Persistent idiopathic ventricular tachycardia in a 28-year-old woman.

The case history is presented of a normally fit and well 28-year-old woman with idiopathic right ventricular outflow tract ventricular tachycardia (RVOT VT). Presentation was with a broad complex tachycardia unresponsive to first-line anti-arrhythmic drugs and DC cardioversion (immediate recurrence) but highly sensitive to flecainide and eventually successfully treated with catheter ablation. Assessment and management of broad complex tachycardia is challenging but requires a structured approach to the underlying differential diagnosis. Ventricular tachycardia may occur in structurally normal hearts and not cause haemodynamic compromise despite persistence over 48 h, as in this case. The clinical history, ECG morphology and response to adenosine were all instrumental in making the diagnosis and hence tailoring appropriate anti-arrhythmic therapy when DC cardioversion failed.

Randomised controlled trial of home based motivational interviewing by midwives to help pregnant smokers quit or cut down.

OBJECTIVE: To determine whether motivational interviewing--a behavioural therapy for addictions-provided at home by specially trained midwives helps pregnant smokers to quit. DESIGN: Randomised controlled non-blinded trial analysed by intention to treat. SETTING: Clinics attached to two maternity hospitals in Glasgow. PARTICIPANTS: 762/1684 pregnant women who were regular smokers at antenatal booking: 351 in intervention group and 411 in control group. INTERVENTIONS: All women received standard health promotion information. Women in the intervention group were offered motivational interviewing at home. All interviews were recorded. MAIN OUTCOME MEASURES: Self reported smoking cessation verified by plasma or salivary cotinine concentration. RESULTS: 17/351 (4.8%) women in the intervention group stopped smoking (according to self report and serum cotinine concentration < 13.7 ng/ml) compared with 19/411(4.6%) in the control group. Fifteen (4.2%) women in the intervention group cut down (self report and cotinine concentration less than half that at booking) compared with 26 (6.3%) in the control group. Fewer women in the intervention group reported smoking more (18 (5.1%) v 44 (10.7%); relative risk 0.48, 95% confidence interval 0.28 to 0.81). Birth weight did not differ significantly (mean 3078 g v 3048 g). CONCLUSION: Good quality motivational interviewing did not significantly increase smoking cessation among pregnant women.

Tuned aperture computed tomography to evaluate osseous healing.

Quantification of osseous healing is a challenging task, requiring expensive advanced imaging modalities. To improve diagnostic osseous imaging, we undertook this prospective study to explore the potential of Tuned Aperture Computed Tomography. Eighty defects in 20 rabbit mandibles, randomly carrying an osteoblast suspension or a polymer matrix or a combination thereof or no treatment, were imaged at 3, 6, 9, and 12 weeks post-surgery. TACT slices, iteratively restored TACT, and conventional digital radiographs were evaluated. Mean-gray-value distribution within regions of interest was correlated with histomorphometric data. Lesions treated with osteoblast/polymer-matrix delivery systems demonstrated the highest mean gray-value, while the diagnostic efficacy of TACT-IR was significantly better than that of other imaging modalities (p < 0.001). Thus, TACT is an accurate imaging modality for non-destructive quantification of osseous dynamics.

Fractal analyses of osseous healing using tuned aperture computed tomography images.

