Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer.

The poor efficacy of systemic cancer therapeutics in pancreatic ductal adenocarcinoma (PDAC) is partly attributed to deposition of collagen and hyaluronan, leading to interstitial hypertension collapsing blood and lymphatic vessels, limiting drug delivery. The intrinsic micro-regional interactions between hyaluronic acid (HA), collagen and the spatial origins of mechanical stresses that close off blood vessels was investigated here. Multiple localized pressure measurements were analyzed with spatially-matched histochemical images of HA, collagen and vessel perfusion. HA is known to swell, fitting a linear elastic model with total tissue pressure (TTP) increasing above interstitial fluid pressure (IFP) directly with collagen content. However, local TTP appears to originate from collagen area fraction, as well as increased its entropy and fractal dimension, and morphologically appears to be maximized when HA regions are encapsulated by collagen. TTP was inversely correlated with vascular patency and verteporfin uptake, suggesting interstitial hypertension results in vascular compression and decreased molecular delivery in PDAC. Collagenase injection led to acute decreases in total tissue pressure and increased drug perfusion. Large microscopic variations in collagen distributions within PDAC leads to microregional TPP values that vary on the hundred micron distance scale, causing micro-heterogeneous limitations in molecular perfusion, and narrows viable treatment regimes for systemically delivered therapeutics

Radiofrequency Heating of the Cornea: An Engineering Review of Electrodes and Applicators

This paper reviews the different applicators and electrodes employed to create localized heating in the cornea by means of the application of radiofrequency (RF) currents. Thermokeratoplasty (TKP) is probably the best known of these techniques and is based on the principle that heating corneal tissue (particularly the central part of the corneal tissue, i.e. the central stroma) causes collagen to shrink, and hence changes the corneal curvature. Firstly, we point out that TKP techniques are a complex challenge from the engineering point of view, due to the fact that it is necessary to create very localized heating in a precise location (central stroma), within a narrow temperature range (from 58 to 76ºC). Secondly, we describe the different applicator designs (i.e. RF electrodes) proposed and tested to date. This review is planned from a technical point of view, i.e. the technical developments are classified and described taking into consideration technical criteria, such as energy delivery mode (monopolar versus bipolar), thermal conditions (dry versus cooled electrodes), lesion pattern (focal versus circular lesions), and application placement (surface versus intrastromal)

Ring electrode for radio-frequency heating of the cornea: modelling and in vitro experiments

