in assessing the model validity of homeopathic treatment (MVHT). We define MVHT as the extent to which a homeopathic intervention and the main measure of its outcome, as implemented in a randomised controlled trial (RCT), reflect 'state-of-the-art' homeopathic practice. Methods Using an iterative process, an international group of experts developed a set of six judgmental domains, with associated descriptive criteria. The domains address: (I) the rationale for the choice of the particular homeopathic intervention; (II) the homeopathic principles reflected in the intervention; (III) the extent of homeopathic practitioner input; (IV) the nature of the main outcome measure; (V) the capability of the main outcome measure to detect change; (VI) the length of follow-up to the endpoint of the study. Six papers reporting RCTs of homeopathy of varying design were randomly selected from the literature. A standard form was used to record each assessor's independent response per domain, using the optional verdicts 'Yes', 'Unclear', 'No'. Concordance among the eight verdicts per domain, across all six papers, was evaluated using the kappa (κ) statistic. Results The six judgmental domains enabled MVHT to be assessed with 'fair' to 'almost perfect' concordance in each case. For the six RCTs examined, the method allowed MVHT to be classified overall as 'acceptable' in three, 'unclear' in two, and 'inadequate' in one. Conclusion Future systematic reviews of RCTs in homeopathy should adopt the MVHT method as part of a complete appraisal of trial validity.

Abstract Background The 'Hawthorne Effect' may be an important factor affecting the generalisability of clinical research to routine practice, but has been little studied. Hawthorne Effects have been reported in previous clinical trials in dementia but to our knowledge, no attempt has been made to quantify them. Our aim was to compare minimal follow-up to intensive follow-up in participants in a placebo controlled trial of Ginkgo biloba for treating mild-moderate dementia. Methods Participants in a dementia trial were randomised to intensive follow-up (with comprehensive assessment visits at baseline and two, four and six months post randomisation) or minimal follow-up (with an abbreviated assessment at baseline and a full assessment at six months). Our primary outcomes were cognitive functioning (ADAS-Cog) and participant and carer-rated quality of life (QOL-AD). Results We recruited 176 participants, mainly through general practices. The main analysis was based on Intention to treat (ITT), with available data. In the ANCOVA model with baseline score as a co-variate, follow-up group had a significant effect on outcome at six months on the ADAS-Cog score (n = 140; mean difference = -2.018; 95%CI -3.914, -0.121; p = 0.037 favouring the intensive follow-up group), and on participant-rated quality of life score (n = 142; mean difference = -1.382; 95%CI -2.642, -0.122; p = 0.032 favouring minimal follow-up group). There was no significant difference on carer quality of life. Conclusion We found that more intensive follow-up of individuals in a placebo-controlled clinical trial of Ginkgo biloba for treating mild-moderate dementia resulted in a better outcome than minimal follow-up, as measured by their cognitive functioning. Trial registration Current controlled trials: ISRCTN45577048

The Heart Allograft Rejection: Detection with Breath Alkanes in Low Levels study evaluated a breath test for oxidative stress in heart transplant recipients, and we report here a mathematical model predicting the probability of grade 3 rejection. The breath test divided the heart transplant recipients into 3 groups: positive for grade 3 rejection, negative for grade 3 rejection, and intermediate. The test was 100% sensitive for grade 3 heart transplant rejection when the p value was >/=0.98, and 100% specific when the p value was

Background: We evaluated a new marker of heart transplant rejection, the breath methylated alkane contour (BMAC). Rejection is accompanied by oxidative stress that degrades membrane polyunsaturated fatty acids, evolving alkanes and methylalkanes, which are excreted in the breath as volatile organic compounds (VOCs)., Methods: Breath VOC samples (n = 1,061) were collected from 539 heart transplant recipients before scheduled endomyocardial biopsy. Breath VOCs were analyzed by gas chromatography and mass spectroscopy, and BMAC was derived from the abundance of C4-C20 alkanes and monomethylalkanes. The "gold standard" of rejection was the concordant set of International Society for Heart and Lung Transplantation (ISHLT) grades in biopsies read by 2 reviewers., Results: Concordant biopsies were: Grade 0, 645 of 1,061 (60.8%); 1A, 197 (18.6%); 1B, 84 (7.9%); 2, 93 (8.8%); and 3A, 42 (4.0%). A combination of 9 VOCs in the BMAC identified Grade 3 rejection (sensitivity 78.6%, specificity 62.4%, cross-validated sensitivity 59.5%, cross-validated specificity 58.8%, positive predictive value 5.6%, negative predictive value 97.2%). Site pathologists identified the same cases with sensitivity of 42.4%, specificity 97.0%, positive predictive value 45.2% and negative predictive value 96.7%., Conclusions: A breath test for markers of oxidative stress was more sensitive and less specific for Grade 3 heart transplant rejection than a biopsy reading by a site pathologist, but the negative predictive values of the 2 tests were similar. A screening breath test could potentially identify transplant recipients at low risk of Grade 3 rejection and reduce the number of endomyocardial biopsies.

Shigella spp. are the aetiologic agents of dysentery, a severe diarrhoeal syndrome characterized by acute inflammation in the colon. The inflammatory response, which includes recruitment of polymorphonuclear leukocytes (PMN), damages the colonic mucosa and exacerbates the infection. Shigella encodes a pathogenicity island (PAI), SHI-2, which is localized in a region of the chromosome linked to the induction of inflammation. Surprisingly, SHI-2 deletion mutants induce a stronger inflammatory response than wild-type Shigella as measured by increased villus blunting, increased PMN infiltration and induction of apoptosis in a rabbit ileal loop model of shigellosis. Mutational analysis mapped the hyper-inflammatory phenotype to a single gene, shiA. Similar to SHI-2 deletion mutants, infection with a shiA mutant strain induces dramatically elevated levels of inflammation when compared to the wild-type strain. Furthermore, infection with a wild-type strain containing multiple copies of shiA results in fewer infiltrating PMN and apoptotic cells, as well as preservation of a normal villus architecture at the site of infection, thus acting in a dominant fashion over the pro-inflammatory mechanisms of Shigella. The molecular mechanism of action of ShiA is independent of any in vitro phenotype associated with Shigella virulence. Our data suggest that ShiA allows Shigella to attenuate the host inflammatory response in a novel manner.

