Numerical assessment of thermal response associated with in vivo skin electroporation: the importance of the composite skin model

Electroporation is an approach used to enhance transdermal transport of large molecules in which the skin is exposed to a series of electric pulses. The structure of the transport inhibiting outer layer, the stratum corneum, is temporarily destabilized due to the development of microscopic pores. Consequently agents that are ordinarily unable to pass into the skin are able to pass through this outer barrier. Of possible concern when exposing biological tissue to an electric field is thermal tissue damage associated with Joule heating. This paper shows the importance of using a composite model in calculating the electrical and thermal effects associated with skin electroporation. A three-dimensional transient finite-volume model of in vivo skin electroporation is developed to emphasize the importance of representing the skin's composite layers and to illustrate the underlying relationships between the physical parameters of the composite makeup of the skin and resulting thermal damage potential.     

Effect of skin pressure by clothing on small bowel transit time

We examined the effect of increased skin pressure from tight clothing on small bowel transit time by means of the breath hydrogen test, using milk that contained lactulose as an additional indigestible disaccharide, which is used as a test meal after overnight fasting. In this experiment, we measured the small bowel transit time from 9 healthy and non-constipated female subjects with two different skin pressures that were applied by loose-fitting experimental garment or an additional tight-fitting girdle on two consecutive days. The skin pressure of the latter condition was 8-9 mmHg higher than that of the former one on the participants' waist, abdomen and hip region. The experimental order of the two skin pressure conditions was counterbalanced. As a result, the small bowel transit time obtained with and without girdle did not differ significantly (165.0 +/- 26.0 minutes for less skin pressure condition and 173.3 +/- 26.8 minutes for more skin pressure condition, n = 9, p = 0.43). This result indicated that the skin pressure from clothing has no effect on the passage rate of food through the small intestine.     

Surface potential determination in planar lipid bilayers: a simplification of the conductance-ratio method

One of the methods available for the measurement of surface potentials of planar lipid bilayers uses the conductance ratio between a charged and a neutral bilayer doped with ionophores to calculate the surface potential of the charged bilayer. We have devised a simplification of that method which does not require the use of an electrically neutral bilayer as control. The conductance of the charged bilayer is measured before and after the addition of divalent cations (Ba(2+)) to the bathing solution. Ba(2+) ions screen fixed surface charges, decreasing the surface potential. If the membrane is negatively charged the screening has the effect of decreasing the membrane conductance to cations. The resulting conductance ratio is used to calculate the surface potential change, which is fed into an iterative computer program. The program generates pairs of surface potential values and calculates the surface charge density for the two conditions. Since the surface charge density remains constant during this procedure, there is only one pair of surface potentials that satisfies the condition of constant charge density. Applying this method to experimental data from McLaughlin et al. [McLaughlin, S.G.A., Szabo, G. and Eisenman, G., Divalent ions and the surface potential of charged phospholipid membranes, J. Gen. Physiol., 58 (1971) 667-687.] we have found very similar results. We have also successfully used this method to determine the effect of palmitic acid on the surface potential of asolectin membranes.     

Permeability parameters of the toad isolated stratum corneum.

A technique for isolating the stratum corneum from the subjacent layers of the epithelium was developed which permits studying the stratum corneum as an isolated membrane mounted between half-chambers. The method basically consists of an osmotic shock induced by immersing a piece of skin in distilled water at 50 degrees C for 2 min. When the membrane is bathed on each surface by NaCl-Ringer's solution, its electrical resistance is 14.1 +/- 1.3 omega cm2 (n=10). This value is about 1/100 of the whole skin resistance in the presence of the same solution. The hydraulic filtration coefficient (Lp) measured by a hydrostatic pressure method, with identical solutions on each side of the membrane, is 8.8 X 10(-5) +/- 1.5 X 10(-5) cm sec-1 atm-1 (n=10) in distilled water and 9.2 X 10(-5) +/- 1.4 X 10(-5) cm sec-1 atm-1 (n=10) in NaCl-Ringer's solution. These values are not statistically different and are within the range of 1/80 to 1/120 of the whole skin Lp. The stratum corneum shows an amphoteric character when studied by KCl diffusion potentials at different pH'S. The membrane presents an isoelectric pH of 4.6 +/- 0.3 (n=10). Above the isoelectric pH the potassium transport number is higher than the chloride transport number; below it, the reverse situation is valid. Divalent cations (Ca++ or Cu++) reduce membrane ionic discrimination when the membrane is negatively charged and are ineffective when the membrane fixed charges are protonated at low pH.     

Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin

Osmotically inactive skin Na(+) storage is characterized by Na(+) accumulation without water accumulation in the skin. Negatively charged glycosaminoglycans (GAGs) may be important in skin Na(+) storage. We investigated changes in skin GAG content and key enzymes of GAG chain polymerization during osmotically inactive skin Na(+) storage. Female Sprague-Dawley rats were fed a 0.1% or 8% NaCl diet for 8 wk. Skin GAG content was measured by Western blot analysis. mRNA content of key dermatan sulfate polymerization enzymes was measured by real-time PCR. The Na(+) concentration in skin was determined by dry ashing. Skin Na(+) concentration during osmotically inactive Na(+) storage was 180-190 mmol/l. Increasing skin Na(+) coincided with increasing GAG content in cartilage and skin. Dietary NaCl loading coincided with increased chondroitin synthase mRNA content in the skin, whereas xylosyl transferase, biglycan, and decorin content were unchanged. We conclude that osmotically inactive skin Na(+) storage is an active process characterized by an increased GAG content in the reservoir tissue. Inhibition or disinhibition of GAG chain polymerization may regulate osmotically inactive Na(+) storage.     

Surface potential determination in planar lipid bilayers: A simplification of the conductance-ratio method

One of the methods available for the measurement of surface potentials of planar lipid bilayers uses the conductance ratio between a charged and a neutral bilayer doped with ionophores to calculate the surface potential of the charged bilayer. We have devised a simplification of that method which does not require the use of an electrically neutral bilayer as control. The conductance of the charged bilayer is measured before and after the addition of divalent cations (Ba²⁺) to the bathing solution. Ba²⁺ ions screen fixed surface charges, decreasing the surface potential. If the membrane is negatively charged the screening has the effect of decreasing the membrane conductance to cations. The resulting conductance ratio is used to calculate the surface potential change, which is fed into an iterative computer program. The program generates pairs of surface potential values and calculates the surface charge density for the two conditions. Since the surface charge density remains constant during this procedure, there is only one pair of surface potentials that satisfies the condition of constant charge density.Applying this method to experimental data from McLaughlin et al. [McLaughlin, S.G.A., Szabo, G. and Eisenman, G., Divalent ions and the surface potential of charged phospholipid membranes, J. Gen. Physiol., 58 (1971) 667–687.] we have found very similar results. We have also successfully used this method to determine the effect of palmitic acid on the surface potential of asolectin membranes.     

Reflection and penetration depth of millimeter waves in murine skin

Millimeter (mm) wave reflectivity was used to determine murine skin permittivity. Reflection was measured in anesthetized Swiss Webster and SKH1-hairless mice in the 37-74 GHz frequency range. Two skin models were tested. Model 1 was a single homogeneous skin layer. Model 2 included four skin layers: (1) the stratum corneum, (2) the viable epidermis plus dermis, (3) fat layer, and (4) muscle which had infinite thickness. We accepted that the permittivity of skin in the mm wave frequency range results from the permittivity of cutaneous free water which is described by the Debye equation. Using Fresnel equations for reflection we determined the skin parameters best fitting to the reflection data and derived the permittivity of skin layers. The permittivity data were further used to calculate the power density and specific absorption rate profiles, and the penetration depth of mm waves in the skin. In both murine models, mm waves penetrate deep enough into tissue to reach muscle. In human skin, mm waves are mostly absorbed within the skin. Therefore, when extrapolating the effects of mm waves found in animals to humans, it is important to take into account the possible involvement of muscle in animal effects.     