[EN] Radio-frequency thermokeratoplasty (RF-TKP) is a technique used to reshape the cornea curvature by means of thermal lesions using radio-frequency currents. This curvature change allows refractive disorders such as hyperopia to be corrected. A new electrode with ring geometry is proposed for RF-TKP. It was designed to create a single thermal lesion with a full-circle shape. Finite element models were developed, and the temperature distributions in the cornea were analysed for different ring electrode characteristics. The computer results indicated that the maximum temperature in the cornea was located in the vicinity of the ring electrode outer perimeter, and that the lesions had a semi-torus shape. The results also indicated that the electrode thickness, electrode radius and electrode thermal conductivity had a significant influence on the temperature distributions. In addition, in vitro experiments were performed on rabbit eyes. At 5 IN power the lesions were fully circular. Some lesions showed non-uniform characteristics along their circular path. Lesion depth depended on heating duration (60% of corneal thickness for 20s, and 30% for 10s). The results suggest that the critical shrinkage temperature (55-63degreesC) was reached at the central stroma and along the entire circular path in all the cases.Berjano, E.; Saiz Rodríguez, FJ.; Alió, J.; Ferrero, JM. (2003). Ring electrode for radio-frequency heating of the cornea: modelling and in vitro experiments. Medical & Biological Engineering & Computing. 41(6):630-639. https://doi.org/10.1007/BF02349970S630639416Alió, J. L., Ismail, M. M., Artola, A., andPérez-Santonja, J. J. (1997a): ‘Correction of hyperopia induced by photorefractive keratectomy using non-contact Ho: YAG laser thermal keratoplasty’,J. Refract. Surg.,13, pp. 13–16Alió, J. L., Ismail, M. M., andSanchez, J. L. (1997b): ‘Correction of hyperopia with non-contact Ho: YAG laser thermal keratoplasty’,J. Refract. Surg.,13, pp. 17–22Alió, J. L., andPérez-Santonja, J. J. (1999): ‘Correction of hyperopia by laser thermokeratoplasty (LTK)’ inPallikaris, I., andAgarwal, S. (Eds): ‘Refractive Surgery’ (Jaypee Brothers Medical Publishers Ltd, New Delhi, 1999), pp. 583–591Alió, J. L., andPérez-Santonja, J. J. (2002): ‘Correction of hyperopia by laser thermokeratoplasty (LTK)’ inAgarwal, S., Agarwal, A., Apple, D. J., Buratto, L., Alió, J. L., Pandey, S. K., andAgarwal, A. (Eds): ‘Textbook of ophthalmology’ (Lippincott Williams & Wilkins, Philadelphia, 2002), pp. 1331–1337Ayala, M. J., Alió, J. L., Ismail, M. M., andSánchez-Castro, J. M. (2000): ‘Experimental corneal histological study after thermokeratoplasty with holmium laser’,Arch. Soc. Esp. Oftalmol.,75, pp. 619–626Asbell, P. A., Maloney, R. K., Davidorf, J., Hersh, P., McDonald, M., Manche, E., andConductive Keratoplasty Study Group (2001): ‘Conductive keratoplasty for the correction of hyperopia’,Tr. Am. Ophtalmol. Soc.,99, pp. 79–87Avitall, B., Mughal, K., Hare, J., Helms, R., andKrum, D. (1997): ‘The effects of electrode-tissue contact on radiofrequency lesion generation’PACE,20, pp. 2899–2910Avitall, B., Helms, R. W., Koblish, J. B., Sieben, W., Kotov, A. V., andGupta, G. N. (1999): ‘The creation of linear contiguous lesions in the atria with an expandable loop catheter’,J. Am. Coll. Cardiol.,33, pp. 972–984Berjano, E. J., Saiz, J., andFerrero, J. M. (2002): ‘Radio-frequency heating of the cornea: Theoretical model andin vitro experiments’,IEEE Trans. Biomed. Eng.,49, pp. 196–205Brickmann, R., Kampmeier, J., Grotehusmann, U., Vogel, A., Koop, N., Asiyo-Vogel, M., Kamm, K., andBirngruber, R. (1996): ‘Corneal collagen denaturation in laserthermokeratoplasty’,SPIE Proc.,2681, pp. 56–63Choi, B., Kim, J., Welch, A. J., andPearce, J. A. (2002): ‘Dynamic impedance measurements during radio-frequency heating of cornea’,IEEE Trans. Biomed. Eng.,49, pp. 1610–1616Curley, M. G., andHamilton, P. S. (1997): ‘Creation of large thermal lesions in liver using saline-enhanced RF ablation’. Proc. 19th Ann. Int. Conf. IEEE Eng. Med. Biol. Soc., Chicago, pp. 2516–2519Doss, J. D., andAlbillar, J. I. (1980): ‘A technique for the selective heating of corneal stroma’,Contact Intraocular Lens Med.,6, pp. 13–17Doss, J. D. (1982): ‘Calculation of electric fields in conductive media’,Med. Phys.,9(4), pp. 566–573Gruenberg, P., Manning, W., Miller, D. andOlson, W. (1981): ‘Increase in rabbit corneal curvature by heated ring application’,Ann. Ophthalmol.,13, pp. 67–70Hata, C., andRaymond Chia, W.-K. (2001): ‘Catheter for circular tissue ablation and methods thereof’. US Patent 2001/0044625 A1Jain, M. K., andWolf, P. D. (1998): ‘Effect of electrode contact on lesion growth during temperature controlled radiofrequency ablation’, Proc. 20th Ann. Int. Conf. IEEE Eng. Med. Biol. Soc. Hong Kong (IEEE, Piscataway NJ) pp. 245–247Jain, M. K., andWolf, P. D. (1999): ‘Temperature controlled and constant power radiofrequency ablation: what affects lesion growth?’,IEEE Trans. Biomed. Eng.,46, pp. 1405–1412Krasteva, V. Tz., andPapazov, S. P. (2002): ‘Estimation of current density distribution under electrodes for external defibrillation’,Biomed. Eng. OnLine,1, 7Labonté, S. (1992): ‘A theoretical study of radio-frequency ablation of the myocardium’,PhD dissertation, Department of Electrical Engineering, University of Ottawa, CanadaLabonté, S. (1994): ‘Numerical model for radio-frequency ablation of the endocardium and its experimental validation’,IEEE Trans. Biomed. Eng.,41, pp. 108–115Mannis, M. J., Segal, W. A., andDarlington, J. K. (2001): ‘Making sense of refractive surgery in 2001: Why, when, for whom, and by whom?’,Mayo Clin. Proc.,76, pp. 823–829McCally, R. L., Bargeron, R. A., andGreen, W. R. (1983): ‘Stromal damage in rabbit corneas exposed to CO2 laser radiation’,Exp. Eye Res.,37, pp. 543–550McDonald, M. B., Hersh, P. S., Manche, E. 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V., Arruda, M., Wang, X., Ohtomo, K., Beckman, K. J., McClelland, J. H., Lazzara, R., andJackman, W. M. (1995): ‘Comparison ofin vivo tissue temperature profile and lesion geometry for radiofrequency ablation with a saline-irrigated electrode versus temperature control in a canine thigh muscle preparation’,Circ.,91, pp. 2264–2273Panescu, D., Whayne, J. G., Fleischman, S. D., Mirotznik, M. S., Swanson, D. K., andWebster, J. G. (1995): ‘Three-dimensional finite element analysis of current density and temperature distributions during radio-frequency ablation’,IEEE Trans. Biomed. Eng.,42, pp. 879–890Plonsey, R., andHeppner, D. B. (1967): ‘Considerations of quasistationarity in electrophysiological systems’,Bull. Math. Biophys.,29, pp. 657–664Rowsey, J. J. (1987): ‘Electrosurgical keratoplasty: Update and retraction’,Invest. Ophthalmol. Vis. Sci.,28, p. 224Rutzen, A. R., Roberts, C. W., Driller, J., Gomez, D., Lucas, B. C., Lizzi, F. L., andColeman, D. J. (1990): ‘Production of corneal lesions using high-intensity focused ultrasound’,Cornea,9, pp. 324–330Schwan, H. P., andFoster, K. R. (1980): ‘RF-fields interactions with biological systems: electrical properties and biophysical mechanism’,Proc. IEEE,68, pp. 104–113Seiler, T., Matallana, M., andBende, T. (1990): ‘Laser thermokeratoplasty by means of a pulsed Holmium:YAG Laser for the hyperopic correction’,Refrac. Corneal Surg.,6, pp. 335–339Silvestrini, T. A. (1998): ‘Electrosurgical procedure for the treatment of the cornea’. US Patent 5,766,171Simmons, W. N., Mackey, S., He, D. S. andMarcus, F. L. (1996): ‘Comparison of gold versus platinum electrodes on myocardial lesion size using radiofrequency energy’,PACE,19, pp. 398–402Stringer, H., andParr, J. (1964): ‘Shrinkage temperature of eye collagen’,Nature,204, p. 1307Trembly, B. S., andKeates, R. H. (1991): ‘Combined microwave heating and surface cooling of the cornea’,IEEE Trans. Biomed. Eng.,38, pp. 85–91Trembly, B. 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Syphilis at the Crossroad of Phylogenetics and Paleopathology

