Overcoming Nonlinear Partial Volume Effects in Known-Component Reconstruction of Cochlear Implants.

Nonlinear partial volume (NLPV) effects can be significant for objects with large attenuation differences and fine detail structures near the spatial resolution limits of a tomographic system. This is particularly true for small metal devices like cochlear implants. While traditional model-based approaches might alleviate these artifacts through very fine sampling of the image volume and subsampling of rays to each detector element, such solutions can be extremely burdensome in terms of memory and computational requirements. The work presented in this paper leverages the model-based approach called "known-component reconstruction" (KCR) where prior knowledge of a surgical device is integrated into the estimation. In KCR, the parameterization of the object separates the volume into an unknown background anatomy and a known component with unknown registration. Thus, one can model projections of an implant at very high spatial resolution while limiting the spatial resolution of the anatomy - in effect, modeling NLPV effects where they are most significant. We present modifications of the KCR approach that can be used to largely eliminate NLPV artifacts, and demonstrate the efficacy of the modified technique (with improved image quality and accurate implant position estimates) for the cochlear implant imaging scenario.

Percutaneous inner-ear access via an image-guided industrial robot system.

Image-guided robots have been widely used for bone shaping and percutaneous access to interventional sites. However, due to high-accuracy requirements and proximity to sensitive nerves and brain tissues, the adoption of robots in inner-ear surgery has been slower. In this paper the authors present their recent work towards developing two image-guided industrial robot systems for accessing challenging inner-ear targets. Features of the systems include optical tracking of the robot base and tool relative to the patient and Kalman filter-based data fusion of redundant sensory information (from encoders and optical tracking systems) for enhanced patient safety. The approach enables control of differential robot positions rather than absolute positions, permitting simplified calibration procedures and reducing the reliance of the system on robot calibration in order to ensure overall accuracy. Lastly, the authors present the results of two phantom validation experiments simulating the use of image-guided robots in inner-ear surgeries such as cochlear implantation and petrous apex access.

Lack of a clinically relevant effect of an antacid on the pharmacokinetics of lersivirine.

Lersivirine (UK-453,061) is a next-generation nonnucleoside reverse transcriptase inhibitor that displays potent antiviral activity. Lersivirine solubility is pH dependent; therefore, the effect of coadministration of antacid on the pharmacokinetics of lersivirine in healthy subjects was investigated. The ratio of adjusted geometric means (750 mg lersivirine plus 20 ml Maalox Max/750 mg lersivirine alone) for the area under the curve from time zero extrapolated to infinite time (AUC(inf)) was 101.86%, showing that coadministration of an antacid had no effect on lersivirine exposure. Coadministration appeared to be safe and relatively well tolerated.

Temporal bone imaging: comparison of flat panel volume CT and multisection CT.

BACKGROUND AND PURPOSE: A recent development in radiology is the use of flat panel detectors in CT to obtain higher-resolution images. This technique is known as flat panel volume CT (fpVCT). We sought to compare the image quality and diagnostic value of 2 different flat panel detector-equipped scanners: one is a prototype fpVCT scanner, and the other is a so-called flat panel digital volume tomography (fpDVT) scanner, which is routinely used in clinical setup with current state-of-the-art multisection CT (MSCT) scanners. MATERIALS AND METHODS: Five explanted temporal bones and 2 whole-head cadaveric specimens were scanned with fpVCT, fpDVT, and MSCT scanners. The image series were blindly evaluated by 3 trained observers who rated 38 anatomic structures with regard to their delineation/appearance. RESULTS: Although the image quality obtained with fpVCT and fpDVT was rated significantly better compared with MSCT on isolated temporal bones, the differences were not significant when whole cadaveric heads were scanned. CONCLUSIONS: Theoretic and practical advantages exist for flat panel detector-equipped scanners, including improved image quality. However, when imaging whole cadaveric heads, no significant difference could be demonstrated between them and standard-of-care MSCT.

