[Blood donation in the light of anthropology]. / Le don du sang à la lumière de l'anthropologie.

In his well-known Essai sur le don, French anthropologist Marcel Mauss has shown that in all societies, donation and exchange of gifts are part of people's commitments. Although systematically denied, that obligation is one of the main sources of sociability. In this respect, blood donation can be considered as a very common act, except that, since blood comes from human body, that act is, at the same time, very special and meaningful.

[Not-for-profit: A report from the fourth annual symposium of ethics held by the National Institute for Blood Transfusion (France)]. / À propos du non-profit : rapport du quatrième symposium annuel d'éthique transfusionnelle de l'Institut national de la transfusion sanguine.

The not-for-profit issue has been debated in November 2016 in Paris; this issue is one of the four canonical pillars of ethical blood donation. It is intimately bound to benevolence though it is distinct, as not-for-profit calls for institutions while benevolence calls for individuals. It is indeed intended that voluntary blood donors do not benefit from their donation and are thus non-remunerated. Not-for-profit is essential since it refers to the public character of blood as a putative public resource aimed at being shared as a tribute of solidarity. A central question however is linked to the capacity- or not -of public sectors to ensure that blood components are universally available, with special mention to plasma derived drugs, without the contribution of the for profit, private sector.

[Voluntariness and blood donation: Proceedings of an ethics seminar held at the National Institute for Blood Transfusion]. / Volontariat et don de sang : compte rendu d'un séminaire de l'Institut national de transfusion sanguine.

Voluntariness stands for one of the four pillars of ethics in blood donation; it is, however, more related to tradition than to legislation. Because it seems necessary to apply "marketing" techniques to blood collection in order to meet the needs in blood components, both in terms of quantity and quality, one wonders if this may be at the expense of this principle of voluntariness. This seminar-belonging actually to a series of seminars in Ethics in Transfusion Medicine-aimed at questioning the possible weakness of voluntariness in the field of blood donation. To achieve this goal, specialists of numerous disciplines in medical sciences, law and humanities gathered to discuss all related issues to voluntariness in blood donation.

[Ethics and transfusion--seminar report]. / Éthique et transfusion sanguine--Échos d'un séminaire.

This paper brings together the abstracts and proceedings of a seminar held on the topic of "ethics and transfusion", October 15, 2013 at the National Institute of Blood Transfusion, Paris.

Treatment of hypertension in rural Cambodia: results from a 6-year programme.

This study was aimed to describe the outcomes of a hypertension treatment programme in two outpatient clinics in Cambodia. We determined proportions of patients who met the optimal targets for blood pressure (BP) control and assessed the evolution of mean systolic and diastolic BP (SBP/DBP) over time. Multivariate analyses were used to identify predictors of BP decrease and risk factors for LTFU. A total of 2858 patients were enrolled between March 2002 and June 2008 of whom 69.2% were female, 30.5% were aged ≥64 years and 32.6% were diabetic. The median follow-up time was 600 days. By the end of 2008, 1642 (57.4%) were alive-in-care, 8 (0.3%) had died and 1208 (42.3%) were lost to follow-up. On admission, mean SBP and DBP were 162 and 94 mm Hg, respectively. Among the patients treated, a significant SBP reduction of 26.8 mm Hg (95% CI: 28.4-25.3) was observed at 6 months. Overall, 36.5% of patients reached the BP targets at 24 months. The number of young adults, non-overweight patients and non-diabetics reaching the BP targets was more. Older age (>64 years), uncontrolled DBP (≥90 mm Hg) on last consultation and coming late for the last consultation were associated with LTFU, whereas non-diabetic patients were 1.5 times more likely to default than diabetics (95% CI: 1.3-1.7). Although the definite magnitude of the BP decrease due to antihypertension medication over time cannot be assessed definitely without a control group, our results suggest that BP reduction can be obtained with essential hypertension treatment in a large-scale programme in a resource-limited setting.

