All Publications


  • Histologic evaluation of activation of acute inflammatory response in a mouse model following ultrasound-mediated blood-brain barrier using different acoustic pressures and microbubble doses. Nanotheranostics Pascal, A. n., Li, N. n., Lechtenberg, K. J., Rosenberg, J. n., Airan, R. D., James, M. L., Bouley, D. M., Pauly, K. B. 2020; 4 (4): 210–23

    Abstract

    Rationale: Localized blood-brain barrier (BBB) opening can be achieved with minimal to no tissue damage by applying pulsed focused ultrasound alongside a low microbubble (MB) dose. However, relatively little is known regarding how varying treatment parameters affect the degree of neuroinflammation following BBB opening. The goal of this study was to evaluate the activation of an inflammatory response following BBB opening as a function of applied acoustic pressure using two different microbubble doses. Methods: Mice were treated with 650 kHz ultrasound using varying acoustic peak negative pressures (PNPs) using two different MB doses, and activation of an inflammatory response, in terms of microglial and astrocyte activation, was assessed one hour following BBB opening using immunohistochemical staining. Harmonic and subharmonic acoustic emissions (AEs) were monitored for all treatments with a passive cavitation detector, and contrast-enhanced magnetic resonance imaging (CE-MRI) was performed following BBB opening to quantify the degree of opening. Hematoxylin and eosin-stained slides were assessed for the presence of microhemorrhage and edema. Results: For each MB dose, BBB opening was achieved with minimal activation of microglia and astrocytes using a PNP of 0.15 MPa. Higher PNPs were associated with increased activation, with greater increases associated with the use of the higher MB dose. Additionally, glial activation was still observed in the absence of histopathological findings. We found that CE-MRI was most strongly correlated with the degree of activation. While acoustic emissions were not predictive of microglial or astrocyte activation, subharmonic AEs were strongly associated with marked and severe histopathological findings. Conclusions: Our study demonstrated that there were mild histologic changes and activation of the acute inflammatory response using PNPs ranging from 0.15 MPa to 0.20 MPa, independent of MB dose. However, when higher PNPs of 0.25 MPa or above were applied, the same applied PNP resulted in more severe and widespread histological findings and activation of the acute inflammatory response when using the higher MB dose. The potential activation of the inflammatory response following ultrasound-mediated BBB opening should be considered when treating patients to maximize therapeutic benefit.

    View details for DOI 10.7150/ntno.49898

    View details for PubMedID 32802731

    View details for PubMedCentralID PMC7425053

  • MRI monitoring of focused ultrasound sonications near metallic hardware. Magnetic resonance in medicine Weber, H. n., Ghanouni, P. n., Pascal-Tenorio, A. n., Pauly, K. B., Hargreaves, B. A. 2018; 80 (1): 259–71

    Abstract

    To explore the temperature-induced signal change in two-dimensional multi-spectral imaging (2DMSI) for fast thermometry near metallic hardware to enable MR-guided focused ultrasound surgery (MRgFUS) in patients with implanted metallic hardware.2DMSI was optimized for temperature sensitivity and applied to monitor focus ultrasound surgery (FUS) sonications near metallic hardware in phantoms and ex vivo porcine muscle tissue. Further, we evaluated its temperature sensitivity for in vivo muscle in patients without metallic hardware. In addition, we performed a comparison of temperature sensitivity between 2DMSI and conventional proton-resonance-frequency-shift (PRFS) thermometry at different distances from metal devices and different signal-to-noise ratios (SNR).2DMSI thermometry enabled visualization of short ultrasound sonications near metallic hardware. Calibration using in vivo muscle yielded a constant temperature sensitivity for temperatures below 43 °C. For an off-resonance coverage of ± 6 kHz, we achieved a temperature sensitivity of 1.45%/K, resulting in a minimum detectable temperature change of ∼2.5 K for an SNR of 100 with a temporal resolution of 6 s per frame.The proposed 2DMSI thermometry has the potential to allow MR-guided FUS treatments of patients with metallic hardware and therefore expand its reach to a larger patient population. Magn Reson Med 80:259-271, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