The relationship of sodium uptake,potassium rejection,and skin potential in isolated frog skin

1. Isolated surviving frog skin, when bathed with the same kind of diluted Ringer's solution on both sides, shows a negative correlation between net active salt uptake by the epithelium and spontaneous skin potential. Average values of 0.15 to 0.86 µeq. x hr.^–1 x cm.^–2 were measured and correlated with average skin potentials ranging from 107 to 25 mv. 2. Sodium uptake exceeded chloride uptake by about the same amount, irrespective of the height of the skin potential. 3. The same skins which exhibited a negative correlation between net uptake of sodium chloride and skin potential showed a positive correlation between net potassium rejection from the epithelium and skin potential, for voltages above 30 to 40 mv. In skins of voltages lower than this, potassium ions were taken up rather than rejected. Average values for rejection of +11.8 to –0.8 centi-µeq. x hr.^–1 x cm.^–2 were measured. 4. Net fluid uptake, associated with active uptake of sodium chloride, was small and occurred in the direction of the salt uptake. No dependence of net fluid uptake upon skin potential was observed. 5. Skins of winter frogs, pretreated with a commercial purified ACTH preparation, were less active than their respective controls with regard to uptake of sodium chloride. Rejection of potassium was the same in treated and untreated skins. Posterior pituitary factors, as possible contaminants, did not account for the effect of the ACTH preparation. 6. DOCA, DOC, and cortisone did not alter the normal correlation referred to under (1) and (3). 7. In interpreting the experimental results on theoretical grounds, it is suggested (a) that in normal skin, it is the variation in the electric conductance in skin of chloride ions which essentially, although not exclusively, determines the rate of net uptake of sodium chloride, (b) that a factor in the ACTH preparation used, possibly ACTH itself, may have lowered the electric conductance in skin of sodium ions either truly or apparently, (c) that potassium ions are treated by the skin primarily as passive ions. There is some indication that potassium ions are also actively taken up by the epithelium of skin.     

Effect of skin surface cooling on central venous pressure during orthostatic challenge

Orthostatic stress leads to a reduction in central venous pressure (CVP), which is an index of cardiac preload. Skin surface cooling has been shown to improve orthostatic tolerance, although the mechanism resulting in this outcome is unclear. One possible mechanism may be that skin surface cooling attenuates the drop in CVP during an orthostatic challenge, thereby preserving cardiac filling. To test this hypothesis, CVP, arterial blood pressure, heart rate, and skin blood flow, as well as skin and sublingual temperatures, were recorded in nine healthy subjects during lower body negative pressure (LBNP) in both normothermic and skin surface cooling conditions. Cardiac output was also measured via acetylene rebreathing. Progressive LBNP was applied at -10, -15, -20, and -40 mmHg at 5 min/stage. Before LBNP, skin surface cooling lowered mean skin temperature, increased CVP, and increased mean arterial blood pressure (all P < 0.001) but did not change mean heart rate (P = 0.38). Compared with normothermic conditions, arterial blood pressure remained elevated throughout progressive LBNP. Although progressive LBNP decreased CVP under both thermal conditions, during cooling CVP at each stage of LBNP was significantly greater relative to normothermia. Moreover, at higher levels of LBNP with skin cooling, stroke volume was significantly greater relative to normothermic conditions. These data indicate that skin surface cooling induced an upward shift in CVP throughout LBNP, which may be a key factor for preserving preload, stroke volume, and blood pressure and improving orthostatic tolerance.     