New directions in photodynamic therapy.

Photodynamic therapy (PDT), a treatment approach that makes use of a photosensitizer to generate a localized toxic species in diseased tissue, has recently become an approved treatment modality. So far, however, only a handful of photosensitizers have received regulatory approval and for a small number of diseases. This chapter outlines the major limitations of PDT and speculates on the possible improvements that are required in order to advance PDT to a front line therapy. Seven areas of improvements are discussed: drug selectivity, drug delivery, light delivery, combination therapies, pigmented tumors, other potential uses, and protocol optimization. For each area, current limitations are discussed, and further required studies are recommended.

An affordable, portable fluorescence imaging device for skin lesion detection using a dual wavelength approach for image contrast enhancement and aminolaevulinic acid-induced protoporphyrin IX. Part I. Design, spectral and spatial characteristics.

Steady-state fluorescence imaging can be used in conjunction with selective exogenous or endogenous fluorescent compounds for the diagnosis of skin lesions, for example cancerous lesions. Depending on the excitation and emission properties of the fluorescent compound used, various excitation and/or emission wavelengths can be chosen in order to allow fluorescence imaging. Unwanted background signals like autofluorescence and scattering can decrease the image quality and hence the diagnosis potential of this imaging method. A method involving two excitation and/or emission wavelengths was used in order to suppress the unwanted background signal and allow contrast enhanced fluorescence imaging. A fluorescence imaging device prototype was assembled using both the two wavelength excitation method and the two wavelength emission method. Additionally, a white light source was included to allow the collection of images as seen with the naked eye. The prototype was designed to be affordable and portable and was laid out towards the diagnosis of skin lesions using aminolaevulinic acid-induced protoporphyrin IX (PpIX). This paper describes the excitation and detection characteristics of a fluorescence imaging device prototype. This includes spectral and spatial characteristics of the various light sources included in the device as well as specifications of the image detector used. Furthermore, the image analysis procedure used for the dual wavelength excitation/emission is described.

An affordable, portable fluorescence imaging device for skin lesion detection using a dual wavelength approach for image contrast enhancement and aminolaevulinic acid-induced protoporphyrin IX. Part II. In vivo testing.

A fluorescence imaging prototype for skin lesion detection and diagnosis using aminolaevulinic acid (ALA) induced protoporphyrin IX (PpIX) was tested in vivo and in the clinic. The prototype was designed as an affordable, portable device to allow contrast enhanced imaging of skin lesions using either the dual excitation wavelength method or the dual emission wavelength method or both. In this study the prototype was tested first on an animal model. Topical application of ALA on defined spots on mouse skin gave PpIX fluorescence after about 3 hours of application. After successful in vivo testing the instrument was tested on basal cell carcinoma patients before ALA-PpIX photodynamic therapy. The patients were topically applied with ALA. After three hours the device was tested (immediately before treatment). The prototype showed good results in terms of contrast enhancement (elimination of unwanted background signals, e.g. autofluorescence) using either contrast enhancement method, both methods achieving similar results. The results achieved in this study, combined with the affordable design of the device, seem to allow cost-effective, contrast-enhanced imaging of skin lesions before or during photodynamic therapy using ALA induced PpIX.

Quantification of the selective retention of palladium octabutoxynaphthalocyanine, a potential photothermal drug, in mouse tissues.

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.

Evaluation of novel nonlaser light source for endometrial ablation using 5-aminolevulinic acid.