The origin of syphilis is still controversial. Different research avenues explore its fascinating history. Here we employed a new integrative approach, where paleopathology and molecular analyses are combined. As an exercise to test the validity of this approach we examined different hypotheses on the origin of syphilis and other human diseases caused by treponemes (treponematoses). Initially, we constructed a worldwide map containing all accessible reports on palaeopathological evidences of treponematoses before Columbus's return to Europe. Then, we selected the oldest ones to calibrate the time of the most recent common ancestor of Treponema pallidum subsp. pallidum, T. pallidum subsp. endemicum and T. pallidum subsp. pertenue in phylogenetic analyses with 21 genetic regions of different T. pallidum strains previously reported. Finally, we estimated the treponemes' evolutionary rate to test three scenarios: A) if treponematoses accompanied human evolution since Homo erectus; B) if venereal syphilis arose very recently from less virulent strains caught in the New World about 500 years ago, and C) if it emerged in the Americas between 16,500 and 5,000 years ago. Two of the resulting evolutionary rates were unlikely and do not explain the existent osseous evidence. Thus, treponematoses, as we know them today, did not emerge with H. erectus, nor did venereal syphilis appear only five centuries ago. However, considering 16,500 years before present (yBP) as the time of the first colonization of the Americas, and approximately 5,000 yBP as the oldest probable evidence of venereal syphilis in the world, we could not entirely reject hypothesis C. We confirm that syphilis seems to have emerged in this time span, since the resulting evolutionary rate is compatible with those observed in other bacteria. In contrast, if the claims of precolumbian venereal syphilis outside the Americas are taken into account, the place of origin remains unsolved. Finally, the endeavor of joining paleopathology and phylogenetics proved to be a fruitful and promising approach for the study of infectious diseases