Increased transglutaminase activity during skin wound healing in rats

Outer, middle and inner layers from wounded or unwounded rat dorsal skin were separated and extracted first with buffer and then with Triton X-100 and dithiothreitol. The extracts and residues were assayed for transglutaminase activity and tissue transglutaminase antigen. Transglutaminase activities in all skin layers are increased in the period 1-5 days after wounding. Most of the increased activity is in the buffer-soluble fraction in the inner skin layer though there is no corresponding increase in antigen in this fraction. This suggests that there is production of activated soluble tissue transglutaminase in the wounded inner layer. In the 3-5 day wounded outer layer the largest fraction of both activity and antigen is associated with the insoluble residue remaining after extraction with Triton X-100. On DEAE-cellulose chromatography Triton X-100 extracts of the inner layer of wounded skin showed a single major peak of activity, corresponding approximately with rabbit liver transglutaminase; the outer layer showed the same peak plus a different one, eluting at lower salt concentration, which is thought to be epidermal transglutaminase.     

Novel cyclosporin derivatives featuring enhanced skin penetration despite increased molecular weight

Topical cyclosporin A (CsA, 1) is not effective in the treatment of skin diseases, due to its low skin penetration. Following a prodrug strategy, a series of novel derivatives of 1 and of 2-[O-(2-hydroxyethyl)-d-Ser(8)]-CsA (SDZ IMM 125, 5) with potentially enhanced skin penetration properties were synthesized, in order to achieve higher levels of the active parent drugs in the skin. Permeation through skin and prodrug/drug levels in the skin were measured in vitro using rat and human skin. Introduction of a polar side chain, either in the form of a positively charged quaternary amine, a negatively charged phosphate or sulfate, or an amphiphilic phosphocholine moiety, generally increased permeability. Maximal increase in permeability through skin relative to CsA was up to 300-fold with rat skin, and up to 16-fold with human skin. Penetration into skin, as evaluated by measurement of prodrug/drug concentrations in the skin after 48 h, could be enhanced up to 14-fold (rat and human skin). Increases of permeation rates and skin concentrations showed no strict correlation. Using the phosphate 10 as prodrug, a 2.5-fold higher concentration of the active parent compound (5) could be achieved in rat skin as when administering 5 itself. The results demonstrate that in contrast with the '500 Dalton rule', which postulates poor skin penetration of molecules larger than 500 Da, high skin permeation can be achieved also with compounds of a molecular weight in the range between 1200 and 1600 Da. Results also indicate that in principle higher skin levels of active drug can be attained with a prodrug strategy in this class of compounds.     

Biomechanical and viscoelastic properties of skin,SMAS, and composite flaps as they pertain to rhytidectomy

Previous studies have focused on biomechanical and viscoelastic properties of the superficial musculoaponeurotic system (SMAS) flap and the skin flap lifted in traditional rhytidectomy procedures. The authors compared these two layers with the composite rhytidectomy flap to explain their clinical observations that the composite dissection allows greater tension and lateral pull to be placed on the facial and cervical flaps, with less long-term stress-relaxation and tissue creep. Eight fresh cadavers were dissected by elevating flaps on one side of the face and neck as skin and SMAS flaps and on the other side as a standard composite rhytidectomy flap. The tissue samples were tested for breaking strength, tissue tearing force, stress-relaxation, and tissue creep. For breaking strength, uniform samples were pulled at a rate of 1 inch per minute, and the stress required to rupture the tissues was measured. Tissue tearing force was measured by attaching a 3-0 suture to the tissues and pulling at the same rate as that used for breaking strength. The force required to tear the suture out of the tissues was then measured. Stress-relaxation was assessed by tensing the uniformly sized strips of tissue to 80 percent of their breaking strength, and the amount of tissue relaxation was measured at 1-minute intervals for a total of 5 minutes. This measurement is expressed as the percentage of tissue relaxation per minute. Tissue creep was assessed by using a 3-0 suture and calibrated pressure gauge attached to the facial flaps. The constant tension applied to the flaps was 80 percent of the tissue tearing force. The distance crept was measured in millimeters after 2 and 3 minutes of constant tension. Breaking strength measurements demonstrated significantly greater breaking strength of skin and composite flaps as compared with SMAS flaps (p < 0.05). No significant difference was noted between skin and composite flaps. However, tissue tearing force demonstrated that the composite flaps were able to withstand a significantly greater force as compared with both skin and SMAS flaps (p < 0.05). Stress-relaxation analysis revealed the skin flaps to have the highest degree of stress-relaxation over each of five 1-minute intervals. In contrast, the SMAS and composite flaps demonstrated a significantly lower degree of stress-relaxation over the five 1-minute intervals (p < 0.05). There was no difference noted between the SMAS flaps and composite flaps with regard to stress-relaxation. Tissue creep correlated with the stress-relaxation data. The skin flaps demonstrated the greatest degree of tissue creep, which was significantly greater than that noted for the SMAS flaps or composite flaps (p < 0.05). Comparison of facial flaps with cervical flaps revealed that cervical skin, SMAS, and composite flaps tolerated significantly greater tissue tearing forces and demonstrated significantly greater tissue creep as compared with facial skin, SMAS, and composite flaps (p < 0.05). These biomechanical studies on facial and cervical rhytidectomy flaps indicate that the skin and composite flaps are substantially stronger than the SMAS flap, allowing significantly greater tension to be applied for repositioning of the flap and surrounding subcutaneous tissues. The authors confirmed that the SMAS layer exhibits significantly less stress-relaxation and creep as compared with the skin flap, a property that has led aesthetic surgeons to incorporate the SMAS into the face lift procedure. On the basis of the authors' findings in this study, it seems that that composite flap, although composed of both the skin and SMAS, acquires the viscoelastic properties of the SMAS layer, demonstrating significantly less stress-relaxation and tissue creep as compared with the skin flap. This finding may play a role in maintaining long-term results after rhytidectomy. In addition, it is noteworthy that the cervical flaps, despite their increased strength, demonstrate significantly greater tissue creep as compared with facial flaps, suggesting earlier relaxation of the neck as compared with the face after rhytidectomy.     