BACKGROUND AND OBJECTIVE: This research evaluated the effectiveness of a new nonlaser prototype short-arc lamp to achieve photodynamic ablation of endometrium in a rat. STUDY DESIGN/MATERIALS AND METHODS: Thirty female Sprague-Dawley rats were divided into two groups. 5-Aminolevulinic acid (ALA), the precursor to the photosensitizer protoporphyrin IX, was injected into the left uterine horn and vehicle alone (Hyskon) was injected into the right horn of 23 rats (group 1). An additional seven rats received vehicle only into both uterine horns (group 2). Three hours later, a cylindrical diffusing optical fiber was inserted into the lumen of the uterine horns, and light treatment was delivered from either a laser or a nonlaser light source. Rats in group 1 received either 1 hour (n = 15) or 10 minutes (n = 8) of light treatment into both uterine horns. In rats in group 2, the left horn was exposed to 1 hour of light treatment. Uterine tissues were examined histologically 4 days after light treatment. RESULTS: One hour of light exposure to the uterine horns injected with ALA produced extensive necrosis of the rat uterine wall. No difference in the magnitude of destruction was seen between the groups treated with the laser and nonlaser light sources. Ten minutes of light exposure resulted in endometrial ablation that was comparable in both the laser- and the prototype-treated groups, but the destruction of the deepest layers of the uterine wall was more consistent in the group treated with the nonlaser prototype. One hour of light treatment from either light source did not result in any histological changes in the uterine horns not exposed to ALA. CONCLUSION: The extent of endometrial ablation in the rat uterine horn achieved with the nonlaser prototype was comparable to that achieved with the laser. Thus, the nonlaser prototype may provide a less expensive approach to photodynamic endometrial ablation.

Rodent fibroblast model for studies of response of malignant cells to exogenous 5-aminolevulinic acid.

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.

Effect of mammalian cell differentiation on response to exogenous 5-aminolevulinic acid.

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.

The Monitoring of ALA-Induced Protoporphyrin IX Accumulation and Clearance in Patients with Skin Lesions by In Vivo Surface-Detected Fluorescence Spectroscopy.

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.

Effect of 5-aminolevulinic acid dose and estrogen on protoporphyrin IX concentrations in the rat uterus.

OBJECTIVES: To determine the in vivo dose-response relation between administered 5-aminolevulinic acid (ALA) and the concentration of protoporphyrin IX (PpIX) produced in rat uterine tissue, to determine the effect of estrogen on ALA-induced PpIX production in the rat endometrium and myometrium, and to determine the selectivity of ALA-induced PpIX production in uterine tissue. METHODS: Ovary-intact female rats (n = 53) received a subcutaneous estradiol-17 beta (E2) implant. Three days later, ALA dissolved in saline (0, 1, 2.5, 10, 25, or 50 mg/100 microL) was injected into one uterine horn. Three hours after ALA administration, the uterus was removed and the endometrium was scraped from the myometrium. In a second study, rats (n = 35) were ovariectomized and 8 days later given either an E2 or sham implant. After 3 days of hormonal or sham priming, ALA (10 or 25 mg) was injected into the uterine horn 3 hours before hysterectomy. In both studies, PpIX was extracted in a methanol/ perchloric acid (1:1) solution and quantified spectrofluorometrically. RESULTS: Five-aminolevulinic acid increased PpIX concentrations in the endometrium and myometrium in a dose-dependent fashion. Twenty-five milligrams of ALA produced maximum PpIX concentrations in both the endometrium and myometrium. In the second study, sham-implanted ovariectomized rats had endometrial PpIX concentrations approximately two times higher than those in the estrogen-primed rats after doses of either 10 or 25 mg ALA. In the third study, the endometrium had two to three times higher PpIX concentrations than the myometrium at 1, 10, 25, and 50 mg of ALA. CONCLUSIONS: An in vivo dose-response relation was demonstrated between ALA and uterine production of PpIX, with maximum PpIX concentrations occurring after 25 mg of intrauterine ALA. Because estrogen was not required to convert ALA to PpIX, complete endometrial ablation may best be achieved with an unstimulated endometrium.

Effect of continuous and multiple doses of 5-aminolevulinic acid on protoporphyrin IX concentrations in the rat uterus.