The hydrostatic-pneumatic system of certain trees; movements of liquids and gases,

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NOVEL TECHNOLOGIES FOR GASEOUS CONTAMINANTS CONTROL

Overall objective of this project was to develop a technology platform for cleaning/conditioning the syngas from an integrated gasification combined cycle (IGCC) system at elevated temperatures (500-1,000 F) and gasifier pressures to meet the tolerance limits for contaminants, including H{sub 2}S, COS, NH{sub 3}, HCl, Hg, and As. This technology development effort involved progressive development and testing of sorbent/catalytic materials and associated processes through laboratory, bench, pilot, and demonstration testing phases, coupled with a comprehensive systems analysis at various stages of development. The development of the regenerable RTI-3 desulfurization sorbent - a highly attrition-resistant, supported ZnO-based material - was the key discovery in this project. RTI-3's high attrition resistance, coupled with its high reactivity, effectively allowed its application in a high-velocity transport reactor system. Production of the RTI-3 sorbent was successfully scaled up to an 8,000-lb batch by Sued-Chemie. In October 2005, RTI obtained U.S Patent 6,951,635 to protect the RTI-3 sorbent technology and won the 2004 R&D 100 Award for development of this material. The RTI-3 sorbent formed the basis for the development of the High-Temperature Desulfurization System (HTDS), a dual-loop transport reactor system for removing the reduced sulfur species from syngas. An 83-foot-tall, pilot HTDS unit was constructed and commissioned first at ChevronTexaco's gasification site and later at Eastman's gasification plant. At Eastman, the HTDS technology was successfully operated with coal-derived syngas for a total of 3,017 hrs over a 12-month period and consistently reduced the sulfur level to <10 ppmv. The sorbent attrition rate averaged {approx}31 lb/MM lb of circulation. To complement the HTDS technology, which extracts the sulfur from syngas as SO{sub 2}, RTI developed the Direct Sulfur Recovery Process (DSRP). The DSRP, operating at high pressure and high temperature, uses a small slipstream of syngas to catalytically reduce the SO{sub 2} produced in the warm syngas desulfurization process to elemental sulfur. To demonstrate this process at Eastman, RTI constructed and commissioned a skid-mounted pilot DSRP unit. During its 117-h operation, the DSRP system achieved 90% to 98% removal of the inlet sulfur. The DSRP catalyst proved very robust, demonstrating consistent reaction rates in multiple experiments over a 3-year period. Sorbent materials for removing trace NH{sub 3}, Hg, and As impurities from syngas at high temperature and high pressure were developed and tested with real syngas. A Li{sub 4}SiO{sub 4} sorbent for removal of CO{sub 2} from syngas at high temperature was also developed and tested. The Li{sub 4}SiO{sub 4} material demonstrates excellent CO{sub 2} removal, but its regeneration was found to be technically challenging. Additionally, reverse-selective polymer membrane materials were investigated for the bulk removal of CO{sub 2} and H{sub 2}S from syngas. These materials exhibited adequate separation at ambient conditions for these acid gases. Field testing of these membrane modules with real syngas demonstrated potential use for acid-gas separation from syngas. The HTDS/DSRP technologies are estimated to have a significant economic advantage over conventional gas cleanup technologies such as Selexol{trademark} and Rectisol. From a number of system studies, use of HTDS/DSRP is expected to give a 2-3 percentage point increase in the overall IGCC thermal efficiency and a significant reduction in capital cost. Thus, there is significant economic incentive for adaptation of these warm gas cleanup technologies due to significantly increased thermal efficiency and reduction in capital and operating costs. RTI and Eastman are currently in discussions with a number of companies to commercialize this technology