Effects of methoxylation of apocynin and analogs on the inhibition of reactive oxygen species production by stimulated human neutrophils.

Owing to their multiple side effects, the use of steroidal drugs is becoming more and more controversial, resulting in an increasing need for new and safer anti-inflammatory agents. In the inflammatory process, reactive oxygen species produced by phagocytic cells are considered to play an important role. We showed that apocynin (4'-hydroxy-3'-methoxy-acetophenone or acetovanillone), a non-toxic compound isolated from the medicinal plant Picrorhiza kurroa, selectively inhibits reactive oxygen species production by activated human neutrophils. Apocynin proved to be effective in the experimental treatment of several inflammatory diseases such as arthritis, colitis and atherosclerosis. These features suggest that apocynin could be a prototype of a novel series of non-steroidal anti-inflammatory drugs (NSAIDs). So far, apocynin is mainly used in vitro to block NADPH oxidase-dependent reactive oxygen species generation by neutrophils. In order to get a better insight in what chemical features play a role in the anti-inflammatory effects of apocynin, a structure-activity relationship study with apocynin analogs was performed. We show here that especially substances with an additional methoxy group at position C-5 display enhanced anti-inflammatory activity in vitro. Our approach may lead to the development of more effective anti-inflammatory agents which are safe and which lack the side effects of steroids.

Immunomodulatory and anti-inflammatory activity of Picrorhiza scrophulariiflora.

Extracts of the rhizomes of Picrorhiza scrophulariiflora Pennell (Scrophulariaceae) were investigated for their in vitro and in vivo immunomodulatory properties. Diethyl ether extracts showed potent inhibitory activity towards the classical pathway of the complement system, the respiratory burst of activated polymorphonuclear leukocytes, and mitogen-induced proliferation of T-lymphocytes. Furthermore, such extracts showed anti-inflammatory activity towards carrageenan-induced paw edema. No effects were observed in experimentally induced arthritis in mice.

Cochlear implant performance in senior citizens.

Cochlear implants are indicated for elderly patients with severe-to-profound hearing loss (sensorineural hearing loss >/=70 dB). Their use has been limited, possibly by the misconception that elderly patients will perform poorly. To document the performance of older adults (> or =65 years old), we undertook a retrospective analysis of our postlingually deafened adult patients who underwent implantation with the CLARION Multi-Strategy Cochlear Implant and underwent formal audiologic analysis (sentence recognition [Central Institute for the Deaf, CID] and monosyllabic word recognition (consonant-noun-consonant, CNC)). Both younger (n = 20; mean age = 46.9 years) and older (n = 16; mean age = 71.5 years) adults showed statistically significant increases in CID and CNC scores after cochlear implantation. No statistically significant difference could be detected in operative time, anesthesia time, length of hospitalization, or CID or CNC scores between the two age groups. We conclude that age should not be a criterion for deciding who should receive cochlear implants.

Inhibition of T-lymphocyte proliferation by cucurbitacins from Picrorhiza scrophulariaeflora.

Two cucurbitacin aglycons were isolated from the dried rhizomes of Picrorhiza scrophulariaeflora and were identified as 25-acetoxy-2,3, 16,20-tetrahydroxy-9-methyl-19-norlanosta-5,23-dien-22-one (picracin, 1) and 2,3,16,20,25-pentahydroxy-9-methyl-19-norlanosta-5, 23-dien-22-one (deacetylpicracin, 2). Both compounds inhibit mitogen-induced T-lymphocyte proliferation at an IC(50) value of 1 microM.

Nodal volume reduction after concurrent chemo- and radiotherapy: correlation between initial CT and histopathologic findings.

