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The emergent imbalance in rare earths is primarily a self-imposed construct outside China. International regulations pertaining to source material have had a significant role in today's outsized market distortions related to rare earths. The resulting market concentration has caused severe economic dislocation and national security problems for the United States (US), Japan, Korea, the European Union (EU), and other nations. A solution to this problem is required. Traditional free market solutions are failing. These failures are largely linked to regulatory obstacles preventing the use of monazite, apatite, and other thorium and uranium-bearing rare earth resources that are common byproducts of existing mining operations throughout the US and the world. These regulatory obstacles force Western producers to develop low thorium/uranium deposits with rare earth distributions that do not conform to market demand. This chapter demonstrates that the status quo is not economically or strategically viable. Developing rare earth resource supply chains within the current regulatory constraints is unworkable. Lowering environmental standards or fast-tracking new mining permits is not necessary or desirable. To develop an alternative rare earth resource outside China, these regulatory issues must be addressed. Furthermore, the development of additional rare earth resources cannot resolve economic or national security issues without a corresponding fully integrated value chain of rare earth products such as metals, alloys, magnets, and garnets.

The basic design concepts for strong-post w-beam guardrail systems were developed more than 30 years ago. Although the vehicle fleet today differs significantly from vehicles for which the systems were designed, those systems are still in widespread use. One of the changes in the vehicle fleet with the most influence on the performance of guardrails and other safety barriers is the emergence of pickup trucks and SUVs. These vehicles are heavy and have relatively high centers of gravity, so in addition to overloading the guardrail, such vehicles are highly unstable during redirection and are likely to roll over. One of the most serious problems with these systems is the front impact-side wheel snagging on the guardrail posts. Conventional post types used in strong-post guardrail systems consist of either large wooden posts or steel I-beam section posts, both of which are unforgiving when impacted by a wheel. Recently, HALCO, LLC, developed the HALCO X-44 post, a guardrail post that is lightweight, strong, and designed to be used in strong-post w-beam guardrail applications as an alternative to conventional post types. The X-44 post was designed to be more forgiving when crashed into by the wheel of a vehicle, yet strong enough to limit guardrail deflection under NCHRP Report 350 Test Level 3 impact conditions. In this study the HALCO X-44 post was evaluated in a length-of-need section of w-beam guardrail. A finite element model of the guardrail system was developed, and the finite element program LS-DYNA was used to assess its performance under NCHRP Report 350 Test 3-11 impact conditions. A full-scale crash test was subsequently conducted after favorable results from the finite element analysis. The system successfully passed the safety requirements of NCHRP Report 350 for Test Level 3. This paper discusses the evaluation procedure and presents results of the HALCO X-44 post and guardrail system analysis.

The National Park Service Road Inventory Program (RIP) uses automated collection and processing of pavement-condition data. The study examines various approaches to quality assurance (QA) sampling used to evaluate those data. The RIP includes automated collection and processing of pavement-condition and roadside-inventory-feature data at 258 national parks, covering over 5,000 mi of paved roads. Evaluating the quality of some data elements requires manual data assessment conducted by trained data analysts. Because of the high volume of the collected and processed data, it is economically impractical to check quality of all data manually. To overcome this difficulty, a search for an appropriate QA data sampling methodology was conducted. The goal of the investigation was to determine appropriate statistical procedures and required sample sizes so that conclusions based on QA sample testing could be extrapolated to the whole data set with a certain level of confidence. Evaluation of QA sampling approaches, including the selection of statistical procedures for QA testing, determination of QA sample sizes, and development of the procedures for evaluating the QA testing results applicable to the RIP, is presented. The results will be of interest to practitioners involved in automated collection of pavement data and to researchers involved in the design of statistical testing procedures for engineering QA applications.

The method of surface-detected fluorescence has been used to monitor the emission intensity from 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) in lesions and corresponding adjacent normal skin. Three types of lesions were examined: psoriatic plaques, actinic keratosis and basal cell carcinoma. This study included a total of 14 human volunteers on whom ALA-induced PpIX formation and clearance was monitored for a total of 48 h post-ALA application. Both an ALA dose-ranging study, as well as a comparison of results between normal and lesional tissue at a fixed ALA dose, were carried out. For the dose range examined (10-30%), there was no ALA dose dependency of the PpIX fluorescence for any of the lesions tested. Although all three lesions tested did show enhanced PpIX fluorescence as compared with normal skin, there was considerable lesion-to-lesion variability. Thick psoriatic plaques seem to give longer PpIX retention times than those of thin lesions. Limitations of the surface-detected fluorescence methodology are discussed.