We used a gamma camera to monitor the retention and clearance of radiolabeled human serum albumin (HSA), a water-soluble material with molecular weight of 66,000 Daltons, and radiolabeled sulfur colloid (SC), an insoluble submicron (0.22 microm) particle, following localized deposition in a 4-5-mm bronchus in each of five dogs. The average retention time of HSA was significantly greater than that of SC both in the deposition site (23.3 +/- 2.3 vs. 18.2 +/- 2.9 min respectively, p < 0.05) and in the clearance pathway (26.5 +/- 2.0 vs. 22.0 +/- 1.4 min, respectively, p < 0.05). The mean percent retention at the deposition site at 60 minutes post-deposition also was significantly greater for HSA than for SC (33.5 +/- 10.1 vs. 11.6 +/- 4.7%, respectively, p < 0.05). The percentage of HSA which had cleared to the level of the cuffed endotracheal tube was significantly less than that of SC (18.0 +/- 6.7 vs. 35.8 +/- 3.5%, respectively, p < 0.05) at 60 min post-deposition. These findings indicate that a low-permeating water-soluble material such as HSA deposited on the surface of an airway remains in contact with the sensitive airway epithelium to a greater extent than does a solid insoluble particle. Based on our results, we speculate that the slower clearance of HSA compared to SC was likely due to diffusion of a greater portion of the HSA into the periciliary sol layer which may be transported less efficiently than the mucus layer during mucociliary clearance. Additionally, some degree of uptake of HSA by bronchial epithelium may have contributed to its increased retention.

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase of beta cell mass and impaired glucose-dependent insulin release. beta cell proliferation and secretion are thought to be regulated by signaling through receptor tyrosine kinases. In this regard, we sought to examine the potential proliferative and/or antiapoptotic role of IGFs in beta cells by tissue-specific conditional mutagenesis ablating type 1 IGF receptor (IGF1R) signaling. Unexpectedly, lack of functional IGF1R did not affect beta cell mass, but resulted in age-dependent impairment of glucose tolerance, associated with a decrease of glucose- and arginine-dependent insulin release. These observations reveal a requirement of IGF1R-mediated signaling for insulin secretion.

The PhoP/PhoQ two-component regulatory system controls transcription of several key virulence genes essential for Salmonella survival in the host cell phagosome. Here, we determine that the PhoP/PhoQ system also regulates virulence in the aetiological agent of bacillary dysentery, Shigella flexneri, even though this pathogen escapes from the phagosome into the cytoplasm of the host cell. A phoP mutant of Shigella established infections and induced an acute inflammatory response in two different animal models. However, infections with phoP mutant bacteria were resolved more rapidly than infections with wild-type Shigella. Moreover, the Shigella phoP mutant was more sensitive than the wild-type strain to killing by polymorphonuclear leucocytes (PMNs), cationic polypeptides extracted from PMNs and other animal-derived antimicrobial peptides. The phoP mutant, however, invaded epithelial cells, spread intercellularly, induced apoptosis in macrophages and tolerated extreme acid pH as efficiently as the wild-type strain. PhoP appears to regulate Shigella susceptibility to PMNs and antimicrobial molecules that are important for the late stages of infection with this enteric bacterium.

The effect of hyperthermia on the accumulation of technetium-99m-labeled liposomes was studied in feline sarcomas. Each cat received two separate injections of liposomes. The first was used to quantify the amount of technetium-99m-labeled liposomes within the tumor under normothermic conditions. The second injection was made at the beginning of a 60-min hyperthermia procedure. Planar scintigraphy was used to measure the activity of technetium-99m-labeled liposomes within the tumor at predetermined times up to 18 h after injection. Regions of interest were drawn for the tumor, lungs, liver, kidney, and aorta. Counts in the regions of interest were decay corrected. Counts/pixel in the tumor under normothermic and hyperthermic conditions were normalized to aorta counts/pixel. A total of 16 cats were eligible for the study. In two of the 16 cats, incomplete count data precluded analysis. In the remaining 14 cats, hyperthermia resulted in a significant increase in liposome accumulation in the tumor (P = 0.001). Tumor volume ranged from 1.2 to 236.2 cm3, and thermal dose ranged from 2.0 to 243.3 CEM43CT90 (equivalent time that the 10th percentile temperature was equal to 43 degrees C). There was not a relationship between either tumor volume or hyperthermia dose on the magnitude of increased liposome accumulation, suggesting that this method has application across a range of tumor volumes and degrees of heatibility.

Objective: Inhibition of inducible nitric oxide synthase (nitric oxide II) activity has been proposed as a method to attenuate capillary leak and edema during rejection of heterotopically transplanted rat hearts. Myocardial edema has previously been implicated in diastolic dysfunction during allograft rejection. Accordingly, we tested the hypothesis that inducible nitric oxide synthase inhibition with aminoguanidine would alleviate left ventricular stiffening and myocardial edema formation in 4-day heterotopic rat heart allografts., Methods: Passive left ventricular filling was studied in American Cancer Institute Lewis rats receiving heterotopic heart transplants receiving either aminoguanidine, a selective nitric oxide synthase inhibitor (n = 6); dexamethasone (1 mg. kg(-1). d(-1) administered subcutaneously) for 4 days after transplantation (n = 6); or intravenous saline solution (n = 6). American Cancer Institute-to-American Cancer Institute isografts (n = 6) were used as controls., Results: Serum nitrite/nitrate levels in the aminoguanidine group (18 +/- 3 mmol/L) and dexamethasone group (22 +/- 4 mmol/L) were reduced versus the intravenous saline group (144 +/- 36 mmol/L [SEM]) to levels seen in controls (25 +/- 9 mmol/L). Left ventricular volume at 15 mm Hg for the aminoguanidine group was increased versus that for the intravenous saline solution group, similar to that for controls, and reduced versus dexamethasone-treated animals. Myocardial water content for the aminoguanidine-treated animals (78.3% +/- 0.4%) was similar to those of intravenous saline-treated animals (78.0% +/- 0. 3%) but greater than those of controls (77.1% +/- 0.2%) and dexamethasone-treated animals (76.7% +/- 0.3%)., Conclusions: Nitric oxide II inhibition with aminoguanidine minimizes the reduction in left ventricular filling that is seen with allograft rejection through a mechanism that is not associated with attenuation of myocardial edema.

Computerized tomography scans of a ferruginous concretion within the chest region of an ornithischian dinosaur reveal structures that are suggestive of a four-chambered heart and a single systemic aorta. The apparently derived condition of the cardiovascular system in turn suggests the existence of intermediate-to-high metabolic rates among dinosaurs.