The aim of this study was to evaluate osseous healing in mandibular defects using fractal analyses on conventional radiographs and tuned aperture computed tomography (TACT; OrthoTACT, Instrumentarium Imaging, Helsinki, Finland) images. Eighty test sites on the inferior margins of rabbit mandibles were subject to lesion induction and treated with one of the following: no treatment (controls); osteoblasts only; polymer matrix only; or osteoblast-polymer matrix (OPM) combination. Images were acquired using conventional radiography and TACT, including unprocessed TACT (TACT-U) and iteratively restored TACT (TACT-IR). Healing was followed up over time and images acquired at 3, 6, 9, and 12 weeks post-surgery. Fractal dimension (FD) was computed within regions of interest in the defects using the TACT workbench. Results were analyzed for effects produced by imaging modality, treatment modality, time after surgery and lesion location. Histomorphometric data were available to assess ground truth. Significant differences (p < 0.0001) were noted based on imaging modality with TACT-IR recording the highest mean fractal dimension (MFD), followed by TACT-U and conventional images, in that order. Sites treated with OPM recorded the highest MFDs among all treatment modalities (p < 0.0001). The highest MFD based on time was recorded at 3 weeks and differed significantly with 12 weeks (p < 0.035). Correlation of FD with results of histomorphometric data was high (r = 0.79; p < 0.001). The FD computed on TACT-IR showed the highest correlation with histomorphometric data, thus establishing the fact TACT is a more efficient and accurate imaging modality for quantification of osseous changes within healing bony defects.

Emission tuned-aperture computed tomography: a novel approach to scintimammography.

UNLABELLED: Emission tuned-aperture computed tomography (ETACT) is a new approach to acquiring and processing scintimammography data. A gamma camera with a pinhole collimator is used to acquire projections of the radionuclide distribution within the breast. Fiducial markers are used to reconstruct these projections into tomographic slices. Simulation and phantom experiments were performed to evaluate the potential of the ETACT method. METHODS: In the simulation study, a hemispheric object of 15 cm in diameter was constructed to model a breast. A ray-tracing technique was used to generate ideal projections. These were blurred and noise was added to create images that resemble scintigraphic images. Tumor size, pinhole size, and target-to-nontarget radioactivity ratios (TNTs) were varied. The simulated projections were reconstructed into slices, and contrast and contrast-to-noise ratios were calculated to evaluate the effect of pinhole size. These results were compared with a simulated planar acquisition of the same object. A preliminary phantom evaluation was performed using an 8-mm "tumor" with a 10:1 TNT to validate the simulation results. RESULTS: A 3-mm pinhole was shown by the simulation study to be the optimal size. The ETACT images consistently yielded higher contrast than simulated planar images. The phantom study validated the simulation results and showed the feasibility of ETACT in a simulated clinical environment. CONCLUSION: ETACT is shown to be useful for imaging tumors <1 cm in diameter. Because ETACT requires only a gamma camera with a pinhole collimator, it has the potential to be applied in any hospital in a simple, flexible, and practical manner.

Evaluation of linear and nonlinear tomosynthetic reconstruction methods in digital mammography.

RATIONALE AND OBJECTIVES: The purpose of this study was to comparatively evaluate digital planar mammography and both linear and nonlinear tomosynthetic reconstruction methods. MATERIALS AND METHODS: A "disk" (ie, target) identification study was conducted to compare planar and reconstruction methods. Projective data using a composite phantom with circular disks were acquired in both planar and tomographic modes by using a full-field, digital mammographic system. Two-dimensional projections were reconstructed with both linear (ie, backprojection) and nonlinear (ie, maximization and minimization) tuned-aperture computed tomographic (TACT) methods to produce three-dimensional data sets. Four board-certified radiologists and one 4th-year radiology resident participated as observers. All images were compared by these observers in terms of the number of disks identified. RESULTS: Significant differences (P < .05, Bonferroni adjusted) were observed between all reconstruction and planar methods. No significant difference, however, was observed between the planar methods, and only a marginally significant difference (P < .054, Bonferroni adjusted) was observed between TACT-backprojection and TACT-minimization. CONCLUSION: A combination of linear and nonlinear reconstruction schemes may have potential implications in terms of enhancing image visualization to provide radiologists with valuable diagnostic information.

Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus.