Many different types of mammalian cells accumulate fluorescing and photosensitizing concentrations of protoporphyrin IX (PpIX) when exposed to exogenous 5-aminolevulinic acid (ALA) in vivo or in vitro. Most types of malignant cells accumulate substantially more ALA-induced PpIX than do the normal cells from which they arose. Most types of malignant cells also are less differentiated than their normal counterparts. We therefore considered the possibility that malignant cells demonstrate a malignant ALA phenotype (accumulate abnormally large amounts of PpIX when exposed to exogenous ALA) as a direct consequence of their less differentiated state. Human promyelocyte cell line HL-60 and mouse preadipocyte cell line 3T3 L1 were induced to differentiate by exposing them to inducing agents in vitro. The HL-60 cells accumulated less ALA-induced PpIX when differentiated, but the 3T3 L1 cells accumulated more. It appears then that changes in the ALA phenotype with changes in the state of differentiation are cell-type specific. The decreased accumulation of ALA-induced PpIX that accompanied differentiation of the promyelocytic leukemia cells may have clinical application for rapid quantitation of the response of myelocytic leukemia patients to differentiation therapy.

Photothermal catalytic oxidation of ethanol over TiO{sub 2} and Pt/TiO{sub 2} has been investigated. Platinum was deposited on the titania using both photoreduction and adsorption of the PtCl{sub 6}{sup 2{minus}} anion. The nominal weight loadings of Pt were less than 1 wt%. Thermal contributions to ethanol oxidation over Pt could be distinguished from photo-contributions to ethanol oxidation over TiO{sub 2} by comparing illuminated and dark reactions under the same conditions. A significant photothermal synergistic effect was seen for Pt/TiO{sub 2} catalysts. The activity for complete oxidation to CO{sub 2} is much greater than the contribution from photo-oxidation over TiO{sub 2} plus thermal oxidation over Pt. Experiments were conducted to investigate the mechanistic nature of the synergistic effect. The synergistic effect was found to be sensitive to preparation conditions, with photoreduced catalysts having higher activities compared to thermally reduced catalysts prepared by adsorption of the PtCl{sub 6}{sup 2{minus}} anion. The differences between the photo and thermally reduced Pt/TiO{sub 2} are attributed to differing extents of etching of the TiO{sub 2} surface by the acidic solution of chloroplatinic acid. An experiment with layered beds of Pt/TiO{sub 2} and TiO{sub 2} showed that adding unetched TiO{sub 2} to etched Pt/TiO{sub 2} could improvemore » CO{sub 2} production. The photothermal synergistic enhancement of CO{sub 2} production appears to be caused primarily by gas phase transport of intermediates between the two catalyst phases in a mixed series-parallel kinetic pathway. Increased levels of acetaldehyde produced by photo-oxidation over TiO{sub 2} can lead to CO{sub 2} production by thermal reaction of the acetaldehyde over Pt.« less

Methods of cost allocation for highway pavement rehabilitation and maintenance activities and pavement management estimations are based on empirical and semiempirical founded predictions that come up short, particularly when a roadway is subjected to heavy multiaxle vehicles. Additionally, materials used in constructing the pavement structure do not always behave in an elastic manner, and the ability to predict the pavement response in the presence of other than elastic material behavior is essential. Finally, prediction of pavement states of distress, based on empirical methods, and elastic material behavior is inadequate, particularly when traffic of heavy vehicles is involved. Battelle has been working on a mechanistic approach to address the issues and concerns at the core of current pavement design methods. The overall approach consists of combining three major software modules—a structural module that includes a general primary response model, a material characterization module, and a damage and distress module—are interconnected so that the influence of one on the other is continually updated. Four miles of highway pavement have been heavily instrumented with structural and environmental sensors so that pavement response can be monitored on both short- and long-term bases. Field test results from these pavements have been acquired and, along with laboratory data, have been used to partially validate and provide insight into pavement behavior under various loading conditions. The unique requirements for the design and implementation of the structural and environmental sensing elements are discussed. The mechanistic aspects in the software for the structural and material models are described, and predicted and field-measured results are compared.