Objective: To determine the benefits of reducing the interval between surgical cytoreduction and intratumoral administration of cisplatin., Design: Randomized clinical study., Animals: 70 horses with 89 incompletely resected T2- and T3-stage sarcoids (n = 64) and squamous cell carcinomas (25)., Procedure: Horses were given 4 intratumoral treatments of cisplatin at 2-week intervals. The first treatment was given at the time of, or immediately after, surgical resection for horses treated in accordance with the perioperative protocol (group 1). Horses in group 2 were treated with cisplatin after the skin healed following surgical resection in accordance with the postoperative protocol., Results: A difference was not found in duration of overall local tumor control between the 2 groups. Patterns of treatment failures and interval to failure differed between the 2 groups. Length of the surgical scar was the only factor that affected prognosis; an increase in length was associated with a poorer prognosis. A detrimental effect of postoperative treatment was only found in tumors with a high tumor proliferative fraction. Local reactions were similar for the 2 treatment groups, and chronic reactions were not observed., Conclusions and Clinical Relevance: Intratumoral administration of cisplatin is beneficial for treatment of cutaneous tumors in horses. Tumor repopulation during the interval between surgery and intratumoral administration of cisplatin decreases treatment efficacy. These results provide evidence of rapid tumor repopulation following surgical resection without a lag period for tumors with a high proliferation index. When tumor proliferation index is not known, it may be prudent to use the perioperative protocol.

Background: Recent studies found that edema, histology, and left ventricular diastolic compliance exhibit quantitative relationships in rats. Edema due to low osmolarity coronary perfusates increases myocardial water content and histologic edema score and decreases left ventricular filling. The present study examined effects of perfusate osmolarity and chemical composition on rat hearts., Methods: Arrested American Cancer Institute (ACI) rat hearts (4 degrees C) were perfused with different cardioplegia solutions, including Plegisol (289 mOsm/L), dilute Plegisol (172 mOsm/L), Stanford solution (409 mOsm/L), and University of Wisconsin solution (315 mOsm/L). Controls had blood perfusion (310 mOsm/L). Postmortem left ventricular pressure-volume curves and myocardial water content were measured. After glutaraldehyde or formalin fixation, dehydration, and paraffin embedding, edema was graded subjectively., Results: Myocardial water content reflected perfusate osmolarity, being lowest in Stanford and University of Wisconsin solutions (p<0.05 versus other groups) and highest in dilute Plegisol (p<0.05). Left ventricular filling volumes were smallest in dilute Plegisol and Plegisol (p<0.05). Osmolarity was not a major determinant of myocardial edema grade, which was highest with University of Wisconsin solution and dilute Plegisol (p<0.05 versus other groups)., Conclusions: Perfusate osmolarity determined myocardial water content and left ventricular filling volume. However, perfusate chemical composition influenced the histologic appearance of edema. Pathologic grading of edema can be influenced by factors other than osmolarity alone.

Pten/Mmac1+/- heterozygous mice exhibited neoplasms in multiple organs including the endometrium, liver, prostate, gastrointestinal tract, thyroid, and thymus. Loss of the wild-type allele was detected in neoplasms of the thymus and liver. Surprisingly, tumors of the gastrointestinal epithelium developed in association with gut lymphoid tissue. Tumors of the endometrium, thyroid, prostate, and liver were not associated with lymphoid tissue and appeared to be highly mitotic. In addition, these mice have nonneoplastic hyperplasia of lymph nodes that was caused by an inherited defect in apoptosis detected in B cells and macrophages. Examination of peripheral lymphoid tissue including lymphoid aggregates associated with polyps revealed that the normal organization of B and T cells was disrupted in heterozygous animals. Taken together, these data suggest that PTEN is a regulator of apoptosis and proliferation that behaves as a "landscaper" tumor suppressor in the gut and a "gatekeeper" tumor suppressor in other organs.

Background: Studies of myocardial edema and diastolic dysfunction in rat heart transplantation have been flawed by ischemic injury. This study uses improved methods to prevent ischemic contracture., Methods: Hearts of 30 ACI rats were transplanted into the abdomen of Lewis rats by use of cold University of Wisconsin solution for improved preservation. Left ventricular diastolic properties were expressed as volume at standardized pressure intervals., Results: On posttransplantation day 3, mean left ventricular volume at 15 mm Hg in allografts (290 +/- 9 microl, SEM) was not significantly different vs isografts (299 +/- 32 microl), allografts on day 0 (337 +/- 28 ml) or day 1 (324 +/- 20 microl), or native hearts (334 +/- 19 microl). However, volume was reduced to 173 +/- 17 microl on day 4 and to 70 +/- 23 microl on day 5 (p < 0.05). Similar findings were obtained for volume at 5 and 10 mm Hg. Allograft myocardial water content on day 3, 76.3% +/- 5%, similar to allografts on day 0 and 1 and to isografts on day 3, increased to 77.6% +/- 8% on day 4 (NS) and 79.4% +/- 6% on day 5 (p < 0.05 vs day 0). Histologically, rejection in allografts was mild on day 3, moderate on day 4, and severe on day 5., Conclusions: Reduced left ventricular filling volume during rejection is only partially explained by edema. Abnormalities of diastolic properties previously attributed to the unloaded state of nonworking heart models may actually reflect inadequate peritransplantation myocardial protection.

Background: Transmyocardial laser revascularization is a new therapy for patients with refractory angina. Although clinical studies suggest that transmyocardial laser revascularization decreases angina and may improve regional blood flow, the underlying mechanisms are not elucidated. We hypothesized that one mechanism may relate to stimulation of vascular growth in laser-treated regions., Methods: Transmyocardial laser revascularization channels were made with holmium:yttrium-aluminum garnet or carbon dioxide lasers in eight normal canine hearts; animals were sacrificed 2 to 3 weeks later and examined for vascular density and for evidence of smooth muscle proliferation., Results: The original channels were infiltrated by granulation tissue with associated vascularity. Vascular growth was stimulated immediately surrounding the channel remnant as evidenced by an increase in the number of vessels (approximately twice that of the control region) and an increase in the number of vascular cells staining positive for markers of cellular proliferation., Conclusions: Transmyocardial laser revascularization leads to local vascular growth as early as 2 weeks after treatment. It remains to be determined whether this mechanism contributes to increased regional blood flow or to clinical benefits associated with this novel form of therapy.