BACKGROUND: Recent studies suggest that paraneoplastic pemphigus (PNP) is a heterogeneous autoimmune syndrome involving several internal organs and that the pathophysiological mechanisms mediating cutaneous, mucosal, and internal lesions are not limited to autoantibodies targeting adhesion molecules. OBJECTIVE: To classify the diverse mucocutaneous and respiratory presentations of PNP and characterize the effectors of humoral and cellular autoimmunity mediating epithelial tissue damage. METHODS: We examined 3 patients manifesting the lichen planus pemphigoideslike subtype of PNP. A combination of standard immunohistochemical techniques, enzyme-linked immunosorbent assay with desmoglein (DSG) baculoproteins, and an immunoprecipitation assay were used to characterize effectors of humoral and cellular autoimmunity in patients with PNP and in neonatal wild-type and DSG3-knockout mice with PNP phenotype induced by passive transfer of patients' IgGs. RESULTS: In addition to the known "PNP antigenic complex," epithelial targets recognized by PNP antibodies included 240-, 150-, 130-, 95-, 80-, 70-, 66-, and 40/42-kd proteins but excluded DSG1 and DSG3. In addition to skin and the epithelium lining upper digestive and respiratory tract mucosa, deposits of autoantibodies were found in kidney, urinary bladder, and smooth as well as striated muscle. Autoreactive cellular cytotoxicity was mediated by CD8(+) cytotoxic T lymphocytes, CD56(+) natural killer cells, and CD68(+) monocytes/macrophages. Inducible nitric oxide synthase was visualized both in activated effectors of cellular cytotoxicity and their targets. Keratin 14-positive basal epithelial cells sloughed from the large airways and obstructed small airways. CONCLUSIONS: The paraneoplastic disease of epithelial adhesion known as PNP in fact represents only 1 manifestation of a heterogeneous autoimmune syndrome in which patients, in addition to small airway occlusion and deposition of autoantibodies in different organs, may display a spectrum of at least 5 different clinical and immunopathological mucocutaneous variants (ie, pemphiguslike, pemphigoidlike, erythema multiforme-like, graft-vs-host disease-like, and lichen planus-like). We suggest that the more encompassing term "paraneoplastic autoimmune multiorgan syndrome," or PAMS, be applied. The pathophysiological mechanisms of PAMS involve both humoral and cellular autoimmunity responses. Epithelial cell membrane antigens other than DSG1 or DSG3 are targeted by effectors of PAMS autoimmunity. Apoptosis of damaged basal cells mediates epithelial clefting, and respiratory failure results possibly from obstruction of small airways with sloughed epithelial cells.

Comparison of tomosynthesis methods used with digital mammography.

RATIONALE AND OBJECTIVES: The authors performed this study to investigate the potential applicability of tomosynthesis to digital mammography. Four methods of tomosynthesis-tuned aperture computed tomography (TACT)-backprojection, TACT-iterative restoration, iterative reconstruction with expectation maximization, and Bayesian smoothing-were compared to planar mammography and analyzed in terms of their contrast-detail characteristics. Specific comparisons between the tomosynthesis methods were not attempted in this study. MATERIALS AND METHODS: A full-field, amorphous, silicon-based, flat-panel digital mammographic system was used to obtain planar and tomosynthesis projection images. A composite tomosynthesis phantom with a centrally located contrast-detail insert was used as the object of interest. The total exposure for multiple views with tomosynthesis was always equal to or less than that for the planar technique. Algorithms were used to reconstruct the object from the acquired projections. RESULTS: Threshold contrast characteristics with all tomosynthesis reconstruction methods were significantly better than those with planar mammography, even when planar mammography was performed at more than twice the exposure level. Reduction of out-of-plane structural components was observed in all the tomosynthesis methods analyzed. CONCLUSION: The contrast-detail trends of all the tomosynthesis methods analyzed in this study were better than those of planar mammography. Further optimization of the algorithms could lead to better image reconstruction, which would improve visualization of valuable diagnostic information.

A pilot study to establish a randomized trial methodology to test the efficacy of a behavioural intervention.