Light poles installed within the deflection zone of roadside barriers (guardrails) may influence the ability of the guardrail to safely redirect an impacting vehicle. One concern is that, during an impact, the vehicle may pivot about the relatively rigid light pole and then spin away from the guardrail back into the traffic stream in an uncontrolled, unsafe manner. A large percentage of the highway network in Ohio uses the type of guardrail and light pole configurations, in which the breakaway light poles are placed at either 15.2- or 45.7-cm (6- or 18-in.) lateral distance from the back of the guardrail, depending on one of two light pole base designs in use. These pole-guardrail systems were placed in large numbers some years ago and Ohio accident data have been inadequate to provide information to determine whether or not a problem exists with this system. Proposed highway rehabilitation and reconstruction projects can include changes or adjustments to placement of guardrails and light poles, but there was a lack of information as to whether or not the past practices possessed a problem. A study was conducted to determine if light poles have an adverse effect on the redirecting performance of guardrails. It included six full-scale crash tests involving two vehicle weight classes (2000P and 820C), two light pole base designs (AT-A and AT-X), and a typical guardrail used in Ohio [Type 5 (W-Beam)]. All full-scale tests were carried out according to the recommended procedures in National Cooperative Highway Research Program (NCHRP) Report 350. The actual vehicles used for the 2000P class were half-ton pickup trucks ballasted to simulate the weight and mass characteristics of the 2000P vehicle that is specified in NCHRP Report 350. The guardrail–light pole system was not shown to cause snagging or subsequent unstable motion of the vehicle due to impact. All vehicles exited the guardrail in a stable manner. No change in the arrangement of light poles behind the Type 5 guardrail is contemplated. The redirecting function of the guardrail was not compromised as a result of placement of the light pole behind the length-of-need. Excessive exit angle situations (according to NCHRP Report 350) occurred in three tests involving the simulated 2000P class vehicles. However, the impact conditions employed for these tests were extreme, and the likelihood of this situation occurring under everyday highway usage may be small.

5-Aminolevulinic acid (ALA), when added to many tissues, results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway, to produce a photodynamic effect when exposed to activating light. Therefore, ALA is the only photodynamic therapy (PDT) agent in current clinical development that is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous superficial and nodular basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and in human clinical studies has shown selective formation of PpIX within the endometrium. PpIX induced by ALA application has also been used as a fluorescence detection marker for photodiagnosis (PD) of cancer and dysplastic conditions of the urinary bladder and other organs. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. The current state of knowledge of the mechanisms of endogenous topical and systemic photosensitization using ALA, the results of published clinical trials, and possible methods of increasing the efficacy of endogenous photosensitization for ALA PDT are reviewed in this paper.

OBJECTIVES: To evaluate the selectivity of endometrial photosensitization after intrauterine 5-aminolevulinic acid administration in nonhuman primates, and to assess acute and chronic systemic toxicity after intravenous (i.v.) delivery of 5-aminolevulinic acid. METHODS: Ovariectomized cynomolgus monkeys (n = 19) aged 6-18 years and ovariectomized rheusus monkeys (n = 3) aged 9-14 years were used in these studies, 5-aminolevulinic acid at various doses was administered by a transfundal (n = 8), transcervical (n = 3), or i.v. (n = 11) route. Spectrophoto-fluorometric readings and fluorescence microscopy were used to assess 5-aminolevulinic acid-induced photosensitization of uterine tissues; respiration, heart rate, blood biochemistry, and behavior were used to evaluate potential acute and delayed systemic toxicity. RESULTS: Endometrial fluorescence was achieved in all animals after administration of 5-aminolevulinic acid. Characteristic spectrophotofluorescence peaks of protoporphyrin IX (PpIX) in the endometrium but not myometrium confirmed selective endometrial PpIX production from 5-aminolevulinic acid. A transient (less than 1 week) increase in serum aspartate aminotransferase was observed after systemic instillation of 5-aminolevulinic acid in dosages 24-50-fold greater than that required to induce endometrial photosensitization after intrauterine injection. CONCLUSIONS: The endometrium but not myometrium in nonhuman primates is capable of converting 5-aminolevulinic acid into protoporphyrin IX. At large doses, systemic 5-aminolevulinic acid causes a transient increase in the serum aspartate aminotransferase level. No other evidence of acute or delayed systemic toxicity was observed.

OBJECTIVE: Our purpose was to evaluate and compare the conversion of 5-aminolevulinic acid into the endogenous photosensitizer protoporphyrin IX in experimentally induced endometriosis and in other normal tissues in a rat model. STUDY DESIGN: Fluorescence of experimental endometriotic lesions, uterus, peritoneum, bowel mesentery, bladder, eye, skin, and skeletal muscle was assessed 3 hours after either intravenous, oral, or intrauterine administration of 5-aminolevulinic acid with use of spectrophotofluorometry. In another experiment the fluorescence of surgically induced endometriosis and adjacent normal peritoneum was evaluated every 15 minutes after 5-aminolevulinic acid administration to assess the time course of protoporphyrin IX production. RESULTS: In the rat endometriosis model intralesional and systemic 5-aminolevulinic acid produced fluorescence within implants showing viable endometrial cells. Treatment with 5-aminolevulinic acid produced low-intensity fluorescence in peritoneum, bowel mesentery, and eye. Relatively intense fluorescence was seen in skin, bladder, and uterus. No fluorescence was observed in skeletal muscle. The intensity of fluorescence varied with the dosage and route of administration of 5-aminolevulinic acid. Fluorescence intensity of protoporphyrin IX was significantly greater in implants than in adjacent normal peritoneum between 2 and 4 hours after treatment. CONCLUSIONS: Protoporphyrin IX fluorescence in experimentally induced endometriosis lesions after intravenous and oral delivery of 5-aminolevulinic acid was significantly greater than the fluorescence detected in adjacent normal peritoneum. (AM J OBSTET GYNECOL 1996;174:154-60.)