Background: Although myocardial edema is known to impair diastolic filling of the left ventricle, the interrelation of edema, histologic condition, and function has not been quantitated sufficiently for extrapolation to studies of multifactorial influences on diastolic properties., Methods: Accordingly, ACI rat hearts arrested at 4 degrees C underwent coronary artery perfusion with a cardioplegia solution that was either unaltered (288 mOsm/L, P288 group, n = 6), diluted (144 mOsm/L, P144 group, n = 6), or concentrated (380 mOsm/L, P380 group, n = 6). Postmortem left ventricular pressure-volume curves and myocardial water content were measured. Myocardial samples were fixed in varying dilutions of glutaraldehyde. After dehydration and paraffin embedding, edema was graded subjectively (0 to 5), and myocardial interstitial spaces were determined by use of a semiquantitative method., Results: Mean normalized left ventricular filling volume at 20 mm Hg filling pressure in the P144 group, 189 +/- 16 microliters (SEM), was reduced versus both the P288 (278 +/- 26 microliters) and the P380 (332 +/- 18 microliters) groups (p < 0.05, ANOVA). Mean myocardial water content in the P144 group, 80.7% +/- 1%, was increased versus the P380 (76.7% +/- 0.4%, p < 0.05) but not versus the P288 group (78.4% +/- 0.8%). In hearts preserved with 2.5% glutaraldehyde, mean edema grade and interstitial space in the P144 group (4.0 +/- 0.3) were increased versus the P380 (1.8 +/- 0.3, p < 0.05) but not the P288 group (2.7 +/- 0.5). Derived linear regressions relate water content to filling volume and histologic condition., Conclusions: Coronary perfusate osmolarity is thus associated with predictable changes in myocardial water content, left ventricular filling volume, and edema. These correlations allow definition of new hypotheses for the study of cardiac allograft rejection in patients and experimental animals.

Background: Allograft rejection is mediated by T cells that recognize allogeneic major histocompatibility complex (MHC) molecules via the direct and indirect pathway. The direct pathway involves T cells that react against MHC/peptide complexes expressed on the surface of donor antigen-presenting cells (APCs). In contrast, T cells involved in the indirect pathway recognize peptides derived from processing and presentation of allogeneic MHC molecules by self (recipient) APCs. To explore the relative contribution of these two pathways to rejection, we have evaluated the response of peripheral blood T cells from 50 heart transplant recipients against donor APCs (direct recognition) and against self APCs pulsed with synthetic peptides corresponding to the hypervariable region of the mismatched HLA-DR antigens of the donor (indirect recognition)., Methods: T cell reactivity against donor APCs was quantitated by measuring the expression of CD69 on allostimulated CD3+ LDA1+ cells. Reactivity to synthetic allopeptides was determined in limited dilution assays., Results: Serial studies of the kinetics of direct and indirect recognition showed that both pathways contribute to early acute rejection episodes. Primary rejection was accompanied invariably by indirect recognition of a dominant allopeptide. Intermolecular spreading of T cell epitopes was observed during recurrent rejections. Enhanced recognition of donor alloantigens via the direct pathway was found predominantly during early rejection episodes. A single form of allorecognition was shown to occur in some rejection episodes., Conclusions: Monitoring of the direct and indirect pathway of allorecognition provides a reliable method for prediction and differential diagnosis of acute rejection of heart allografts.

Background: Transmyocardial laser revascularization using different lasers is being tested in the treatment of refractory angina. We conducted comparative analysis of the acute and chronic myocardial effects of these different lasers., Methods: Transmyocardial channels were made in normal dog hearts with either a holmium:yttrium-aluminum garnet or a CO2 laser. Channels were examined histologically 6 to 24 hours, 2 to 3 weeks, and 6 weeks after creation., Results: Regardless of the laser source, the channels were occluded by thrombus within 6 to 24 hours. Subsequently, organization and neovascularization of the channel region occurred. Thermoacoustic damage was initially greater with the holmium:yttrium-aluminum garnet laser, but the channel appearances were indistinguishable from those made with the CO2 laser by 6 weeks., Conclusions: Histologically, the myocardial effects of the CO2 and holmium:yttrium-aluminum garnet lasers are similar and differ predominantly in the amount of acute thermoacoustic injury. Channels are rapidly occluded by thrombus and are replaced by neovascularized collagen. This suggests that the physiologic effects of these two lasers may be similar and that mechanisms other than blood flow through chronic patent channels should be considered as contributing to the clinical benefits observed with this procedure.

Background: Transmyocardial revascularization with a CO2 laser appears to improve symptoms in patients with refractory angina. However, it remains controversial as to whether blood flow through the channels is the mechanism of benefit, especially in the acute setting., Methods and Results: Three protocols were used to test whether blood flows through transmyocardial CO2 laser revascularization channels. First, channels were made in excised, cross-perfused dog hearts (n = 5) using a CO2 laser (The Heart Laser; PLC Systems Inc, Milford, MA; 40 J/pulse) followed by ligation of the proximal left anterior descending coronary artery. Colored microspheres injected into the left ventricular chamber failed to detect any significant transmyocardial blood flow. In the second protocol (n = 4), laser channels were created in the left anterior descending artery territory, the left anterior descending artery was ligated, and the hearts were excised after 24 hours. Triphenyltetrazolium chloride staining revealed that no viable myocardium was detected around the laser channels in the ischemic myocardium. Finally, channels examined 2 weeks after creation in normal (n = 6) or ischemic (n = 4) myocardium did not maintain their original caliber but were invaded by granulation tissue, which included a large amount of smaller vascular spaces and vessels of various sizes., Conclusions: Transmyocardial laser revascularization channels made with this CO2 laser did not provide acute myocardial perfusion or preserve myocardial viability in the face of acute ischemia. Channel morphology changes dramatically within the first 2 weeks. To the degree that these findings pertain to human myocardium, the results suggest that transmyocardial blood flow may not be the mechanism of benefit of this procedure, particularly in the acute setting.

Background: Techniques for achieving myocardial perfusion directly from the left ventricular chamber are currently under investigation. Although originally based on the anatomy of reptilian hearts, which are rich in transmural channels and reported to have a poorly developed coronary vasculature, the blood flow capacity of a transmyocardial blood supply has not been studied in these hearts. With the ultimate goal of providing insight into the potential for achieving transmyocardial perfusion in human hearts, we studied the relative contribution of transmyocardial and coronary perfusion in alligator hearts., Methods and Results: After explanation from six American alligators, the left ventricle was instrumented, and coronary arteries were perfused with oxygenated physiological solution. Using microspheres to estimate regional myocardial perfusion in the beating hearts, we show that although the epicardium was well perfused by the coronary arteries (0.20 +/- 0.08 versus 0.07 +/- 0.01 mL.min-1.g-1 owing to flow from the ventricular chamber), a significant proportion of endocardial perfusion was from the ventricular chamber (0.21 +/- 0.07 mL.min-1.g-1 from the left ventricle versus 0.13 +/- 0.04 mL.min-1.g-1 from coronary arteries)., Conclusions: A significant amount of direct transmyocardial perfusion is present in alligator hearts. The conditions that apparently permit this situation in reptilian hearts are reviewed, and their implications for aiding in the optimization of techniques for achieving transmyocardial flow in humans are discussed.