How can pregnant women be helped to stop smoking? This was a pilot study of midwife home-based motivational interviewing. Clients were 100 consecutive self-reported smokers booking at clinics in Glasgow from March to May 1997. Smoking guidance is routinely given at booking. In addition, intervention clients received a median of four home-based motivational interviewing sessions from one specially trained midwife. All sessions (n = 171) were audio-taped and interviews (n = 49) from 13 randomly selected clients were transcribed for content analysis. Three 'experts' assessed intervention quality using a recognized rating scale. Cotinine measurement on routine blood samples confirmed self-reported smoking change from late pregnancy telephone interview. Postnatal telephone questionnaire measured client satisfaction. Focus groups of routine midwives explored acceptability, problems and disruption of normal care. Fisher exact, chi 2 and Mann-Whitney tests compared enrolment characteristics. Two-sample t-tests assessed outcome between groups. Motivational interviewing was satisfactory in more than 75% of transcribed interviews. In this pilot study, self-reported smoking at booking (100 of 100 available) corroborated by cotinine (93 of 100) compared with late pregnancy self-reports (intervention 47 of 48; control 49 of 49) and cotinine (intervention 46 of 48; control 47 of 49) showed no significant difference between groups. Tools have been developed to answer the question: 'Can proactive opportunistic home-based motivational interviewing help pregnant smokers reduce their habit?'.

The normal response to prolonged passive head up tilt testing.

OBJECTIVE: To define the responses to head up tilt in a large group of normal adult subjects using the most widely employed protocol for tilt testing. METHODS: 127 normal subjects aged 19-88 years (mean (SD), 49 (20) years) without a previous history of syncope underwent tilt testing at 60 degrees for 45 minutes or until syncope intervened. Blood pressure monitoring was performed with digital photoplethysmography, providing continuous, non-invasive, beat to beat heart rate and pressure measurements. RESULTS: 13% of subjects developed vasovagal syncope after a mean (SD) tilt time of 31.7 (12. 4) minutes (range 8.5-44.9 minutes). Severe cardioinhibition during syncope was observed less often than is reported in patients investigated for syncope. There were no differences in the age or sex distributions of subjects with positive or negative outcomes, or in the proportions with cardioinhibitory and vasodepressor vasovagal syncope compared with previously reported patient populations. Subjects with negative outcomes showed age related differences in heart rate and blood pressure behaviour throughout tilt. CONCLUSIONS: False positive results with tilting appear to be common. This has important implications for the use of diagnostic tilt testing. The magnitude of the heart rate and blood pressure changes observed during negative tilts largely invalidates previously suggested criteria for abnormal non-syncopal outcomes.

Choline acetyltransferase, acetylcholinesterase, and nicotinic acetylcholine receptors of human gingival and esophageal epithelia.

A non-neuronal cholinergic system that includes neuronal-like nicotinic acetylcholine receptors (nAChRs) has recently been described in epithelial cells that line the skin and the upper respiratory tract. Since the use of nicotine-containing products is associated with morbidity in the upper digestive tract, and since nicotine may alter cellular functions directly via nAChRs, we sought to identify and characterize a non-neuronal cholinergic system in the gingival and esophageal epithelia. mRNA transcripts for alpha3, alpha5, alpha7, and beta2 nAChR subunits, choline acetyltransferase, and the asymmetric and globular forms of acetylcholinesterase were amplified from gingival keratinocytes (KC) by means of polymerase chain-reactions. These proteins were visualized in the gingival and esophageal epithelia by means of specific antibodies. Variations in distribution and intensity of immunostaining were found, indicating that the repertoire of cholinergic enzymes and receptors expressed by the cells changes during epithelial maturation, and that an upward concentration gradient of free acetylcholine exists. Blocking of the nAChRs with mecamylamine resulted in reversible loss of cell-to-cell adhesion, and shrinking and rounding of cultured gingival KC. Activation of the receptors with acetylcholine or carbachol caused stretching and peripheral ruffling of the cytoplasmic aprons, and formation of new intercellular contacts. These results demonstrate that both the keratinizing epithelium of attached gingiva and the non-keratinizing epithelium lining the upper two-thirds of the esophageal mucosa possess a non-neuronal cholinergic system. The nAChRs expressed by these epithelia are coupled to regulation of cell adhesion and motility, and may provide a target for the deleterious effects of nicotine.