Results are reported on the sensitivity of various gynaecological tumour cell lines to 5-aminolaevulinic acid-induced protoporphyrin IX-sensitised photodynamic therapy (ALA-PDT) in vitro. All cell lines tested accumulated ALA-induced protoporphyrin IX (PpIX) and demonstrated good sensitivity to ALA-PDT. Localisation of PpIX in the mitochondria was demonstrated by fluorescence microscopy. Subcellular damage following ALA-PDT was observed using transmission electron microscopy. This damage was localised initially to the mitochondria, with damage to membranes and the nucleus and complete loss of intracytoplasmic organisation being observed subsequently. There was no apparent difference in ALA-PDT response between a multidrug-resistant ovarian carcinoma cell line and its parent line. These results indicate that ALA-PDT has potential for application to therapy of gynaecological malignancies. Images Figure 5 Figure 6 Figure 7

Surface-detected fluorescence spectroscopy can be used to monitor the pharmacokinetics of uptake and clearance of red-absorbing fluorophores such as zinc(II) phthalocyanine (ZnPc) in vivo. When this technique is applied to mice that have been fed on a normal chlorophyll-based diet, and particularly when measurements are performed in the abdominal region, oscillations are sometimes observed superimposed on the pharmacokinetic curve of the ZnPc. An oscillatory signal has also been observed arising from the abdominal region of control mice fed a normal diet but not injected with the ZnPc photosensitizer; this oscillatory component to the signal is reduced when mice are fed a chlorophyll-free diet. The oscillatory signal component has been attributed to fluorescence arising from chlorophyll derivatives (pheophorbide/pheophytin) contained in the rodent food, whose concentration in the measured abdominal region changes substantially with time, presumably due to digestive processes. Thus it is important to be aware of the possibility of such artifactual contributions to in vivo fluorescence pharmacokinetic measurements.

— 5-Aminolevulinic acid (ALA), a precursor of protoporphyrin IX (Pp IX), was administered into the rat uterine cavity in an attempt to selectively ablate the endometrium. Doses of ALA ranging from 4 to 50 mg were injected into one uterine horn of rats while the vehicle (saline) was injected into the contralateral horn. Animals were divided into three groups. In group one, the uterine horns were removed and processed for either fluorescent mi- croscopy or spectrophotofluorometry 3 h later. In group two, rats were allowed to survive for either 2 or 10 days, and then the uterine horns were harvested and processed histologically. In group three, both uterine horns were exposed to transmural light (approximately 150 J/cm*) 3 h after administration of ALA or saline and processed histologically either 2 or 10 days later. Fluorescent microscopy showed fluorescence in the endometrium and not in the myometrium. The maximum emission spectra of endometrial fluorescence occurred at 630 and 690 nm, characteristic of Pp IX. In contrast, no fluorescence was detected in saline-treated uterine horns. Light exposure resulted in extensive damage only to the ALA-treated endometrium. There was no indication of regeneration 10 days after treatment. We conclude from these studies that ALA administered into the lumen of the rat uterus is selectively converted into Pp IX within the endometrium. Furthermore, photoactivation of the Pp IX results in selective ablation of the endometrium.

We evaluated disruption of endometrial function after treatment with 5-aminolevulinic acid with or without light exposure.In a conventional laboratory setting adult Sprague-Dawley female rats were treated with various doses of 5-aminolevulinic acid in one uterine horn and saline in the contralateral horn. Three hours after treatment both uterine horns were exposed to light, and the rats were bred to a fertile male 10 or 60 days later. Ablation of endometrium was evaluated by both rate of implantation and histologic features.In the absence of light exposure 5-aminolevulinic acid had no significant effect on the rate of implantation, compared with saline (76% vs 92%, n = 25, p0.05). In contrast, 5-aminolevulinic acid treatment plus light exposure profoundly decreased the rate of implantation in the 5-aminolevulinic acid-treated uterine horns of rats bred 10 days (3.8% vs 100%, n = 26, p0.001) or 60 days after treatment (16.7% vs 100%, n = 24, p0.001). Histologic examination revealed that the 5-aminolevulinic acid plus light-treated uterine horns were completely devoid of endometrium.Photodynamic treatment with 5-aminolevulinic acid resulted in a persistent disruption of rat endometrial function and was consistent with the histologic evidence of complete endometrial ablation. In addition, a partial destruction of myometrium adjacent to endometrium was observed. The myometrial damage may be through a nonphotodynamic mechanism because myometrium is unable to synthesize protoporphyrin IX from 5-aminolevulinic acid.