The purpose of this study was to determine the best method to ultrasonographically monitor renal size changes associated with acute allograft rejection in dogs. Qualitative changes in renal cortical and medullary echogenicity were also evaluated, although this was not a major focus of the study. Four unrelated, mixed-breed dogs underwent bilateral nephrectomies and heterotopic renal allograft transplantation. Ultrasound examinations of transplanted kidneys were initiated at 3 days after surgery and continued at 2-3 day intervals until death (38 +/- 2 days). Ultrasound measurements of kidney length, width, height, cross-sectional area, and estimated volume were used to assess relative changes in renal size associated with transplantation and rejection. Transplanted kidneys had a rapid increase in volume and cross-sectional area that averaged 103% and 83% above baseline levels, respectively, by 17 days after transplantation. The increased size was attributed to a combination of hypertrophy and acute rejection, the latter of which was confirmed at postmortem. Kidney volume decreased to approximately 35% above baseline volume by day 34 as rejection became more advanced. Qualitative changes associated with rejection included medullary enlargement with decreased echogenicity early in the study, followed by increased cortical thickness and echogenicity with poor cortical medullary definition in the latter stages of the survival period. It was concluded that relative changes in renal allograft size can be easily monitored with ultrasound. In regard to linear measurements, changes in renal width were more pronounced than changes in height or length with acute rejection. Therefore measurements that incorporate the width, namely volume or cross-sectional area, appear to be the most sensitive for monitoring changes in allograft size. Renal cross-sectional area measurements are preferred because they are simple to perform using the automated calculation capability of most newer ultrasound units.

Myocardial mechanics and energetics were investigated in an animal model of moderate chronic heart failure (CHF) created by repeated coronary microembolizations in six dogs. The final fractional area change was 34 +/- 4%. Hearts of these animals were isolated and cross-perfused, and balloons were placed in the left ventricle (LV). Chamber contractile state was markedly depressed in embolized hearts as assessed by the slope (Ees 2.74 +/- 0.49 vs. 4.00 +/- 1.18 mmHg/ml, P < 0.01) and volume axis intercept (V: 8.7 +/- 5.9 vs. 1.0 +/- 3.2 ml, P < 0.01) of end-systolic pressure-volume relation compared with a group of six normal dogs. The end-diastolic pressure-volume relation of embolized hearts was shifted to the right, indicating a dilation of the LV. However, systolic and diastolic stress strain relationships were similar in the two groups, suggesting that the average myocardial properties of the embolized hearts are similar to those of normal hearts. The relationship between oxygen consumption and pressure-volume area in embolized hearts had smaller intercept (2.98 +/- 0.44 vs 3.92 +/- 0.39 x 10(-2) ml O2.beat-1.100 g LV-1, P < 0.01) compared with the control group, with no change in the slope. These results contrast with previous findings in pacing CHF and serve as an important characterization of ventricular properties in this model of CHF from different etiology.

To determine whether indirect allorecognition is involved in heart allograft rejection T cells obtained from peripheral blood and graft biopsy tissues were expanded in the presence of IL-2 and tested in limiting dilution analysis (LDA) for reactivity to synthetic peptides corresponding to the hypervariable regions of the mismatched HLA-DR antigen(s) of the donor. Serial studies of 32 patients showed that T cell reactivity to donor allopeptides was strongly associated with episodes of acute rejection. The frequency of allopeptide reactive T cells was 10-50-fold higher in the graft than in the periphery indicating that T cells activated via the indirect allorecognition pathway participate actively in acute allograft rejection. In recipients carrying a graft differing by two HLA-DR alleles the response appeared to target only one of the mismatched antigens of the donor. Indirect allorecognition was restricted by a single HLA-DR antigen of the host and directed against one immunodominant peptide of donor HLA-DR protein. However, intermolecular spreading was demonstrated in patients with multiple rejection episodes by showing that they develop allopeptide reactivity against the second HLA-DR antigen. These data imply that early treatment to suppress T cell responses through the indirect pathway of allorecognition, such as tolerance induction to the dominant donor determinant, may be required to prevent amplification and perpetuation of the rejection process.

The selective production of monoclonal antibodies (mAbs) reacting with defined cell surface-expressed molecules is now readily accomplished with an immunological subtraction approach, surface-epitope masking (SEM). Using SEM, prostate carcinoma (Pro 1.5) mAbs have been developed that react with tumor-associated antigens expressed on human prostate cancer cell lines and patient-derived carcinomas. Screening a human LNCaP prostate cancer cDNA expression library with the Pro 1.5 mAb identifies a gene, prostate carcinoma tumor antigen-1 (PCTA-1). PCTA-1 encodes a secreted protein of approximately 35 kDa that shares approximately 40% sequence homology with the N-amino terminal region of members of the S-type galactose-binding lectin (galectin) gene family. Specific galectins are found on the surface of human and marine neoplastic cells and have been implicated in tumorigenesis and metastasis. Primer pairs within the 3' untranslated region of PCTA-1 and reverse transcription-PCR demonstrate selective expression of PCTA-1 by prostate carcinomas versus normal prostate and benign prostatic hypertrophy. These findings document the use of the SEM procedure for generating mAbs reacting with tumor-associated antigens expressed on human prostate cancers. The SEM-derived mAbs have been used for expression cloning the gene encoding this human tumor antigen. The approaches described in this paper, SEM combined with expression cloning, should prove of wide utility for developing immunological reagents specific for and identifying genes relevant to human cancer.

Preliminary results of clinical studies suggest that transmyocardial laser revascularization is an effective treatment for patients with chronic angina that cannot be treated by other means. The mechanism of this effect remains controversial. We present autopsy results from a patient obtained 4 1/2 weeks after operation that show that the channels do not maintain patency. Further work is needed to determine the frequency of channel patency and its relation to clinical benefit.