Receptor-mediated inhibition of keratinocyte migration by nicotine involves modulations of calcium influx and intracellular concentration.

Early stages of wound healing rely on the ability of keratinocytes (KCs) to move over the denuded dermis to re-epithelialize the defect. The agarose gel keratinocyte outgrowth system (AGKOS) is an in vitro model of skin re-epithelialization designed to study the migratory function of KCs. Endogenously secreted acetylcholine controls crawling locomotion of KCs in AGKOS by binding to the cholinergic receptors of both the nicotinic and the muscarinic classes that are expressed by KCs. In this study, we used AGKOS to elucidate the nicotinic pathway of cholinergic control of keratinocyte migration. Activation of the nicotinic acetylcholine receptors decreased the migration distance of KC in a dose-dependent fashion without altering cell viability. Nicotine also increased in a dose-dependent manner transmembrane influx of (45)Ca(2+), and caused a transient rise in the concentration of [Ca(2+)](i). Perfect correlation between concentration responses found in the migration and (45)Ca(2+) influx assays suggested that nicotine-induced inhibition of crawling locomotion relies on modulation of Ca(2+) metabolism in KCs. The effects of nicotine could be mediated by the alpha3- and the alpha7-containing nicotinic receptors visualized on KCs by immunostaining. Long-term incubation with nicotine up-regulated alpha7 and down-regulated alpha3 expression. Thus, nicotine exerts inhibitory effects on keratinocyte migration, and Ca(2+) serves as a second messenger in the signaling pathway. These results help explain deleterious effects of nicotine on wound re-epithelialization, and suggest that smoking may delay wound healing via nicotinic receptor-mediated pathway.

A controlled evaluation of tuned-aperture computed tomography applied to digital spot mammography.

The purpose of this work was to compare the detection accuracy of 3-dimensional (3D) modalities of tuned-aperture computed tomography (TACT) with that of conventional 2-dimensional (2D) digital spot mammograms. A standardized mammographic phantom was placed beneath cadaveric breast tissues of varying densities. Five radiologists were asked to detect as many objects (specks, fibers, and low-contrast masses) as possible from 90 displays in a controlled and factorially balanced multivariate experiment. Radiographic exposure was varied systematically, and projections were averaged to ensure stochastic comparability. Scores were weighted to eliminate task-specific bias and were analyzed by multivariate analyses of variance. All display modalities based on the linear application of the 3D TACT reconstruction method yielded significantly higher detection scores for all tasks than did conventional 2D digital spot mammography, which served as the scientific control modality. This effect was found to be statistically significant (P < .001) in spite of significant variations between tissues (P < .001), observers (P < .001), and exposures (P < .01). TACT may be a promising alternative or enhancement to conventional 2D digital mammography for tasks well simulated by this experimental design.

An in vivo comparison of diagnostic information obtained from tuned-aperture computed tomography and conventional dental radiographic imaging modalities.

OBJECTIVE: The purpose of this study was to compare diagnostic information obtained by means of 3-dimensional tuned-aperture computed tomography (TACT) and by means of conventional radiography of patients requiring surgery. STUDY DESIGN: TACT produced digital images that yielded a series of tomographic slices viewed interactively. Controls were conventional periapical and/or panoramic radiographs. Each of 4 independent dentists performed 2 tasks, one requiring an estimation of confidence in their clinical assessments of the patient and the other requiring an estimation of the resulting diagnostic potential for altering associated treatment options. Data were analyzed through use of the nonparametric Mann-Whitney U Wilcoxon rank sum W test. RESULTS: A statistically significant difference for both tasks was observed (2-sided; P<.001). CONCLUSIONS: TACT displays were more diagnostically informative and had more impact on potential treatment options than did conventional radiographs.