The tissue photosensitizer protoporphyrin IX (PpIX) is an immediate precursor of heme in the biosynthetic pathway for heme. In certain types of cells and tissues, the rate of synthesis of PpIX is determined by the rate of synthesis of 5-aminolevulinic acid (ALA), which in turn is regulated via a feedback control mechanism governed by the concentration of free heme. The presence of exogenous ALA bypasses the feedback control, and thus may induce the intracellular accumulation of photosensitizing concentrations of PpIX. However, this occurs only in certain types of cells and tissues. The resulting tissue-specific photosensitization provides a basis for using ALA-induced PpIX for photodynamic therapy. The topical application of ALA to certain malignant and non-malignant lesions of the skin can induce a clinically useful degree of lesion-specific photosensitization. Superficial basal cell carcinomas showed a complete response rate of approximately 79% following a single exposure to light. Recent preclinical studies in experimental animals and human volunteers indicate that ALA can induce a localized tissue-specific photosensitization if administered by intradermal injection. A generalized but still quite tissue-specific photosensitization may be induced if ALA is administered by either subcutaneous or intraperitoneal injection or by mouth. This opens the possibility of using ALA-induced PpIX to treat tumors that are too thick or that lie too deep to be accessible to either topical or locally injected ALA.

Photochemotherapeutic agents are photosensitizers that are selectively retained by neo-plastic tissue. When tumor tissue containing these drugs is irradiated with visible electromagnetic radiation, the photosensitizing reaction may lead to tumor eradication, termed photodynamic therapy. Exogenous photosensitizers commonly used in clinical trials are mainly porphyrin derivatives. Phthalocyanines are currently being investigated as “second generation” photochemotherapeutic agents. The mechanism by which these photosensitizers are selectively retained in neoplastic tissue is unclear. This review examines the role of tissue and cellular pH as a factor in selective biodistribution. The pH values of normal and tumor tissue are summarized and the ionic species distribution diagram of porphyrins is presented. A two-fold mechanism of selective biodistribution is advanced, one involving normal tissue vs. tumor tissue selectivity, the other involving intracellular vs. intercellular distribution of sensitizer ionic species.

Volumetric titration of aqueous solutions of haematoporphyrin IX (HP) yields two inflexion points, whereas four pK values can be obtained via mathematical fitting of the experimental data. Assignment of all pK protonation sites is made. A zwitterion is proposed as the neutral species of HP. Evaluation of the pK values of HP in the presence of sodium dodecyl sulphate (SDS) leads to a drastically altered ionic species distribution. On the basis of the distribution diagrams obtained, a pH-sensitive twofold mechanism is proposed for the selective biodistribution of porphyrin-type photochemotherapeutic agents, one involving tissue distribution and the other involving cell membrane penetration by the neutral zwitterion.

5-Aminolaevulinic acid (ALA) is a precursor of protoporphyrin IX (Pp IX) in the biosynthetic pathway for haem. Certain types of cells have a large capacity to synthesize Pp IX when exposed to an adequate concentration of exogenous ALA. Since the conversion of Pp IX into haem is relatively slow, such cells tend to accumulate photosensitizing concentrations of Pp IX. Pp IX photosensitization can be induced in cells of the epidermis and its appendages, but not in the dermis. Moreover, since ALA in aqueous solution passes readily through abnormal keratin, but not through normal keratin, the topical application of ALA in aqueous solution to actinic keratoses or superficial basal cell or squamous cell carcinomas induces Pp IX photosensitization that is restricted primarily to the abnormal epithelium. Subsequent exposure to photoactivating light selectively destroys such lesions. In our ongoing clinical trial of ALA-induced Pp IX photodynamic therapy, the response rate for basal cell carcinomas following a single treatment has been 90% complete response and 7.5% partial response for the first 80 lesions treated. The cosmetic results have been excellent, and patient acceptance has been very good.