We conducted a single-center, double-blind, placebo-controlled phase I study in HIV-positive subjects to ascertain the safety, tolerance, bioavailability, pharmacokinetics, and maximum tolerated dose of HPMPC (cidofovir). Five subjects were randomized to receive drug and two to receive placebo at each of three dosage tier (1, 3, and 10 mg/kg) with a 2-week washout period doses. Subjects at 1 and 3 mg/kg received single doses of HPMPC by subcutaneous (s.c.) intravenous (i.v.), and oral (p.o.) routes, while subjects at 10 mg/kg received only i.v. and p.o. doses. For subjects already taking zidovudine, zidovudine AUC values are determined before and then with HPMPC administration for each route. The AUC values of HPMPC were dose-proportional. Subcutaneous bioavailability was essentially equivalent to that of the intravenous route, but the development of transient local fibrosis ad the volumes needed for subcutaneous dosing precluded higher subcutaneous dosing than 3 mg/kg. Oral bioavailability was poor, estimated to be less than 5%. Drug elimination was predominantly renal. Nephrotoxicity in one subject was the only serious adverse event observed. This subject had a significant lag period prior to oral absorption and also had the highest AUC values for both HPMPC and zidovudine. We found no consistent effect on zidovudine AUC concomitant HPMPC.

Background: Early reports indicate that transmyocardial laser revascularization improves symptoms in patients with refractory angina. However, there is little experimental evidence of whether blood flow through channels is the mechanism of action., Methods: Endocardial channels were made in the distribution of the left anterior descending coronary artery in canine hearts (n = 5) using a holmium:yttrium-aluminum garnet laser. Hearts were excised acutely while perfused in a retrograde fashion from a second dog so that the aortic valve always remained closed. The proximal left anterior descending coronary artery was ligated. To measure direct transmyocardial blood flow, colored microspheres were injected into the left ventricular chamber., Results: The number of spheres per gram of tissue in the channel region was significantly higher than in the control region (low load, 302.5 +/- 169.0 versus 41.8 +/- 59.4; high load, 208.4 +/- 138.3 versus 5.8 +/- 11.7; both, p < 0.05). However, the estimated regional blood flow through the channels was extremely low (<0.01 mL/g/min. In the chronic setting (n = 4) (2-week survival), no flow as detected through the channels, and the endocardial entry points were closed., Conclusions: Transmyocardial blood flow does not appear to occur through channels made with the holmium:yttrium-aluminum garnet laser. It remains to be determined whether this is the case with other types of lasers.

Background: Currently the sole method available for diagnosis of heart allograft rejection is endomyocardial biopsy. Although this procedure offers important criteria for treatment, it cannot always discriminate between mild episodes of rejection which might be self-limiting and forms which may progress. In an effort to monitor rejection, we have implemented a cellular monitoring strategy aimed at identifying episodes of rejection in biopsy specimens which may evolve into higher grades of rejection. The lymphocyte growth assay is based on the capacity of interleukin-2 receptor-positive T cells to expand in the presence of interleukin-2 and antigen provided by the biopsy fragment. In this study we investigated whether a positive lymphocyte growth assay correlated with and was predictive of subsequent histologic allograft rejection and the development of anti-human leukocyte antigen antibodies., Methods: Lymphocyte growth assay was performed on 437 biopsy specimens from 76 patients. Patients with mild allograft rejection defined as grade 2 rejection were randomized to treatment according to the results of the lymphocyte growth assay. Anti-human leukocyte antigen antibodies was also measured monthly. Cells grown from the biopsy specimens were tested against the donor cells and allopeptides derived from the donor human leukocyte antigen-DR., Results: A highly significant correlation was observed between the histologic grade of rejection and growth of graft infiltrating cells (p < 0.0001). Lymphocyte growth occurred in 10% of grade 0 versus 60% of grade 3A biopsy specimens. Only 4% of histologically negative cases with negative lymphocyte growth assay progressed to rejection in the next month. In the randomized study in which treatment was based on the lymphocyte growth assay results, progressive rejection occurred in three of four cases with positive lymphocyte growth assay versus only 1 of 11 with a negative lymphocyte growth assay (p < 0.001). A highly significant correlation was found between a positive lymphocyte growth assay and subsequent development of antihuman leukocyte antigen antibodies (p < 0.0006). This finding indicates that cellular rejection evidenced by lymphocyte growth assay ultimately results in humoral antihuman leukocyte antigen antibody mediated rejection. Limiting dilution analysis showed that although the direct recognition pathway prevails in early rejection, cells participating in the indirect pathway also proliferate vigorously in the graft during rejection., Conclusions: Monitoring of rejection with lymphocyte growth assay is a simple method which provides prognostic information on the outcome of cardiac allografts. Lymphocyte growth assay correlates with histologic rejection and is predictive of future histologic rejection episodes. Lymphocyte growth assay also predicts subsequent development of antihuman leukocyte antigen antibodies and thus may provide a useful method for ascertaining the onset of chronic rejection.

The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 h (n = 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean +/- standard deviation total clearance of the drug from serum (148 +/- 25 ml/h/kg; n = 25) approximated renal clearance (129 +/- 42 ml/h/kg; n = 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 +/- 21 ml/h/kg; n = 12). These data indicate that active tubular secretion played a significant role in the clearance of cidofovir. The steady-state volume of distribution of cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of cidofovir at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to block tubular secretion of cidofovir and reduce its renal clearance to a level approaching glomerular filtration.

Technetium-99m sulfur colloid scintigraphy was used to study alterations of reticuloendothelial function in 7 dogs with experimentally induced biliary cirrhosis and portosystemic shunting. Scintigraphic studies were performed before and 6 weeks after common bile duct ligation. Radiocolloid plasma clearance rate was determined by measuring activity in plasma samples and by analyzing the rate of liver uptake on dynamic scintigraphic image sequences. Percentage of uptake in the liver, spleen, and lungs, as well as the ratio of hepatic-to-extrahepatic uptake, was determined from static equilibrium images. Relative to preoperative values, there were significant decreases in plasma clearance rate, percentage of liver uptake, and ratio of hepatic-to-extrahepatic uptake and significant increases in percentage of spleen and lung uptake on postoperative studies. The mechanism of technetium-99m-labeled sulfur colloid extraction by the liver is different from that of other radiocolloids; it does not require active phagocytosis or pinocytosis. Thus, liver uptake of this tracer principally reflects effective liver blood flow. Portosystemic shunting was documented in these dogs at the time of the postoperative radiocolloid scans, and we believed was responsible for the decrease in liver reticuloendothelial activity. Possible mechanisms for the increased splenic and pulmonary reticuloendothelial activities are discussed.

Cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) is a nucleotide analog with activity against human cytomegalovirus (CMV). A phase I/II dose escalation trial was conducted with asymptomatic human immunodeficiency virus (HIV)-infected patients with CMV viruria to determine its pharmacokinetics, maximally tolerated dose, and preliminary antiviral activity against CMV. Qualitative CMV blood and urine cultures were monitored weekly to assess anti-CMV activity. Twenty-one HIV-infected persons with CD4 counts from 0 to 389 cells per microliters (median, 39) were enrolled in six dose-ranging groups. The first five groups enrolled four patients each to receive cidofovir infusions either weekly or biweekly for 4 weeks or every 3 weeks for 12 weeks. The sixth group enrolled one patient who received infusions of 5 mg/kg of body weight every other week. Patients receiving 0.5 or 1.5 mg/kg twice weekly experienced no serious toxicity. The first two patients who received 5 mg/kg twice weekly developed glycosuria and 2+ proteinuria. Subsequent patients received concomitant probenecid to attempt to ameliorate renal toxicity. Seventeen patients experienced proteinuria on one or more occasions; 6 of them experienced at least 2+ proteinuria. Four patients did not complete the study as planned because of renal toxicity. Positive CMV urine cultures reverted to negative in 2 of 8 patients receiving doses of < or = 1.5 mg/kg twice weekly and 11 of 13 patients receiving higher doses. Cidofovir has in vivo anti-CMV activity demonstrated by prolonged clearing of CMV viruria, although this observation is tempered by the fact that clearance of viremia could not be demonstrated. The dose-limiting toxicity is renal; however, concurrent administration of probenecid may be protective. The maximally tolerated weekly intravenous dose with probenecid is approximately 5 mg/kg. Efficacy trials with CMV disease will define the therapeutic utility and optimal dosing interval for cidofovir.

Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, is a novel antiviral nucleotide analogue with potent in vitro and in vivo activity against cytomegalovirus (CMV) and other herpesviruses. Thirty-one human immunodeficiency virus-seropositive patients with asymptomatic CMV excretion were evaluated in a phase I/II study with 2 regimens of cidofovir: cidofovir alone at doses of 0.5, 1.0, 3.0, or 10.0 mg/kg/week (20 patients) and cidofovir at 3.0, 5.0, or 7.5 mg/kg with concomitant oral probenecid, saline prehydration, extended dosing intervals, and drug interruption for proteinuria (19 patients). Prolonged and dose-dependent anti-CMV effect was observed with all cidofovir regimens > or = 3.0 mg/kg. The dose-limiting toxicity of cidofovir was dose- and schedule-dependent nephrotoxicity. Four of 20 patients had serum creatinine levels > or = 2.0 mg/dL after a mean cumulative exposure of 14.8 mg/kg cidofovir alone; however, none of 19 patients receiving the modified regimen had elevated creatinine (mean cidofovir exposure, 32.2 mg/kg). The clinical efficacy of cidofovir and its potential for cumulative nephrotoxicity needs further study in patients with end-organ CMV disease.

Rationale and Objectives: We evaluated the imaging characteristics of an interstitially or intraperitoneally delivered iodinated particulate contrast agent for computed tomography (CT) lymphography of the craniocervical and thoracic lymph nodes., Methods: We injected 2-4 ml of 15% wt/vol iodinated nanoparticle suspension subcutaneously, submucosally, or intraperitoneally in eight normal dogs. CT and plain radiographic images were obtained prior to contrast administration and 4 hr, 24 hr, and 7 days after injection. Correlation was made to detailed postmortem assessment., Results: CT images showed enhancement of regional nodes draining injection sites. Mean attenuation of opacified nodes was 313 +/- 297 (mean +/- standard deviation), 536 +/- 453, and 492 +/- 372 Hounsfield units at 4 hr, 24 hr, and 7 days postinjection, respectively. Lymph node opacification on CT images correlated well with node location found at postmortem., Conclusion: Craniocervical and thoracic lymph nodes can be effectively opacified from interstitial or intraperitoneal delivery of this iodinated nanoparticulate contrast agent.

We studied 31 human pelvic cadaver specimens with 57 intact hip joints. The teardrop, which represents the inferior portion of the acetabular notch, was identified as also was the center of rotation in the articulating femoral head. The pelvic height and the horizontal and vertical distances between the acetabular notch and the hip joint center were measured. We found the center of rotation of the hip joint to be 13 percent of the pelvic height lateral and 7 percent of the pelvic height superior to the teardrop. No sex difference was found.

(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a nucleotide analogue with potent in vitro and in vivo activity against a broad range of herpesviruses, including acyclovir-resistant herpes simplex virus (HSV). A patient with severe acyclovir-resistant perineal HSV infection received intravenous HPMPC at 5 mg/kg/week, with concomitant oral probenecid and prehydration, and had 95% healing after four infusions. The patient developed a hypersensitivity reaction to probenecid and discontinued HPMPC after the fourth infusion. Recurrence of the perineal lesions 2 weeks later prompted initiation of an oral desensitization program to probenecid and enabled the patient to resume therapy. The lesions again responded to infusions of HPMPC, but the drug was discontinued before complete healing because of transient nephrotoxicity (proteinuria, 2+; creatinine, 1.7 mg/dL). HPMPC is a potent antiviral agent that holds promise as a potential treatment for acyclovir-resistant HSV infection.

We report the isolation of a novel human POU domain encoding gene named RDC-1. The POU domain of the RDC-1 encoded protein is highly related to the POU domain potentially encoded by the rat brain-3 sequence and to that of the Drosophila I-POU protein; outside of the POU region, RDC-1 is unrelated to any previously characterized protein. The RDC-1 gene is expressed almost exclusively in normal tissues and transformed cells of neural origin. In the developing mouse and human fetus, RDC-1 is expressed in a spatially and temporally restricted pattern that suggests a critical role in the differentiation of neuronal tissues. In addition, RDC-1 is expressed in a unique subset of tumors of the peripheral nervous system including neuroepitheliomas and Ewing's sarcomas but not neuroblastomas. Based on its unique structural characteristics and expression pattern, we discuss potential functions for the RDC-1 protein.