BACKGROUND AND PURPOSE: The role of concurrent chemoradiation for treatment of head and neck squamous cell carcinoma is expanding. We sought to evaluate the CT appearance of diseased and normal cervical lymph nodes before and after concurrent chemoradiation and to correlate lymph node volume reduction as revealed by CT with histopathologic findings of resected nodes. METHODS: Using concurrent chemoradiation, we treated seven patients with locally advanced head and neck squamous cell carcinoma. Our chemotherapeutic regimen consisted of cisplatin (100 mg/m2 body surface area administered on days 1 through 4 and 29 through 32) and 5-fluorouracil (1000 mg/m2 body surface area, administered on days 1 through 4 and 29 through 32). Radiotherapy was administered twice per day on dosing days 1 through 42 to a total dose of 7200 cGy to the primary tumor and 6000 cGy to the involved lymph nodes. Pre- and post-treatment CT scans were used to calculate lymph node volumes for all CT-positive (size criteria or extracapsular spread or both) diseased nodes (n = 19) and one normal node per patient (n = 7). Volume reduction was determined by CT results and correlated with the histopathologic findings of resected nodes. RESULTS: Average volume reduction (+/- standard error of the mean) for the 19 diseased nodes was 91%+/-4% and for the seven normal nodes was 55%+/-21% (P < .02, two-sided t test). Fifteen of 19 of the diseased lymph nodes showed extracapsular spread before treatment and none of 19 after treatment. The histopathologic findings of resected nodes included persistent tumor in one of the 19 diseased lymph nodes. Six of seven patients remained alive and disease-free, with an average follow-up duration of 24 months. CONCLUSION: Nodal volume reduction of greater than 90% was associated with eradication of tumor as assessed by histopathologic analysis of resected nodes. Serial CT scans obtained both before and after concurrent chemoradiation may be useful for predicting which patients will benefit from adjuvant surgical therapy.

Allergy increases susceptibility to otitis media with effusion in a rat model. Second place--Resident Clinical Science Award 1998.

To investigate the possible relationship between allergy and otitis media with effusion (OME), we investigated the hypothesis that allergen presentation to the middle ear causes functional disruption of the eustachian tube predisposing to the development of OME. Thirteen of 19 Brown-Norway rats were sensitized to ovalbumin, and the remaining 6 served as nonallergic controls. To mimic subclinical exposure to allergen, we transtympanically injected ovalbumin at a dose (0.01 mg) that produced no changes detectable by otologic examination. Next, both allergic and nonallergic rats were exposed to transtympanic injection of either low-dose (10 microg/mL) or high-dose (100 microg/mL) lipopolysaccharide to simulate bacterial exposure. The allergic rats were found to have larger middle ear effusions when exposed to high-dose lipopolysaccharide as compared with the nonallergic controls. This response could be inhibited by diphenhydramine. We conclude that allergen presentation to the middle ear of allergic rats causes eustachian tube dysfunction predisposing to OME.

Complement-Inhibiting Constituents of Bridelia ferruginea Stem Bark.

A bioassay-guided fractionation of an 80% acetone extract from BRIDELIA FERRUGINEA stem bark showing a dose-dependent inhibitory effect towards both the classical and the alternative pathways of the complement system resulted in the isolation of a biflavanol (gallocatechin-(4'- O-7)-epigallocatechin) ( 1), 3,5-dicaffeoylquinic acid ( 2), 1,3,4,5-tetracaffeoylquinic acid ( 3), and a series of 3-methoxyflavone derivatives, including quercetin 3-methyl ether ( 4), quercetin 3,7,3',4'-tetramethyl ether ( 5), myricetin 3',4',5'-trimethyl ether ( 6; new compound) named ferrugin, myricetin 3,3',4',5'-tetramethyl ether ( 7), myricetin ( 8), and quercetin 3- O-glucoside ( 9) as the active constituents. Especially the biflavanol 1 and the caffeoyl esters of quinic acid 2 and 3 showed a strong inhibitory effect (IC (50) < 10 microM) on the classical pathway, compared to rosmarinic acid. Also on the alternative pathway, the biflavanol 1, the quinic acid derivatives 2 and 3, and some of the 3-methoxyflavones 5, 7 and 8 were more active than rosmarinic acid. The quinic acid derivatives were shown to be inhibitors of the C1 component and the terminal route of the complement system.