Increased survival and vascularity of random-pattern skin flaps elevated in controlled, expanded skin

Controlled clinical tissue expansion, a new technique of providing donor tissue, results in an increase in surface area of expanded skin. The aim of the present study was to determine the effect of controlled tissue expansion on the surviving lengths of random-pattern skin flaps elevated in expanded tissue. In five pigs the surviving lengths of flaps raised in skin expanded for 5 weeks using a 250-cc rectangular Radovan-type tissue expander were compared with the survival lengths of flaps elevated in tissue in which a similar prosthesis was not expanded, bipedicle flaps delayed for 5 weeks, and control acutely raised random-pattern flaps. The expanded flaps had a mean increase in surviving length of 117 percent over control flaps, which was statistically significant. The delay flaps had an increase in survival of 73 percent over control flaps, which was also statistically significant. There was no significant difference in survival between expanded flaps and delayed flaps. Morphologic studies using radiographic techniques on one pig demonstrated increased vascularity with tissue expansion. The results of this work demonstrate that in addition to providing increased surface area with controlled expansion, flaps raised in expanded skin have a significantly augmented surviving length. The mechanism for this increased vascularity with expansion is not known at this time, but it may be due to physical forces associated with expansion acting as a stimulus for angiogenesis.     

Growth-induced Water Potentials in Plant Cells and Tissues

A physical analysis of water movement through elongating soybean (Glycine max L. Merr.) hypocotyls was made to determine why significant water potentials persist in growing tissues even though the external water potentials were zero and transpiration is virtually zero. The analysis was based on a water transport theory modified for growth and assumed that water for growing cells would move through and along the cells in proportion to the conductivity of the various pathways.

Water potentials calculated for individual cells were nearly in local equilibrium with the water potentials of the immediate cell surroundings during growth. However, water potentials calculated for growing tissue were 1.2 to 3.3 bars below the water potential of the vascular supply in those cells farthest from the xylem. Only cells closest to the xylem had water potentials close to that of the vascular supply. Gradients in water potential were steepest close to the xylem because all of the growth-sustaining water had to move through this part of the tissue. Average water potentials calculated for the entire growing region were −0.9 to −2.2 bars depending on the tissue diffusivity.