Drugs used in disease treatment can cause damage to both malignant and normal tissue. This toxicity limits the maximum therapeutic dose. Drug targeting is of high interest to increase the therapeutic efficacy of the drug without increasing systemic toxicity. Certain tissue abnormalities, disease processes, cancers, and infections are characterized by high levels of activity of specific extracellular and/or intracellular proteases. Abnormally high activity levels of specific proteases are present at sites of physical or chemical trauma, blood clots, malignant tumors, rheumatoid arthritis, inflammatory bowel disease, gingival disease, glomerulonerphritis, and acute pancreatitis. Abnormal protease activity is suspected in development of liver thrombosis, pulmonary emphysema, atherosclerosis, and muscular dystrophy. Inactiviating disease-associated proteases by the administration of appropriate protease inhibitors has had limited success. Instead, one could use such proteases to target drugs to treat the condition. Protease mediated drug delivery offers such a possibility. Solubilizing groups are attached to insoluble drugs via a polypeptide chain which is specifically cleavable by certian proteases. When the solubilized drug enounters the protease, the solubilizing moieties are cleaved, and the drug precipitates at the disease location. Thus, a smaller systemic dosage could result in a therapeutic drug concentration at the treatment site with less systemic toxicity.

Palladium octabutoxynaphthalocyanine (PdNc(OBu)8) is a potential photothermal therapy (PTT) agent, absorbing strongly in the near-infrared region with no ability to induce photodynamic-type sensitisation (unlike many related napthalocyanines). We report here on the application of high pressure liquid chromatography (HPLC) with near-infrared absorption detection for the determination of the tissue accumulation and clearance of PdNc(OBu)8 in a tumour-bearing mouse model (Balb/c mice with EMT6 carcinoma tumour). Due to its insolubility in aqueous-based solvents, the drug was delivered intraperitoneally in a Cremophor-containing vehicle. Good selective accumulation of the drug into the tumour versus muscle or skin is observed, with the best combination of selectivity and tumour concentration occurring at 24-72 h after drug administration. Clearance times are quite long. Comparison with other similar drugs as reported in the literature indicates that the Cremophor-containing vehicle is likely in large part responsible for the observed pharmacokinetic behaviour. This drug shows potential for PTT and will be investigated further for therapy in this animal model.

All nucleated mammalian cells synthesize protoporphyrin IX (PpIX) when exposed to exogenous 5-aminolevulinic acid (ALA). The response to exogenous ALA under standard conditions (the ALA phenotype) is characteristic for each cell type. Significantly more PpIX accumulates in malignant and premalignant cells than in the normal cells from which they were derived. A rodent fibroblast model was developed to study the mechanisms responsible for this phenomenon. Exogenous ALA induced the accumulation of substantial concentrations of PpIX in fibrosarcoma cells, and in immortalized fibroblasts transfected with the oncogene c-myc, IGF-1 receptor, IGF-1 and its receptor, v-fos, v-raf, v-Ki-ras, v-abl, or polyomavirus middle T antigen with G418 resistance selection. Much lower concentrations of PpIX accumulated in primary fibroblast cultures, in immortalized fibroblast cell lines, and in immortalized fibroblasts transfected with the G418-resistance gene only. The mechanisms responsible for the increased accumulation of ALA-induced PpIX by transformed cells (the malignant ALA phenotype) therefore appear to be closely linked to the mechanisms responsible for malignant transformation. Identification of the nature of that linkage may lead to new approaches to cancer therapy. © 1999 Cancer Research Campaign

Certain types of cells may accumulate relatively high concentrations of protoporphyrin IX (PpIX) when exposed to 5- aminolevulinic acid or certain of its derivatives. PpIX is a photosensitizing agent which can be photoactivated in vivo by ultraviolet and/or visible light, thereby initiating a photodynamic reaction that may lead to the destruction of cells and tissues containing high concentrations of PpIX. This process is referred to as ALA-induced PpIX photodynamic therapy (ALA-PDT), a rapidly growing field of research. ALA is effective when administered topically, orally, by intravenous, subcutaneous, or intradermal injection, or by infusion into accessible body cavities. PpIX is the main photosensitizer produced under most conditions, although others may be present also especially during split dose therapy. Multiple wavelength excitation sources are required to produce and subsequently activate the far red absorbing chlorin type photoproducts that are produced under certain conditions.

The need for effective design in the nation's highways is greater now, more than ever, due to shrinking funds for new construction and rehabilitation/maintenance practices and the need to preserve the lands that are not now part of the roadway system. Most of the nation's highways were constructed within the last 30 years and many of these are due for significant rehabilitation and even reconstruction. Thus, the need to infuse robust design methods into these rehabilitation and reconstruction strategies is paramount. Currently, methods for cost allocation for pavement rehabilitation/maintenance activities and pavement management estimations are based on empirical and semi- empirical founded predictions that come up short, particularly when the roadway i subjected to multi-axle, heavy weight vehicles. Additionally, materials currently used int he construction of the pavement structure do not always behave in an elastic manner and the ability to predict the pavement response in the presence of other than elastic material behavior is essential. Finally, prediction of pavement states of distress based on empirical methods and elastic material behavior are inadequate, particularly when heavy weight vehicular traffic is involved. This paper includes descriptions of the overall methodology for pavement design and the unique requirements for the design and implementation of the structural and environmental sensing elements. Description of the mechanistic aspects in the software for the structural and material models is discussed and comparison of predicted and field measured results are presented.