Histopathology of solar lentigines of the face: a quantitative study.

BACKGROUND: Solar lentigines are acquired pigmented lesions on sun-damaged skin that in general have both keratinocytic and melanocytic hyperplasia, but no melanocytic atypia and no nests of melanocytes. Most histopathologic studies of solar lentigines have been limited to sites other than the face and have not included a systematic and quantitative assessment of the diagnostic features. OBJECTIVE: Our purpose was to systematically quantitate a variety of histologic parameters that may be useful in the diagnosis of facial solar lentigines. METHODS: We retrospectively evaluated 51 solar lentigines from 51 patients. This included a review of the hematoxylin-eosin, Mel-5 immunoperoxidase, and Fontana-Masson stains to quantify melanocytes (per millimeter), melanin content of the epidermis, and epidermal area by means of a computer-assisted image analysis program. RESULTS: Lentigines from the face often had a flattened epidermis (25 of 51). They also had a mean 2.1-fold increase in melanocytes (p < 0.001), a 2.1-fold increase in epidermal area (p < 0.001), and a 2.2-fold increase in epidermal melanin content (p < 0.001) compared with normal photoexposed facial skin. CONCLUSION: Facial solar lentigines had a statistically significant twofold increase in both epidermal area and number of melanocytes compared with facial skin with a similar degree of photodamage, but frequently lacked the rete ridge hyperplasia classically associated with lentigines from other anatomic sites. These morphologic data may be helpful in the evaluation of biopsy specimens from pigmented lesions on photodamaged facial skin.

Inhibition of human complement by beta-glycyrrhetinic acid.

Licorice, the root extract of Glycyrrhiza glabra I., is used as a medicine for various diseases. Anti-inflammatory as well as anti-allergic activities have been attributed to one of its main constituents, glycyrrhizin. These activities are mainly ascribed to the action of the aglycone, beta-glycyrrhetinic acid. beta-Glycyrrhetinic acid has a steroid-like structure and is believed to have immunomodulatory properties. To determine whether interference with complement functions may contribute to the immunomodulatory activity of beta-glycyrrhetinic acid, its effects on the classical and alternative activation pathways of human complement were investigated. We found that beta-glycyrrhetinic acid is a potent inhibitor of the classical complement pathway (IC50 = 35 microM), whereas no inhibitory activity was observed towards the alternative pathway (IC50 > 2500 microM). The anticomplementary activity of beta-glycyrrhetinic acid was dependent on its conformation, since the alpha-form was not active. It was also established that naturally occurring steroids, e.g. hydrocortisone and cortisone, did not inhibit human complement activity under similar conditions. Detailed mechanistic studies revealed that beta-glycyrrhetinic acid acts at the level of complement component C2.

Podacycline A and B, two cyclic peptides in the latex of Jatropha podagrica.

Two novel cyclic peptides were isolated from the latex of Jatropha podagrica, which we named podacycline A and B. Podacycline A is a cyclic nonapeptide with the sequence Gly1-Leu2-Leu3-Gly4-Ala5-Val6-Trp7-Ala8-Gly9+ ++-Gly1. The sequence of podacycline B, a cyclic heptapeptide, was determined to be Phe1-Ala2-Gly3-Thr4-Ile5-Phe6-Gly7-Phe1. The amino acid residues of both compounds were found to have the L-configuration.

Pulsatile perfusion system for ex vivo investigation of biochemical pathways in intact vascular tissue.

