Tomato Phytonutrients Balance UV Response: Results from a Double-Blind, Randomized, Placebo-Controlled Study.

BACKGROUND: Our previous double-blinded, placebo-controlled cross-over study indicated that a nutritional supplement named lycopene-rich tomato nutrient complex (TNC) can protect from UVA1-induced (340-400 nm) and UVA- (320-400 nm)/UVB-induced (280-320 nm) upregulation of molecular markers associated with oxidative stress, inflammation, and ageing. OBJECTIVES: in the current double-blind, randomized, placebo-controlled multicenter study, we analyze whether a similar, synergistic carotenoid-rich TNC can protect from broadband UVB-induced threshold erythema formation assessed as increase in minimal erythemal dose (MED) reading, the intensity of erythema formation, and the upregulation of molecular markers associated with inflammation and immunosuppression, and whether this correlates with carotenoid blood levels. METHODS: One hundred and forty-nine healthy volunteers were randomized to two groups and subjected to a 5-week washout phase, followed by a 12-week treatment phase receiving either 15 mg lycopene, 5.8 mg phytoene and phytofluene, 0.8 mg ß-carotene, 5.6 mg tocopherols from tomato extract, and 4 mg carnosic acid from rosemary extract per day or placebo made from medium-chain triglycerides. At the end of each phase, MED determination, UVB irradiation, chromametry, biopsies, and blood samples were undertaken. RESULTS: The active supplement was well tolerated. Interestingly, no significant difference was seen in the MED between the active-supplement and placebo groups, as determined by visual grading by expert assessors. Of note, the carotenoid-containing supplement significantly protected against UVB-induced erythema formation measured as Δa* after the intervention minus Δa* after the washout phase as compared to the placebo. Moreover, intake of the active supplement significantly protected against UVB-induced upregulation of IL6 and TNFα as compared with the intake of placebo. Lastly, carotenoid plasma levels were significantly increased. CONCLUSION: This well-tolerated carotenoid-containing supplement significantly protected against UVB-induced erythema formation and upregulation of proinflammatory cytokines in healthy volunteers.

Carbonate Anion Radical Generated by the Peroxidase Activity of Copper-Zinc Superoxide Dismutase: Scavenging of Radical and Protection of Enzyme by Hypotaurine and Cysteine Sulfinic Acid.

Copper-zinc superoxide dismutase (SOD) is considered one of the most important mammalian antioxidant defenses and plays a relevant role due to its main function in catalyzing the dismutation of superoxide anion to oxygen and hydrogen peroxide. However, interaction between SOD and H2O2 produced a strong copper-bound oxidant (Cu(II)•OH) that seems able to contrast the self-inactivation of the enzyme or oxidize other molecules through its peroxidase activity. The bicarbonate presence enhances the peroxidase activity and produces the carbonate anion radical (CO3•-). CO3•- is a freely diffusible reactive species capable of oxidizing several molecules that are unwieldy to access into the reactive site of the enzyme. Cu(II)•OH oxidizes bicarbonate to the CO3•-, which spreads out of the binding site and oxidizes hypotaurine and cysteine sulfinic acid to the respective sulfonates through an efficient reaction. These findings suggest a defense role for sulfinates against the damage caused by CO3•- . The effect of hypotaurine and cysteine sulfinic acid on the CO3•--mediated oxidation of the peroxidase probe ABTS to ABTS cation radical (ABTS•+) has been studied. Both sulfinates are able to inhibit the oxidation of ABTS mediated by CO3•-. The effect of hypotaurine and cysteine sulfinic acid against SOD inactivation by H2O2 (~42% protection of enzyme activity) has also been investigated. Interestingly, hypotaurine and cysteine sulfinic acid partially avoid the H2O2-mediated SOD inactivation, suggesting that the two sulfinates may have access to the SOD reactive site and preserve it by reacting with the copper-bound oxidant. In this way hypotaurine and cysteine sulfinic acid not only intercept CO3•- which could move out from the reactive site and cause oxidative damage, but also prevents the inactivation of SOD.

Daylight photodynamic therapy in Scotland.