Administration of the heme precursor 5-aminolevulinic acid (ALA) leads to the selective accumulation of the photosensitizer protoporphyrin IX (PpIX) in certain types of normal and abnormal tissues. This phenomenon has been exploited clinically for detection and treatment of a variety of malignant and nonmalignant lesions. The present preclinical study examined the specificity of ALA-induced porphyrin fluorescence in chemically induced murine lung tumors in vivo. During the early stages of tumorigenesis, ALA-induced PpIX fluorescence developed in hyperplastic tissues in the lung and later in early lung tumor foci. In early tumor foci, maximum PpIX fluorescence occurred 2 h after the administration of ALA and returned to background levels after 4 h. There was approximately a 20-fold difference in PpIX fluorescence intensity between tumor foci and the adjacent normal tissue. The specificity of ALA-induced fluorescence for hyperplastic tissues and benign tumors in lung during tumorigenesis suggests a possible use for this fluorochrome in the detection of premalignant alterations in the lung by fluorescence endoscopy. Two non-small cell lung cancer cell lines developed ALA-induced PpIX fluorescence in vitro. These lines exhibited a light-dose-dependent phototoxic response to ALA photodynamic therapy (PDT) in vitro. Because PpIX is a clinically effective photosensitizer for a wide variety of malignancies, these results support the possible use of ALA-induced PpIX PDT for lung cancer.

Numerous photosensitizing pigments that absorb visible light and are selectively retained in neoplastic tissue are being investigated as potential photochemotherapeutic agents. While much emphasis is being placed on the synthesis of new, far-red absorbing photosensitizers, an alternative approach has been to stimulate the human body to produce its own natural photosensitizer, namely protoporphyrin IX (PpIX). Exogenous 5-aminolevulinic acid (ALA) is rapidly bioconverted into PP by mitochondria, the process being particularly efficient in tumor cells. Since PpIX has a natural and rapid clearing mechanism (via the capture of iron in the process of being converted into heme), ALA-PDT does not suffer from lingering skin phototoxicity. ALA may be introduced orally, intravenously, or topically, and ALA-PDT has been shown to be effective in the treatment of both malignant and non-malignant lesions.© (1996) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

All materials are partially transparent in some part of the electromagnetic spectrum, and it is thus logical that the transmission of light has found wide use as a probing tool to characterize and study a large variety of samples. Dual beam spectrophotometric systems, in which the intensity of light transmitted through a sample is directly compared with the same light transmitted through a reference material, have found wide use in many areas such as analytical chemistry, geology, physics and medicine. The fact that all atomic and molecular systems absorb light at some wavelengths (ultraviolet, visible or infrared) has made absorbance spectroscopy a general and widely applicable tool.

Inherent in both plants and animals is the natural porphyrin, Protoporphyrin IX (Pp). Although Pp does not appear to have any intrinsic biological activity, it is a potent natural photosensitizer. When activated with ultraviolet or visible light, this photosensitizer can induce significant photodynamic effects on tissues, cells, subcellular elements, and macromolecules via the production of singlet oxygen. The biosynthesis of endogenous Pp is under strict enzymatic control. It is possible to bypass a rate controlling step and induce large, transient concentrations of Pp by the addition of exogenous 5-aminolevulinic acid (ALA). ALA may be administered systemically or topically. Much larger amounts of Pp are produced in certain types of tumor tissue than in adjacent normal tissue. Topically applied ALA can be used to treat a variety of skin lesions, including actinic keratosis, basal cell carcinomas and psoriasis.

Photoacoustic spectroscopy was used to monitor the photobleaching of Hematoporphyrin IX dissolved in Intralipid. The kinetic behaviour of the effect was observed to be of purely first order with time.

An intensified photodiode array forms the heart of a sensitive spectrophotofluorometry system that permits the rapid and non-invasive determination of fluorescence emission spectra in the skin of living, non-anesthetized animals. Using this system, we found it possible to obtain good emission and excitation spectra of the material responsible for the weak red fluorescence that characterizes normal mouse skin, and to follow the biosynthesis and subsequent clearance of protoporphyrin IX in the skin of non-anesthetized mice that had been given various doses of the porphyrin precursor 5-aminolevulinic acid.