    View details for PubMedID 29215150

    View details for PubMedCentralID PMC5876098

  • Endoluminal ultrasound applicators for MR-guided thermal ablation of pancreatic tumors: Preliminary design and evaluation in a porcine pancreas model MEDICAL PHYSICS Adams, M. S., Salgaonkar, V. A., Plata-Camargo, J., Jones, P. D., Pascal-Tenorio, A., Chen, H., Bouley, D. M., Sommer, G., Pauly, K. B., Diederich, C. J. 2016; 43 (7): 4184-4197

    Abstract

    Endoluminal ultrasound may serve as a minimally invasive option for delivering thermal ablation to pancreatic tumors adjacent to the stomach or duodenum. The objective of this study was to explore the basic feasibility of this treatment strategy through the design, characterization, and evaluation of proof-of-concept endoluminal ultrasound applicators capable of placement in the gastrointestinal (GI) lumen for volumetric pancreas ablation under MR guidance.Two variants of the endoluminal applicator, each containing a distinct array of two independently powered transducers (10 × 10 mm 3.2 MHz planar; or 8 × 10 × 20 mm radius of curvature 3.3 MHz curvilinear geometries) at the distal end of a meter long flexible catheter assembly, were designed and fabricated. Transducers and circulatory water flow for acoustic coupling and luminal cooling were contained by a low-profile polyester balloon covering the transducer assembly fixture. Each applicator incorporated miniature spiral MR coils and mechanical features (guiding tips and hinges) to facilitate tracking and insertion through the GI tract under MRI guidance. Acoustic characterization of each device was performed using radiation force balance and hydrophone measurements. Device delivery into the upper GI tract, adjacent to the pancreas, and heating characteristics for treatment of pancreatic tissue were evaluated in MR-guided ex vivo and in vivo porcine experiments. MR guidance was utilized for anatomical target identification, tracking/positioning of the applicator, and MR temperature imaging (MRTI) for PRF-based multislice thermometry, implemented in the real-time RTHawk software environment.Force balance and hydrophone measurements indicated efficiencies of 48.8% and 47.8% and -3 dB intensity beam-widths of 3.2 and 1.2 mm for the planar and curvilinear transducers, respectively. Ex vivo studies on whole-porcine carcasses revealed capabilities of producing ablative temperature rise (ΔT > 15 °C) contours in pancreatic tissue 4-40 mm long and 4-28 mm wide for the planar transducer applicator (1-13 min sonication duration, ∼4 W/cm(2) applied acoustic intensity). Curvilinear transducers produced more selective heating, with a narrower ΔT > 15 °C contour length and width of up to 1-24 mm and 2-7 mm, respectively (1-7 min sonication duration, ∼4 W/cm(2) applied acoustic intensity). Active tracking of the miniature spiral coils was achieved using a Hadamard encoding tracking sequence, enabling real-time determination of each coil's coordinates and automated prescription of imaging planes for thermometry. In vivo MRTI-guided heating trials in three pigs demonstrated capability of ∼20 °C temperature elevation in pancreatic tissue at 2 cm depths from the applicator, with 5-7 W/cm(2) applied intensity and 6-16 min sonication duration. Dimensions of thermal lesions in the pancreas ranged from 12 to 28 mm, 3 to 10 mm, and 5 to 10 mm in length, width, and depth, respectively, as verified through histological analysis of tissue sections. Multiple-baseline reconstruction and respiratory-gated acquisition were demonstrated to be effective strategies in suppressing motion artifacts for clear evolution of temperature profiles during MRTI in the in vivo studies.This study demonstrates the technical feasibility of generating volumetric ablation in pancreatic tissue using endoluminal ultrasound applicators positioned in the stomach lumen. MR guidance facilitates target identification, device tracking/positioning, and treatment monitoring through real-time multislice PRF-based thermometry.