Effect of number of projections on accuracy of depth discrimination using tuned-aperture computed tomography for 3-dimensional dentoalveolar imaging of low-contrast details.

OBJECTIVE: The purpose of this study was to test the hypothesis that the number of projections influences the accuracy of a simple depth discrimination task when tuned-aperture computed tomography is used. STUDY DESIGN: In each of 4 partially edentulous mandibles, 2 radiopaque steel spheres were attached to the facial and lingual surfaces and 1 ceramic sphere was place in the apical region of an open tooth socket. Errors in estimates of the depth of the apically positioned ceramic sphere relative to the 2 steel spheres were determined from 3-dimensional tuned-aperture computed tomography reconstructions. These data were compared with actual measurements produced independently by means of an optical micrometer. Multiple projections were produced from radially symmetric exposures bearing an angular disparity of 15 degrees. The number of symmetrically dispersed projections per tuned-aperture computed tomography reconstruction was varied systematically (2, 4, 8, 12, and 16 projections). The consequences of this variable, as well as specimen and observer effects, were evaluated in a balanced factorial experimental design. Depth estimates were performed by 10 trained observers. The depth reported was that corresponding to the tuned-aperture computed tomography slice perceived to yield the image of the ceramic sphere in sharpest focus. Resulting data were normalized by logarithmic transformation and analyzed statistically by analysis of variance. RESULTS: No statistically meaningful effects were found for the number of projections (P = .607) or for different observers (P = .093), but a significant specimen effect was demonstrated (P = .006). CONCLUSIONS: Factors other than high contrast limit the perception of image sharpness under these conditions. Depth may be estimated accurately from relatively small numbers of projections.

An automated injection system (with patient selection) for SPECT imaging in seizure localization.

PURPOSE: Ictal single-photon-emission computed tomography (SPECT) provides lateralization but has technical limitations: (a) a "truly ictal" injection must be shortly after seizure onset; (b) therefore, a seizure of brief duration may be missed; (c) more than one patient may need testing at any given time; (d) a trained health professional must stay next to each patient to inject; and (e) because the radionuclide is placed in the syringe in advance of the injection, decay of the radioactive element could result in less than optimal uptake, if the same volume of material were to be used regardless of the time after ligand preparation. METHODS: We developed an automated method of ligand injection that shortens time and increases efficiency of ictal SPECT ligand injection. By using an experimental setup, we compared manual injection times with times using an automated injection system. We determined relative costs and efficiency in work hours for the manual and automated methods. RESULTS: Injection times were 8-14 s with automated versus 19-26 s with manual injection. Readjusting volume for "ligand" decay was simple and accurate with the automated system. Injection times for clinical SPECT studies in three patients were 13, 13, and 12 s, respectively. The price of one pump equals 120 work hours of a nurse or 24 ictal injection attempts. Much of the nurse's time is "wasted" because no seizure occurs. CONCLUSIONS: The method can be more efficient of staff, shorten injection time, and facilitate obtaining "truly ictal" injections. It allows more cost-effective use of personnel.

Effects of projection geometry and number of projections on accuracy of depth discrimination with tuned-aperture computed tomography in dentistry.