SUMMARY:An experimental model for the study of porphyric neuropathy is presented. Injection of either tetraphenylporphinesulfonate (TPPS), hematoporphyrin derivative (HpD), or delta-aminolevulinic acid (ALA) into mice resulted in markedly decreased motor nerve conduction velocity (MNCV). The MNCV returned to normal within one week following the injection of large doses of A LA, and within three weeks following the injection of close to lethal doses of HpD. hut there was no recovery of nerve function within 60 days following injection of substantially smaller doses of TPPS. Ultrastructural examination of motor nerves at various times following TPPS injection revealed the gradual development of structural abnormalities. Ultrastructional examination of the same nerves after a single dose of either A LA or Hp D failed to demonstrate any abnormalities.The present observations call for precaution as to the use of TPPS as photosensitizer in human cancer treatment.

A matrix game format was employed in a 2 × 2 design to study the effects of within group cooperation and competition under conditions of success and failure on subjects' subsequent treatment of own group and outgroup persons. Subjects in two-person groups either succeeded or failed at a cooperative or competitive game and then awarded points (worth money) to themselves, their partner, and two other people. A review of the relevant literature suggested that ingroup-outgroup bias would be greater after successful competition than after unsuccessful competition. The results supported this hypothesis. It was also found that subjects in the Cooperation-Failure condition displayed greater ingroup-outgroup bias than subjects in the Cooperation-Success condition. A qualification of the previous research supporting a positive relationship between group cohesiveness and ingroup-outgroup bias was suggested on the basis of the results.

The absorbance and fluorescence spectra of Hematoporphyrin IX, Photofrin, and Photofrin II are measured as a function of pH, concentration, and temperature, in order to isolate the ionic equilibria from the monomer/dimer/aggregate equilibria. Based on photometric and volumetric titrations, the distribution diagram for four ionic species is presented, with pKa, values of 2.7, 5.2, and 9.1. Protonation sites for these pKa's are assigned.

The addition of small numbers of irradiated mouse fibrosarcoma cells to cultures containing syngeneic mouse spleen cells and sheep erythrocytes resulted in almost complete inhibition of the expected anti-sheep hemolytic plaque-forming cell responses; the addition of even smaller numbers resulted in stimulation rather than inhibition. This same pattern was reproduced when various other types of syngeneic or allogeneic malignant cells were tested under similar conditions; the presence of strong (H-2) histocompatibility differences had no apparent effect. Metabolically active irradiated malignant cells were required to produce inhibition; dying cells or soluble extracts of cells were ineffective. However, serum-free supernatants from healthy cultures of non-irradiated fibrosarcoma cells were found to be inhibitory at high concentrations and stimulatory at low concentrations, in a pattern similar to that found when intact irradiated fibrosarcoma cells were used. High-speed centrifugation of such supernatants sedimented the stimulatory material but left the inhibitory material in solution. When syngeneic fetal fibroblasts were substituted for the fibrosarcoma cells, it was found that both the intact fibroblasts and their culture supernatants were stimulatory, and that the stimulatory material could be sedimented as before by high-speed centrifugation. However, very little inhibitory effect was produced by either intact fibroblasts or their culture supernatants, except when unusually high concentrations were used. It is concluded that at least some types of healthy malignant cells release soluble material capable of inhibiting immune responses: their non-malignant counterparts produce little if any inhibitor.

Human peripheral blood contains cells which are cytotoxic in vitro for certain types of malignant cells, even though the donors have had no known exposure to cancer of any type. The identity of these cytotoxic cells is a matter of controversy since they do not fit readily into any commonly recognized category of peripheral blood cell. In this paper, we present a radiobiological characterization of these cells. The radiation survival curve for the spontaneous cytotoxic function had a D o0 of approximately 750–850 rad and a broad but variable shoulder. The possibility that spurious D o values were obtained as a result of radiation-induced interphase death of the cytotoxic cells was examined experimentally. Moderate doses of radiation caused definite enhancement of cytotoxicity. Evidence was obtained for the existence of ralatively radiosensitive cell interactions which existence of relatively radiosensitive cell interactions which ordinarily result in a decrease in cytotoxic efficiency and which may be responsible for the observed stimulatory effect of irradiation. This parameter of the survival curve does not appear to be a consequence of intrinsic radiobiological properties of the cytotoxic cells. The Fc receptor function (the ability of the cells to bind antigen :IgG complexes via the Fc portion of the IgG molecules) appears to be relatively radioresistent.

Decomposed matrix games were used to study interethnic competition in the triethnic school system of a southwestern city. The sample consisted of sixth-grade males from segragated schools. In addition to the data from the matrix games, brief questionnaire measures of internal vs. external locus of control, self-esteem, and authoritarianism were also obtained. The results on the game matrices indicated that the anglos competed more and were less trusting than the blacks or chicanos. The questionnaire results indicated that the blacks were highest on feelings of external control and on authoritarianism, while the chicanos were lowest in self-esteem. Cooperative interethnic work groups were suggested as a means of coping with the problems that these differences might be expected to cause in integrated schools.