Transgenic mice that contain constructs of the L-myc gene under the transcriptional control of the immunoglobulin heavy chain enhancer (E mu) develop thymic hyperplasia and are predisposed to T cell lymphomas. Here we describe a second form of malignancy that occurs in aging E mu L-myc transgenic mice. The mean latency period for the development of this malignancy is longer compared with the E mu L-myc T cell lymphomas but the overall incidence is increased threefold. The histopathological morphology is that of a highly malignant mesenchymal neoplasm that closely resembles human fibrous histiocytoma. The tumor cells were classified as myelomonocytic on the basis of several lineage-specific markers and the lack of rearrangements of the immunoglobulin heavy chain and the T cell receptor beta loci. Cultured tumor cells produce macrophage colony-stimulating factor (M-CSF) protein and express the M-CSF receptor, suggesting the involvement of an autocrine loop in this malignancy. Similar to the E mu L-myc T cell lymphomas, these tumors show high-level transgene expression but no detectable levels of endogenous c-myc mRNA, directly implicating the deregulated expression of L-myc in the generation of this malignancy. E mu L-myc myelomonocytic tumors show consistent trisomy of chromosome 16, implicating this as a secondary event in the development of this tumor. In the light of recent findings that L-myc is expressed in human myeloid leukemias and in several human myeloid tumor cell lines, the results described here might implicate L-myc in the development of naturally occurring myeloid neoplasias.

Fine needle aspiration (FNA) biopsy is an increasingly popular method for the evaluation of salivary gland tumors. Of the common salivary gland tumors, mucoepidermoid carcinoma is probably the most difficult to diagnose accurately by this means. A series of 96 FNA biopsy specimens of salivary gland masses, including 34 mucoepidermoid carcinomas, 51 other benign and malignant neoplasms, 7 nonneoplastic lesions and 4 normal salivary glands, were analyzed in order to identify the most useful criteria for diagnosing mucoepidermoid carcinoma. Thirteen cytologic criteria were evaluated in the FNA specimens, and a stepwise logistic regression analysis was performed. The three cytologic features selected as most predictive of mucoepidermoid carcinoma were intermediate cells, squamous cells and overlapping epithelial groups. Using these three features together, the sensitivity and specificity of accurately diagnosing mucoepidermoid carcinoma were 97% and 100%, respectively.

A case of benign neurilemoma (schwannoma) arising in the breast is presented, including the fine needle aspiration (FNA) biopsy findings. The aspirate yielded a cellular smear composed of clusters of spindle-shaped cells showing minimal atypia. The absence of mitotic figures and breast epithelium suggested a benign neoplasm. The final diagnosis was established on the excised mass by histopathologic study and the use of special stains. The utility and pitfalls of FNA biopsy in diagnosing this rare entity are discussed.

Detailed post mortem examination of the lungs of horses with exercise-induced pulmonary haemorrhage (EIPH) has demonstrated significant small airway disease and intense bronchial arterial proliferation in the dorsocaudal lungfields. The purpose of this study was to investigate ventilation and perfusion distribution in the lungs of a similar group of horses to compare changes in the live animal with the previously reported post mortem findings. Thoracic radiography and ventilation/perfusion (V/Q) scintigraphy were performed on five racing Thoroughbreds with recent histories of EIPH. Parametric images of V/Q ratios for left and right lungfields were also generated from the scan images. In all horses, ventilation and perfusion deficits were demonstrated in the dorsocaudal areas of the lung corresponding closely to the observed radiographic lesions. In particular, the perfusion images and V/Q ratio displays indicated that, in affected areas of lung, pulmonary arterial perfusion was the more seriously impaired. This finding appears to confirm the post mortem evidence of reduced pulmonary arterial perfusion and bronchial arterial dominance in these areas. Ventilation deficits in the same areas also confirmed the likelihood of partial airway obstruction consistent with the small airway disease noted in previous post mortem observations. These results suggest that the vascular and airway lesions demonstrated in detailed post mortems of horses with EIPH are also functionally important in affected horses, even at rest. As a consequence of the apparent persistent, insidious and progressive nature of the lesions associated with EIPH there are serious long term implications for management of the condition.

This study describes the development of a radioaerosol technique for horses using 99mtechnetium-DTPA (diethylenetriaminepentacetate). In 24 normal, adult horses, very satisfactory ventilation images were obtained with the technique. Four-minute administrations of the aerosol resulted in a mean uptake of radioactivity in the lung fields of 3.02 mCi, with mean maximum counts (+/- sd) of 159,800 +/- 75,000 per camera field. The mean clearance half-time for the 99mtechnetium-DTPA from the lung fields was 55.6 +/- 14.2 mins which is very similar to figures obtained for normal human and dog lungs. The results of this study suggest that ventilation imaging with 99mtechnetium-DTPA is a clinically practical method of obtaining regional information on ventilation function in the horse.

The gastric antisecretory and gastrointestinal (GI) motility activity of the natural and unnatural allenic isomers and degradation products of enprostil (methyl(+/-)-7-[(1R*,2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy - 1-butenyl]-5-oxocyclopentyl]-4,5-heptadienoate, RS-84135-004) were studied in the rat. The natural R-allenic isomer of enprostil was the most potent antisecretory compound. The 8-iso-enprostil, enprostil free acid, and the 5-acetylene isomer had somewhat less activity while the other compounds were relatively inactive. The natural and unnatural allenic isomers increased intestinal dye transit with the same rank potency as the gastric antisecretory activity. Enprostil, 8-iso-enprostil, prostaglandin A-enprostil and enprostil free acid, all increased intestinal dye transit.

This study was initiated to determine the rate and characteristics of 99mTc-DTPA clearance from the lungs of unanesthetized sheep exposed to varying concentrations of O3 for 4 h in a whole-body exposure chamber. Four sheep exposed to 1 ppm O3 had a monoexponential T50 of 274 +/- 81 min (SD), not significantly different from sham exposures (316 +/- 150); 5 sheep exposed to 2 ppm had a T50 of 234 +/- 101 min, not significantly different from sham exposures (364 +/- 131 min). Five additional unanesthetized sheep exposed to 2 ppm for 4 h via a nasotracheal tube had a T50 of 192 +/- 55 min, significantly different from sham exposures (300 +/- 96 min). The results show that the effect of oxidant pollutants on the permeability of alveolobronchiolar epithelium may be assessed in conscious sheep.

Arterial complications following ergotamine therapy have been well recognized since the beginning of this century. Venous complications, however, have only rarely been reported. A 48 year old Nigerian woman developed extra-hepatic portal hypertension coincident with a chronic overdosage of ergotamine. The literature elucidating the possible mechanisms involved is reviewed.