    View details for DOI 10.1118/1.4953632

    View details for Web of Science ID 000379171900027

    View details for PubMedID 27370138

    View details for PubMedCentralID PMC4912561

  • A feasibility study on monitoring the evolution of apparent diffusion coefficient decrease during thermal ablation MEDICAL PHYSICS Plata, J. C., Holbrook, A. B., Marx, M., Salgaonkar, V., Jones, P., Pascal-Tenorio, A., Bouley, D., Diederich, C., Sommer, G., Pauly, K. B. 2015; 42 (9): 5130-5137

    Abstract

    Evaluate whether a decrease in apparent diffusion coefficient (ADC), associated with loss of tissue viability (LOTV), can be observed during the course of thermal ablation of the prostate.Thermal ablation was performed in a healthy in vivo canine prostate model (N = 2, ages: 5 yr healthy, mixed breed, weights: 13-14 kg) using a transurethral high-intensity ultrasound catheter and was monitored using a strategy that interleaves diffusion weighted images and gradient-echo images. The two sequences were used to measure ADC and changes in temperature during the treatment. Changes in temperature were used to compute expected changes in ADC. The difference between expected and measured ADC, ADCDIFF, was analyzed in regions ranging from moderate hyperthermia to heat fixation. A receiver operator characteristic (ROC) curve analysis was used to select a threshold of detection of LOTV. Time of threshold activation, tLOTV, was compared with time to reach CEM43 = 240, tDOSE.The observed relationship between temperature and ADC in vivo (2.2%/ °C, 1.94%-2.47%/ °C 95% confidence interval) was not significantly different than the previously reported value of 2.4%/ °C in phantom. ADCDIFF changes after correction for temperature showed a mean decrease of 25% in ADC 60 min post-treatment in regions where sufficient thermal dose (CEM43 > 240) was achieved. Following our ROC analysis, a threshold of 2.25% decrease in ADCDIFF for three consecutive time points was chosen as an indicator of LOTV. The ADCDIFF was found to decrease quickly (1-2 min) after reaching CEM43 = 240 in regions associated with heat fixation and more slowly (10-20 min) in regions that received slower heating.Simultaneous monitoring of ADC and temperature during treatment might allow for a more complete tissue viability assessment of ablative thermal treatments in the prostate. ADCDIFF decreases during the course of treatment may be interpreted as loss of tissue viability.

    View details for DOI 10.1118/1.4928155

    View details for Web of Science ID 000360645000015

    View details for PubMedCentralID PMC4537482

  • A feasibility study on monitoring the evolution of apparent diffusion coefficient decrease during thermal ablation. Medical physics Plata, J. C., Holbrook, A. B., Marx, M., Salgaonkar, V., Jones, P., Pascal-Tenorio, A., Bouley, D., Diederich, C., Sommer, G., Pauly, K. B. 2015; 42 (9): 5130-5137

    Abstract

    Evaluate whether a decrease in apparent diffusion coefficient (ADC), associated with loss of tissue viability (LOTV), can be observed during the course of thermal ablation of the prostate.Thermal ablation was performed in a healthy in vivo canine prostate model (N = 2, ages: 5 yr healthy, mixed breed, weights: 13-14 kg) using a transurethral high-intensity ultrasound catheter and was monitored using a strategy that interleaves diffusion weighted images and gradient-echo images. The two sequences were used to measure ADC and changes in temperature during the treatment. Changes in temperature were used to compute expected changes in ADC. The difference between expected and measured ADC, ADCDIFF, was analyzed in regions ranging from moderate hyperthermia to heat fixation. A receiver operator characteristic (ROC) curve analysis was used to select a threshold of detection of LOTV. Time of threshold activation, tLOTV, was compared with time to reach CEM43 = 240, tDOSE.The observed relationship between temperature and ADC in vivo (2.2%/ °C, 1.94%-2.47%/ °C 95% confidence interval) was not significantly different than the previously reported value of 2.4%/ °C in phantom. ADCDIFF changes after correction for temperature showed a mean decrease of 25% in ADC 60 min post-treatment in regions where sufficient thermal dose (CEM43 > 240) was achieved. Following our ROC analysis, a threshold of 2.25% decrease in ADCDIFF for three consecutive time points was chosen as an indicator of LOTV. The ADCDIFF was found to decrease quickly (1-2 min) after reaching CEM43 = 240 in regions associated with heat fixation and more slowly (10-20 min) in regions that received slower heating.Simultaneous monitoring of ADC and temperature during treatment might allow for a more complete tissue viability assessment of ablative thermal treatments in the prostate. ADCDIFF decreases during the course of treatment may be interpreted as loss of tissue viability.