The objective of the present study was to determine if the concentration of protoporphyrin IX (PpIX) in the rat endometrium could be increased by administering 5-aminolevulinic acid (ALA) in multiple doses or by continuous infusion. The effect of pH, temperature and time in solution on the stability of ALA were also investigated. Estrogen-filled silastic capsules were implanted subcutaneously into ovary intact female rats (200-225 g) (n = 66). On the third day of hormonal priming, ALA (10 mg or 25 mg) dissolved in saline and adjusted to a pH of 5-5.5 was administered intrauterine either as a single bolus or as two injections 3 hours apart (n = 10). A fifth group of rats was infused with 25 mg ALA over a 12 hour period using an osmotic minipump (n = 6). In a second experiment, ALA (25 mg) was injected immediately after being dissolved in saline (pH 2) (n = 16) or after incubation at 37 degrees C for 12 hour (pH 2) (n = 7). PpIX was then extracted from the endometrium and myometrium using a 1:1 methanol/perchloric acid solution and quantified spectrofluorometrically. A dose-response relationship was observed between 10 and 25 mg of ALA and endometrial PpIX concentrations. However, no differences in endometrial PpIX concentrations were detected between rats administered ALA either as a single bolus or as two doses. Continuous infusion of 25 mg of ALA resulted in statistically lower endometrial PpIX concentrations compared to 25 mg ALA injected either as a single bolus or as two injections. Neither pH, temperature, nor time in solution affected ALA-induced PpIX accumulation. We conclude that the simplest way of achieving the highest PpIX concentration in the rat endometrium in vivo is to administer a bolus injection of 25 mg of ALA.

5-aminolaevulinic-acid-induced formation of different porphyrins and their photomodifications.

The relative amounts of 5-aminolaevulinic acid (ALA)-induced hydrophobic and hydrophilic porphyrins produced in normal mouse tissue and solid Ehrlich ascites carcinoma in mice were investigated as a function of added glucose, light irradiation and restricted blood flow to the tumour. Protoporphyrin IX (PpIX) is the predominant porphyrin produced from exogenous ALA in tissues that have viable mitochondria. However, under special conditions which seem to be connected with a reduced viability of the mitochondria, the formation of water-soluble porphyrins can be observed in vivo. Fluorescence maxima of the water-soluble porphyrins are located in the region between 615 and 625 nm. Irradiation can further lead to the formation of PpIX photoproduct(s), showing a fluorescence emission band at 676 nm. The photobleaching of PpIX in normal tissue and tumour tissue is different under restricted blood flow. ALA-induced PpIX can be observed in the normal blood stream, and can be linked to a slower photobleaching than in tissue with restricted blood flow.

Detection of early stages of carcinogenesis in adenomas of murine lung by 5-aminolevulinic acid-induced protoporphyrin IX fluorescence.

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.

Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): mechanisms and clinical results.

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.

In vitro studies on the potential use of 5-aminolaevulinic acid-mediated photodynamic therapy for gynaecological tumours.

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.

Formation of water-soluble porphyrins and protoporphyrin IX in 5-aminolevulinic-acid-incubated carcinoma cells.

The bioconversion of 5-aminolevulinic acid (ALA) into hydrophobic protoporphyrin IX and other water-soluble porphyrins was investigated in Ehrlich ascite carcinoma (EAC) cells and in a myeloma cell line. The effects of irradiation (514 nm), temperature, incubation time and added glucose on the relative porphyrin concentrations (protoporphyrin vs. water-soluble porphyrins) were examined. Variations in these parameters induced a change in the amount of water-soluble porphyrins relative to protoporphyrin IX. The main component of the hydrophilic porphyrins was found to be uroporphyrin (Up), with minor components of coproporphyrin (Cp) and other carboxyporphyrins. The enhanced production of water-soluble porphyrins appears to be associated with alterations in the activities of the various enzymes in the heme biosynthetic pathway, resulting, for example, in the reduction in the activity of mitochondrial enzymes.