We have constructed and performed initial validation of an innovative perfusion system that allows exposure of intact segments of vascular tissue to realistic physiological and hemodynamic environments ex vivo. Computer-controlled opening and closing of an in-line gate valve allows generation of arterial pressure waveforms. The control algorithm predicted resultant pressure waveforms with a high degree of accuracy (Pearson correlation coefficient > 0.97). To document vascular homeostasis ex vivo, vasomotor bioassays and morphological studies were performed. The bioassays consisted of injecting epinephrine (2 x 10(-3) mg/ml) into the perfusion system followed by acetylcholine (100 microM) while concurrently measuring vessel diameter with a laser micrometer, significant vasomotion was measured for canine carotid arteries (n = 4) bioassayed after 1, 24, and 48 h of perfusion (P < 0.03). Additionally, human saphenous vein segments were perfused for 24 h (n = 4) and viewed with laser confocal scanning microscopy and transmission electron microscopy; photomicrographs show typical vascular morphology. We conclude that the vascular perfusion system described herein is well suited for investigating the response of intact vascular tissue to hemodynamic variables.

Cyclogossine A: a novel cyclic heptapeptide isolated from the latex of Jatropha gossypifolia.

From the latex of Jatropha gossypifolia L. (Euphorbiaceae) a novel cyclic heptapeptide was isolated, which we named cyclogossine A. A combination of amino acid analysis, FAB mass spectrometry, and two dimensional 1H-NMR spectroscopy (TOCSY and ROESY) was used to determine the primary structure. The compound was found to contain one glycine, one alanine, one valine, two leucine, one threonine, and one tryptophan residue; its amino acid sequence is: Leu 1 - Ala 2 - Thr 3 - Trp 4 - Leu 5 - Gly 6 - Val 7. The absolute configurations of the amino acids were determined by chiral gas chromatography; all have the L-configuration.

Ayurvedic herbal drugs with possible cytostatic activity.

Ayurveda is considered to be the traditional science of health in India and is based on the principle of subjectivity. All matter is composed of five basic elements, which can be perceived by the five sense organs. All food and drugs are classified according to their pharmacological properties, which are derived from these five elements. To investigate which Ayurvedic plants might have cytostatic activity, an Ayurvedic model for the pathogenesis of cancer was made. Based on this, selection criteria were formed, that were used to select plants from a list of Ayurvedic herbal drugs. Some of the selected species could be collected in India and Nepal. The dried material of 14 species was submitted to ethanol (70% v/v) extraction and the extracts were tested for cytotoxicity on COLO 320 tumour cells, using the microculture tetrazolium (MTT) assay. The IC50-value, the concentration causing 50% growth inhibition of the tumour cells, was used as a parameter for cytotoxicity. Extracts of the flowers of Calotropis procera (Ait.) R. Br. (Asclepiadaceae) and of the nuts of Semecarpus anacardium L.f. (Anacardiaceae) displayed the strongest cytotoxic effect with IC50-values of 1.4 micrograms/ml and 1.6 micrograms/ml, respectively. The extracts of several other plants did not show a cytotoxic effect up to 100 micrograms/ml, the highest concentration tested.

Photoaging versus intrinsic aging: a morphologic assessment of facial skin.

Histologic studies have become increasingly important in recognizing morphologic differences in photoaged versus intrinsically aged skin. Earlier histologic studies have attempted to evaluate these changes by examining anatomical sites which are not comparable, such as face and buttocks. As part of a multicenter study, we have quantitatively examined a panel of 16 histologic features in baseline facial skin biopsies from 158 women with moderate to severe photodamage. When compared to the postauricular area (photo protected), biopsies of the crow's feet area (photo exposed) had a twofold increase in melanocytes and a statistically significant increase in melanocytic atypia (p < .0001) and epidermal melanin (p < .0001). Other epidermal changes included reduced epidermal thickness (p < .01), more compact stratum corneum (p < .0001) and increased granular layer thickness (p < .0001) in the crow's feet skin. There was increased solar elastosis (p < .0001), dermal elastic tissue (p < .0001), melanophages (p < .0001), perivascular inflammation (p < .05) and perifollicular fibrosis (p < .01) but no change in the number of mast cells or dermal mucin in the photo exposed skin. Our data document quantitative differences in photoaged versus intrinsically aged facial skin and provides the groundwork for future studies to evaluate the efficacy of new treatments for photoaged skin.