    View details for DOI 10.1118/1.4928155

    View details for PubMedID 26328964

  • Canine epidermolysis bullosa acquisita: circulating autoantibodies target the aminoterminal non-collagenous (NC1) domain of collagen VII in anchoring fibrils. Veterinary dermatology Olivry, T., Fine, J. D., Dunston, S. M., Chasse, D., Tenorio, A. P., Monteiro-Riviere, N. A., Chen, M., Woodley, D. T. 1998; 9 (1): 19-31

    Abstract

    The classification of autoimmune blistering skin diseases is based on the skin antigen(s) targeted by pathogenic autoantibodies. In humans and dogs, there is increasing evidence that autoimmune subepidermal bullous diseases represent different nosological entities. This study establishes the existence of the canine equivalent of epidermolysis bullosa acquisita (EBA) in humans. Canine EBA, like the inflammatory variant of its human counterpart, is characterized by spontaneous vesicles arising from an inflammatory eruption. Dermo-epidermal separation occurs in association with neutrophilic infiltration in the superficial dermis. Tissue-fixed and circulating IgA and IgG autoantibodies specific for the lower basement membrane zone can be detected by immunofluorescence methods. Using immunoelectron microscopy, autoantibodies are shown to target the distal end of anchoring fibrils in the sublamina densa. ELISA and immunoblotting utilizing eukaryotically expressed recombinant collagen VII subdomains confirm that the circulating autoantibodies are specific for the aminoterminal globular non-collagenous NC1 domain of type VII collagen.

    View details for DOI 10.1046/j.1365-3164.1998.00067.x

    View details for PubMedID 34644960

  • Follicular lipidosis in three Rottweilers. Veterinary dermatology Gross, T. L., Pascal-Tenorio, A., Munn, R. J., Hargis, A. M., Kline, A. 1997; 8 (1): 33-39

    Abstract

    Abstract  Follicular lipidosis is reported in three young Rottweilers that developed hypotrichosis of the mahogany-coloured points of the face and feet. One dog had concurrent lightening and dulling of the remaining hair. Hair matrix cells were swollen with intracellular lipid, identified by electron microscopy and oil-red-O staining. Concurrent abnormalities in one dog included poor somatic growth and elevation in serum concentration of blood urea nitrogen and creatinine. Necropsy of this dog revealed small thyroid glands with no visible colloid production, and chronic renal disease. The two remaining dogs were otherwise healthy. One of these two dogs had partial resolution of the hair loss with persistence of mild histological changes of the hair follicles 7 months after first presentation. The second was lost to follow-up but written records had no mention of skin lésions at presentation for cruciate repair 3 years after initial recognition of the haircoat changes. To the authors' knowledge, this is the first report of follicular lipidosis in any species. Résumé- Une lipidose folliculaire est observée sur trois jeunes Rottweilers qui développent une hypotrichose des zones acajou de la face et des pieds. Un chien présente également un éclaircissement et un aspect terne des poils restant. Les cellules matricielles des poils sont gonflées par des lipides en position intracellulaire identifies par la microscopie électronique et une coloration au Rouge Congo. D'autres symptômes sont observes chez un chien: retard de croissance et des elevations de l'urémie et de la créatininémie. L'autopsie de ce chien a montré des glandes