For comparison with the calculations, average water potentials were measured in elongating soybean hypocotyls using isopiestic thermocouple psychrometers for intact and excised tissue. In plants having virtually no transpiration and growing in Vermiculite with a water potential of −0.1 bar, rapidly growing hypocotyl tissue had water potentials of −1.7 to −2.1 bars when intact and −2.5 bars when excised. In mature, nongrowing hypocotyl tissue, average water potentials were −0.4 bar regardless of whether the tissue was intact or excised.

The close correspondence between predicted and measured water potentials in growing tissue indicates that significant gradients in water potential are required to move growth-associated water through and around cells over macroscopic distances. The presence of such gradients during growth indicates that cells must have different cell wall and/or osmotic properties at different positions in the tissue in order for organized growth to occur. The mathematical development used in this study represents the philosophy that would have to be followed for the application of contemporary growth theory when significant tissue water potential gradients are present.

     

First phase microcirculatory reaction to mechanical skin irritation: a three layer model of a compliant vascular tree

Mechanical skin irritation creates vasodilatation in the line of a stroke and in the surrounding tissue. To obtain further insight on underlying physiological mechanisms we developed a model of the vascular network comprised of three layers, where the first and the last one have a tree structure. They represent the arterial and the venous system, respectively. Both are connected via an intermediate zone representing the core of the microcirculation, which is described by means of a compliant compartment model. Irritation induces change in compliance of vessels situated at the entrance of the intermediate zone. Thus the model describes flow and pressure behavior due to mechanical skin irritation.     

Sexual skin in rodents: an across body region, gender, and species analysis

The effect of estrogen on the thickness of skin layers were examined in male and female mice and in female rats. Skin samples were taken from prepubertally castrated subjects given either 17 beta-estradiol or control implants. In agreement with an earlier report, the subcutaneous areolar tissue (SAT) of the lower back was nearly six times thicker, on average, in female mice with estradiol implants than in controls. Estrogen did not effect the thickness of the epidermis or dermis but preferentially increased the thickness of the deepest layer of the SAT. Analysis of skin samples from different body regions revealed that this response to estrogen was limited to the skin of the dorsum and was greatest in the area of the lower back. Castrated male mice with estradiol implants had markedly thicker SAT layers in the lower back region than controls. However, the magnitude of the response was less than that seen in estrogen-treated females. In contrast, the SAT in the lower back regions of castrated female rats with estrogen implants was not significantly different from controls, despite a pronounced uterine response to the hormone treatment. Thus, mice exhibit a species-specific, localized hypertrophy of one of the skin layers in response to estradiol. Mouse mating behavior involves the vigorous grasping and biting of the lower back region of the female. We suggest that at least one function of this estrogen-dependent hypertrophy is to protect the female from injury during mating.     

Epidermal cell proliferation and terminal differentiation in skin organ culture after topical exposure to sodium dodecyl sulphate

Summary Epidermal cell proliferation and differentiation were investigated in vitro after exposure to the anionic surfactant sodium dodecyl sulfate (SDS). Human skin organ cultures were exposed topically to various concentrations of SDS for 22 h, after which the irritant was removed. Cell proliferation was measured immunohistochemically by incorporation of bromodeoxyuridine (BrdU) into the DNA of cells during S-phase, while the expression of transglutaminase and involucrin were used as markers of differentiation. Cell proliferation was moderately increased at concentrations of SDS that did not affect the histomorphology (0.1% and 0.2% SDS). A marked increase of cell proliferation was observed 22 to 44 h after removal of SDS at a concentration (0.4%) that induced slight cellular damage. Exposure of human skin organ cultures to a toxic concentration of SDS (1.0%) led to decreased cell proliferation. Transglutaminase and involucrin were expressed in the more basal layers of the epidermis after exposure to 0.4% or 1.0% SDS. Moreover, intra-epidermal sweat gland ducts were positive for transglutaminase at these irritant concentrations. These in vitro data demonstrate that SDS-induced alterations of epidermal cell kinetics, as described in vivo are at least partly due to local mechanisms and do not require the influx of infiltrate cells. However, we were unable to relate the altered cell kinetics to the release of interleukin-1α or interleukin-6. Furthermore, supplementation of the culture medium with 12-hydroxyeicosantetraenoic acid did not affect epidermal cell proliferation. Rabbit skin cultures appeared more sensitive to SDS than human skin. At nontoxic doses, the irritant induced an increase of epidermal cell proliferation, similar to that observed in human skin discs.     