Novel Technologies for Gaseous Contaminants Control

Overall objective of this project was to develop a technology platform for cleaning/conditioning the syngas from an integrated gasification combined cycle (IGCC) system at elevated temperatures (500-1,000 F) and gasifier pressures to meet the tolerance limits for contaminants, including H{sub 2}S, COS, NH{sub 3}, HCl, Hg, and As. This technology development effort involved progressive development and testing of sorbent/catalytic materials and associated processes through laboratory, bench, pilot, and demonstration testing phases, coupled with a comprehensive systems analysis at various stages of development. The development of the regenerable RTI-3 desulfurization sorbent - a highly attrition-resistant, supported ZnO-based material - was the key discovery in this project. RTI-3's high attrition resistance, coupled with its high reactivity, effectively allowed its application in a high-velocity transport reactor system. Production of the RTI-3 sorbent was successfully scaled up to an 8,000-lb batch by Sued-Chemie. In October 2005, RTI obtained U.S Patent 6,951,635 to protect the RTI-3 sorbent technology and won the 2004 R&D 100 Award for development of this material. The RTI-3 sorbent formed the basis for the development of the High-Temperature Desulfurization System (HTDS), a dual-loop transport reactor system for removing the reduced sulfur species from syngas. An 83-foot-tall, pilot HTDS unit was constructed and commissioned first at ChevronTexaco's gasification site and later at Eastman's gasification plant. At Eastman, the HTDS technology was successfully operated with coal-derived syngas for a total of 3,017 hrs over a 12-month period and consistently reduced the sulfur level to <10 ppmv. The sorbent attrition rate averaged {approx}31 lb/MM lb of circulation. To complement the HTDS technology, which extracts the sulfur from syngas as SO{sub 2}, RTI developed the Direct Sulfur Recovery Process (DSRP). The DSRP, operating at high pressure and high temperature, uses a small slipstream of syngas to catalytically reduce the SO{sub 2} produced in the warm syngas desulfurization process to elemental sulfur. To demonstrate this process at Eastman, RTI constructed and commissioned a skid-mounted pilot DSRP unit. During its 117-h operation, the DSRP system achieved 90% to 98% removal of the inlet sulfur. The DSRP catalyst proved very robust, demonstrating consistent reaction rates in multiple experiments over a 3-year period. Sorbent materials for removing trace NH{sub 3}, Hg, and As impurities from syngas at high temperature and high pressure were developed and tested with real syngas. A Li{sub 4}SiO{sub 4} sorbent for removal of CO{sub 2} from syngas at high temperature was also developed and tested. The Li{sub 4}SiO{sub 4} material demonstrates excellent CO{sub 2} removal, but its regeneration was found to be technically challenging. Additionally, reverse-selective polymer membrane materials were investigated for the bulk removal of CO{sub 2} and H{sub 2}S from syngas. These materials exhibited adequate separation at ambient conditions for these acid gases. Field testing of these membrane modules with real syngas demonstrated potential use for acid-gas separation from syngas. The HTDS/DSRP technologies are estimated to have a significant economic advantage over conventional gas cleanup technologies such as Selexol{trademark} and Rectisol. From a number of system studies, use of HTDS/DSRP is expected to give a 2-3 percentage point increase in the overall IGCC thermal efficiency and a significant reduction in capital cost. Thus, there is significant economic incentive for adaptation of these warm gas cleanup technologies due to significantly increased thermal efficiency and reduction in capital and operating costs. RTI and Eastman are currently in discussions with a number of companies to commercialize this technology

Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer

The poor efficacy of systemic cancer therapeutics in pancreatic ductal adenocarcinoma (PDAC) is partly attributed to deposition of collagen and hyaluronan, leading to interstitial hypertension collapsing blood and lymphatic vessels, limiting drug delivery. The intrinsic micro-regional interactions between hyaluronic acid (HA), collagen and the spatial origins of mechanical stresses that close off blood vessels was investigated here. Multiple localized pressure measurements were analyzed with spatially-matched histochemical images of HA, collagen and vessel perfusion. HA is known to swell, fitting a linear elastic model with total tissue pressure (TTP) increasing above interstitial fluid pressure (IFP) directly with collagen content. However, local TTP appears to originate from collagen area fraction, as well as increased its entropy and fractal dimension, and morphologically appears to be maximized when HA regions are encapsulated by collagen. TTP was inversely correlated with vascular patency and verteporfin uptake, suggesting interstitial hypertension results in vascular compression and decreased molecular delivery in PDAC. Collagenase injection led to acute decreases in total tissue pressure and increased drug perfusion. Large microscopic variations in collagen distributions within PDAC leads to microregional TPP values that vary on the hundred micron distance scale, causing micro-heterogeneous limitations in molecular perfusion, and narrows viable treatment regimes for systemically delivered therapeutics