thyroidiennes petites et une insuffisance rénale chronique. Les deux autres chiens sont en bonnes santé. Un des deux chiens a présente une resolution partielle de l'hypotrichose avec une persistance modérée des modifications histopathologiques des follicules, sept mois après lä premiere visite. Le second a été perdu de vue mais des contacts par écrit ont permis de savoir que le chien ne présentait plus de lésions, trois ans après la premiere visite. A la connaissance de l'auteur, il s'agit de la premiere description de lipidose folliculaire. [Gross, T. L., Pascal-Tenorio, A., Munn, R. J., Hargis, A. M., Kline, A. Follicular lipidosis in three Rottweilers. (Lipidose folliculaire chez trois Rottweilers.) Veterinary Dermatology 1997; 8: 33-40.] Zusammenfassung- Bei drei jungen Rottweilern, die Hypotrichie an den mahagonifarbenen Stellen im Gesicht und an den Pfoten entwickelten, wird von follikulärer Lipidose berichtet. Einer der Hunde hatte gleichzeitig eine Aufhellung und Abstumpfung des übrigen Haarkleides. Haarmatrixzellen waren mit intrazellulärem Lipid angeschwollen, das mittels Elektronenmikroskopie und 'oil-Red-O' Färbung identifiziert wurde. Bei einem Hund waren gleichzeitig schlechtes somatisches Wachstum und erhoehte Harnstoff-und Kreatininspiegel im Serum feststellbar. Nekropsie dieses Hundes ergab kleine Schilddrüsen ohne wahrnehmbare Kolloidproduktion und chronische Nierenerkrankung. Die zwei anderen Hunde wareii ansonsten gesund. Das Haarkleid einer der beiden Hunde wuchs teilweise wieder, leichte histologische Veränderungen waren 7 Monate nach der ersten Unetersuchung immer noch vorhanden. Der zweite Fall wurde nicht weiterverfolgt, jedoch erwähnten die Krankenberichte 3 Jahre nach dem Beginn der Haarkleidveränderungen keine diesbezüglichen Anomalien. Soviel die Autoren wissen, ist dieses der erste Bericht über follikuläre Lipidose bei Tieren. [Gross, T. L., Pascal-Tenorio, A., Munn, R. J., Hargis, A. M., Kline, A. Follicular lipidosis in three Rottweilers. (Folliculäre Lipidose bei 3 Rottweilern.) Veterinary Dermatology 1997; 8: 33-40.] Resumen  Se describió una lipidosis folicular en tres Rottweilers jóvenes que desarrollaron hipotricosis en los puntos color caoba de la cara y patas. Uno de los perros tenia a su vez el resto del pelo más claro y mate. Les células de la matriz del pelo se encontraban tumefactas, con lipido intracelular identificado medíante microscopia electrónica y tinción roja-O. Un perro presentaba concomitantement crecimiento somático deficiente y elevaciones séricas de BUN y creatinina. El estudio de necropsia en este perro revaló glándulae tiroides de pequeño tamaño, sin producción de coloide visible, asi como enfermedad renal crónica. Los otros dos animales se encontraban en buen estado de salud. Uno de ellos experimentó una resolución parcial de la pérdida de pelo con persistencia de alteraciones histológicas leves de los foliculos 7 meses después de la primera presentación. No fue posible el seguimiento del segundo perro, pero no se mencionaban lesiones cutáneas en el informe escrito del animal al presentarse 3 años después para una intervención de ligamentos cruzados, después de la alteraciones iniciales. Según nuestros datos, esta es la primera descripción de lipidosis folicular en cualquier especie. Gross, T. L., Pascal-Tenorio, A., Munn, R. J., Hargis, A. M., Kline, A. Follicular lipidosis in three Rottweilers. (Lipidosis folicular en tres Rottweilers.) Veterinary Dermatology 1997; 8: 33-0.].