Role of human skin in the photodecomposition of bilirubin

1. Human skin epithelium and human skin were found to absorb both free bilirubin and serum-bound bilirubin from an aqueous buffered medium. The serum-bound bilirubin thus absorbed was readily released when human skin epithelium or human skin were transferred to media containing no bilirubin. 2. The K(m) values for serum-bound bilirubin were 1.8x10(-3)m and 2.2x10(-3)m respectively for human skin epithelium and human skin; corresponding K(m) values for free bilirubin were 3.0x10(-4)m and 5x10(-4)m. The V(max.) for bound and free bilirubin was of the same magnitude, the apparent V(max.) being 1.0 and 1.66mumol/g of tissue for human skin epithelium and human skin respectively. 3. When human skin that had acquired a yellow tinge by absorbing bilirubin was incubated in a buffered medium and exposed to a mercury-vapour light, the yellow colour disappeared and decomposition products of bilirubin accumulated in the medium. 4. Experiments with [(3)H]bilirubin indicated that the pigment absorbed by skin was photo-oxidized to products that were soluble in water and the quantity and number of such products increased with the time of exposure of human skin to the light-source. Under similar conditions [(3)H]bilirubin alone in buffered medium was also oxidized and gave products which by paper chromatography appeared to be different from those released by human skin that had absorbed bilirubin. 5. The results suggest that by virtue of its large surface area human skin can act as a matrix for the degradative action of light on bilirubin.     

Why Canny's theory doesn't hold water

A critique of Martin Canny's theory of water transport supported by tissue pressure is given with reference to basic principles of cellular water relations and biomechanics. It is shown that the application of tissue pressure in Canny's theory is neither internally consistent nor compatible with basic biophysics. Canny's translation of tissue pressure into an altered steady-state pressure in the xylem conduits has no defensible mechanism, relying instead on untenable action-at-a-distance and poor definitions. Tissue pressure itself, as defined by Canny and illustrated by the example of a turgid leaf, may well exist. However, it cannot function in whole-plant processes as envisioned by Canny, nor can it exist in the magnitude his theory would require. Rigid outer tissue layers containing internal pressures of the magnitude postulated by Canny would require a tensile strength quite incompatible with the observed biological materials. A simple application of La Place's Law illustrates that this is an issue of scale and that the turgor generated by osmotic potentials must be balanced primarily at the cellular level, and not the tissue level.     

Vascular endothelial growth factor and Kaposi's sarcoma cells in human skin grafts.

Human cancer cells often produce tumors in animal models that incompletely reproduce the histology of the parental tumor. Kaposi's sarcoma (KS) cells, in particular, have not produced durable angiogenic lesions in animal models that resemble those of KS in humans. We investigated the contribution of transformed KS cells, vascular endothelial growth factor (VEGF), and human skin tissue on tumor development in a human skin graft/mouse model. High levels of serum VEGF (322 pg/ml) were seen in HIV-1-infected persons with KS compared with HIV-1-infected persons without KS (115 pg/ml). Human KS lesions expressed VEGF in the spindle cells. Transformed KS cells expressed the mitogenically active 121-amino acid and 165-amino acid isoforms of VEGF. Tumors induced by KS cells implanted in the SCID mice grew preferentially in human skin grafts rather than in ungrafted murine skin. Tumors induced in the presence of human skin grafts developed numerous lumens expressing alpha(v)beta(3) integrin. KS cells inoculated with neutralizing anti-VEGF antibody did not form tumors. This study supports an important role for VEGF in tumor development and shows how a human tissue can preferentially promote tumor growth.