OBJECTIVE: The purpose of this study was to determine the degree to which the number and angular disparity of component projections influence depth discrimination with tuned-aperture computed tomography. STUDY DESIGN: Groups of three tiny steel spheres served as fiducial references on and in four partially edentulous mandibles. Two spheres were attached to the facial and lingual surfaces of each mandible, and the third was fixed in the apical region of an open tooth socket. Errors in estimates of the depth of the apically positioned sphere relative to the other two spheres were determined from three-dimensional tuned-aperture computed tomography reconstructions. These data were compared with actual measurements produced independently with an optical micrometer. Multiple projections required by the tuned-aperture computed tomography reconstruction algorithm were produced from radially symmetric exposures bearing angular disparities of 5, 15, 30, and 45 degrees. The number of symmetrically dispersed projections per tuned-aperture computed tomography reconstruction likewise was varied systematically (2, 4, 8, 12, and 16 projections). These variables were manipulated through the use of a balanced factorial design. Depth estimates were performed by trained observers; the estimates were based on the determination of tuned-aperture computed tomography slices perceived as imaging the respective apical spheres in sharpest focus. Specimen and observer effects were also considered as independent variables. Resulting data were normalized by logarithmic transformation and analyzed statistically by analysis of variance. RESULTS: Significant differences (p < 0.005) were demonstrated for angular disparity and specimen effects, but the number of projections and the effect of the observer were not found to be statistically significant. CONCLUSIONS: In dentistry, angular disparities of 15 degrees or greater should be used when tuned-aperture computed tomography is being applied to diagnostic tasks requiring maximal depth discrimination accuracy.

Lysosomal lipid accumulation from oxidized low density lipoprotein is correlated with hypertrophy of the Golgi apparatus and trans-Golgi network.

Lipid accumulation within macrophages is a major sequelae of atherosclerosis. Much of this lipid accumulation occurs within large, swollen lysosomes. We analyzed lipid accumulation in cultured macrophages using oxidized or acetylated low density lipoprotein (LDL) as the loading agent. Pigeon macrophages incubated for 48 h with mildly oxidized pigeon LDL (TBARS = 5-10 nmol/mg protein) showed significant increases in cellular cholesterol compared with untreated controls. Forty-eight percent of the increased cholesterol occurred as unesterified cholesterol. Treated cells had lipid-swollen lysosomes similar to those of atherosclerotic foam cells. The increase in lysosomal lipid was accompanied (correlation coefficient of 0.96) by increases in acid phosphatase staining cisternae of the Golgi and trans-Golgi network (TGN). THP-1 macrophages incubated with oxidized LDL showed similar lysosomal loading and Golgi/TGN hypertrophy. In contrast, macrophages incubated with acetylated LDL accumulated significant amounts of cholesterol but the increase occurred as cholesteryl ester (81% in pigeons) within cytoplasmic droplets and there was no associated increase in acid phosphatase-containing cisternae of Golgi or TGN. The correlation in both pigeon and THP-1 macrophages of oxidized LDL-induced lysosomal lipid accumulation and Golgi hypertrophy suggests a linkage of these two phenomena. This implicates intracellular membrane trafficking as a possible defect in foam cells of the atherosclerotic lesion.

2-Iminohomopiperidinium salts as selective inhibitors of inducible nitric oxide synthase (iNOS).

An attractive approach to the treatment of inflammatory conditions such as osteo- and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the selective inhibition of human inducible nitric oxide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated in the pathology of these diseases. A series of monosubstituted iminohomopiperidinium salts possessing lipophilic functionality at ring positions 3, 5, 6, and 7 has been synthesized, and series members have demonstrated the ability to inhibit the hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that selectively inhibit hiNOS over the human endothelial constitutive enzyme (heNOS) with a heNOS/hiNOS IC50 ratio in excess of 100 and as high as 314 (9). Potencies for inhibition of hiNOS and the human neuronal constitutive enzyme (hnNOS) are comparable. Substitution in the 3 and 7 positions provides compounds that exhibit the greatest degree of selectivity for hiNOS and hnNOS over heNOS. Submicromolar potencies for 6 and 7 in a mouse RAW cell assay demonstrated the ability of these compounds to inhibit iNOS in a cellular environment. These latter compounds were also found to be orally bioavailable and efficacious due to their ability to inhibit the increase in plasma nitrite/nitrate levels in a rat LPS model.