    View details for DOI 10.1111/j.1365-3164.1997.tb00261.x

    View details for PubMedID 34645028

  • Paraneoplastic alopecia associated with internal malignancies in the cat. Veterinary dermatology Pascal-Tenorio, A., Olivry, T., Gross, T. L., Atlee, B. A., Ihrke, P. J. 1997; 8 (1): 47-52

    Abstract

    Abstract  A paraneoplastic alopecia associated with internal malignancy is reported in four cats. Acute, bilaterally symmetrical, ventral glistening alopecia, weight loss and lethargy were present in all cats. Skin biopsy specimens exhibited severe follicular and adnexal atrophy with follicular miniaturization, minimal inflammation and, in many cases, absence of stratum corneum. At the time of díagnosis, three cats had a metastatic pancreatic adenocarcinoma and one had a bile duct carcinoma. This report confirms, and expands upon the previous report of a syndrome associating ventral alopecia and metastatic visceral carcinomas in cats. Résumé- Une alopécie paranéoplasique associée à une tumeur interne maligne est observée sur 4 chats. Les symptômes sont caractérisés par une alopécie symétrique et bilatérale sur le ventre avec un aspect brillant et lisse, un amaigrissement, une lethargic Les lésions histopathologiques sont caractérisées par une atrophie folliculaire et annexielle avec des petits follicules pileux, une inflammation dermique discréte et dans beaucoup de cas, une absence du stratum corneum. Trois chats présentent un adénocarcinome pancréatique métastasé et un chat un cholangiocarcinome. Ces cas confirment l'existence d'un syndrome associant une alopécie ventrale et des carcinomes viscéraux métastatiques chez le chat. [Pascal-Tenorio, A., Olivry, T., Gross, T. L., Atlee, B. A., Ihrke, P. J. Paraneoplastic alopecia associated with internal malignancies in the cat. (Alopécie paranéoplasique associée à des tumeurs malignes internes chez le chat.) Veterinary Dermatology 1997; 8: 47-52.] Resumen  Se describe en cuatro gatos una alopecia paraneoplasica asociada a procesos malignos internos. Todos los gatos presentaban una alopecia bilateral, simétrica, ventral, de aspecto brillante, pérdida de peso y letargia. Las biopsias cutáneas mostraron atrofia folicular y adnexal marcada, miniaturización de foliculos, inflamación minima y, en muchos casos, ausencia del estrato córneo. En el momento del díagnóstico, tres de los gatos tenian un adenocarcinoma metastático y uno tenia un carcinoma de conducto biliar. Este articulo confirma y amplia un informe previo sobre el sindrome de alopecia ventral y carcinomas viscerales metastáticos en gatos. [Pascal-Tenorio, A., Olivry, T., Gross, T. L., Atlee, B. A., Ihrke, P. J. Paraneoplastic alopecia associated with internal malignancies in the cat. (Alopecia paraneoplasica asociada a procesos malignos internos en el gato.) Veterinary Dermatology 1997; 8: 47-52.] Zusammenfassung- Es wird über eine paraneoplastische Alopezie in Verbindung mit inneren malignen Prozessen bei vier Katzen berichtet. Bei alien Katzen traten eine akute bilateral symmetrische ventrale Alopezie, Gewichtsverlust und Lethargie auf. Die Hautbiopsien zeigten eine schwere follikuläre und adnexale Atrophie mit follikulärer Miniaturisation, geringer Entzündung und in vielen Fallen ein Fehlen des Stratum corneum. Zum Zeitpunkt der Diagnose litten drei Katzen an einem metastasierenden Adenokarzinom des Pankreas und eine Katze an einem Gallengangskarzinom. Dieser Bericht erhärtet und erweitert den früheren Bericht über ein Syndrom, das ventrale Alopezie in Verbindung mit metastasierenden Eingeweidekarzinomen bei der Katze beschreibt. (Paraneoplastische Alopezie in Verbindung mit inneren malignen Prozessen bei der Katze.) Veterinary Dermatology 1997; 8: 47-52.].

    View details for DOI 10.1111/j.1365-3164.1997.tb00263.x

    View details for PubMedID 34645026

  • Chronic oral infections of cats and their relationship to persistent oral carriage of feline calici-, immunodeficiency, or leukemia viruses. Veterinary immunology and immunopathology Tenorio, A. P., Franti, C. E., Madewell, B. R., Pedersen, N. C. 1991; 29 (1-2): 1-14

    Abstract

    Two hundred and twenty-six cats from the Veterinary Medical Teaching Hospital (VMTH), a cat shelter, and a purebred cattery were tested for chronic feline calicivirus (FCV), feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) infections. Chronic oral carriage of FCV was present in about one-fifth of the cats in each of the groups. FIV infection was not present in the purebred cattery, was moderately prevalent (8%) in the pet population of cats examined at the VMTH for various complaints and was rampant in the cat shelter (21%). Unexpectedly high FeLV infection rates were found in the hospital cat population (28%) and in the purebred cattery (36%), but not in the cat shelter (1.4%). FCV and FeLV infections tended to occur early in life, whereas FIV infections tended to occur in older animals. From 43 to 100% of the cats in these environments had oral cavity disease ranging from mild gingivitis (23-46%), proliferative gingivitis (18-20%), periodontitis (3-32%) and periodontitis with involvement of extra-gingival tissues (7-27%). Cats infected solely with FCV did not have a greater likelihood of oral lesions, or more severe oral disease, than cats that were totally virus free. This was also true for cats infected solely with FeLV, or for cats dually infected with FeLV and FCV. Cats infected solely with FIV appeared to have a greater prevalence of oral cavity infections and their oral cavity disease tended to be more severe than cats without FIV infection. FIV-infected cats that were coinfected with either FCV, or with FCV and FeLV, had the highest prevalence of oral cavity infections and the most severe oral lesions.

    View details for DOI 10.1016/0165-2427(91)90048-h

    View details for PubMedID 1659031