Chronic sun-induced dysplastic skin changes (actinic keratoses) are extremely common in fair-skinned people in Scotland. These changes are a major cause of morbidity and may develop into skin cancer. Actinic keratoses are often extensive and pose a therapeutic challenge as field-directed treatment is required for chronic disease management. One such treatment approach is hospital-based photodynamic therapy, which is a well-established treatment in Scotland for actinic keratoses, using a photosensitiser pro-drug and red LED light irradiation. However, photodynamic therapy using daylight as the activating light source is increasingly and effectively used in continental Europe, but had not been explored in Scotland until we initiated this in 2013. We report our experience of daylight photodynamic therapy in 64 patient-treatment courses and demonstrate that this can be an effective, well-tolerated treatment, which is liked by patients. Our most recent data show that most patients (73%) achieved clearance or at least a good response to treatment and had high levels of satisfaction with daylight photodynamic therapy. Daylight exposure measurements indicated that treatment is feasible in Scotland between April to September. Daylight photodynamic therapy is an important advancement in treatment options for Scottish patients with extensive pre-cancerous field changes and provides opportunities for home-based treatment and increased efficiency of photodynamic therapy services.

The effect of 222-nm UVC phototesting on healthy volunteer skin: a pilot study.

BACKGROUND: Frequent topical antiseptic use to hands is now common in healthcare and other work environments. Inevitably, the use of such antiseptics will present an occupational risk for irritancy and allergic dermatitis. New, less irritant and even non-chemical antimicrobial approaches are under investigation. METHODS: A Sterilray disinfectant source (222 nm) conventionally used to sterilize equipment and work surfaces was assessed for tolerability in human skin. Using an escalating dosage study methodology, four skin phototype I and II healthy volunteers had their minimal erythema dose (MED) determined. Punch biopsies of irradiated sites were stained for cyclobutane pyrimidine dimers (CPD). The degree of CPD was compared with that in biopsies from unexposed skin and from areas exposed to UVB (280-315 nm) radiation. RESULTS: Calibrated spectral measurements revealed emission at a peak wavelength of 222 nm with 97% emission at wavelengths less than 250 nm. At low doses below the threshold bacteriostatic effect, the source was capable of inducing both erythema and CPD formation in human skin. In two individuals, cells in the basal layer were not shielded by the overlying tissue as indicated by the presence of CPD. CONCLUSION: The source showed an erythemogenic or CPD potential at lower doses than those required to reach the reported threshold bacteriostatic effect.

UV emissions from low energy artificial light sources.

Energy efficient light sources have been introduced across Europe and many other countries world wide. The most common of these is the Compact Fluorescent Lamp (CFL), which has been shown to emit ultraviolet (UV) radiation. Light Emitting Diodes (LEDs) are an alternative technology that has minimal UV emissions. This brief review summarises the different energy efficient light sources available on the market and compares the UV levels and the subsequent effects on the skin of normal individuals and those who suffer from photodermatoses.

Photodynamic diagnostic ureterorenoscopy with orally administered 5-aminolaevulinic acid as photosensitiser: how I do it.

OBJECTIVE: To explain our use of photodynamic diagnostic ureterorenoscopy, we provide a detailed description of the choice of photosensitiser, equipment needed, a safety profile, and pointers on our technique. TECHNIQUE: Patients are given oral 5-aminolaevulinic acid (5-ALA) as a photosensitiser 3-4 h pre-operatively, and by using a Xenon blue light source, an eyepiece which blocks light below 450 nm which is fitted onto the ureterorenoscope, we are able to conduct a thorough photodiagnosis of the upper urinary tract. CONCLUSION: Our technique of photodynamic diagnostic ureterorenoscopy has shown that the sensitivity, specificity and detection rates of upper urinary tract lesions can be significantly increased with the use of oral 5-ALA. Therefore, we provide a detailed explanation of the use of oral 5-ALA photosensitiser, indications and contraindications of the technique in addition to equipment used and potential complications of the procedures.

Modelling fluorescence in clinical photodynamic therapy.

Understanding the interactions of non-ionizing radiation with living organisms has been the focus of much research over recent decades. The complex nature of these interactions warrants development of theoretical and experimental studies to gain an insight into predicting and monitoring the success of photodynamic therapy (PDT) protocols. There is a major impetus towards evidence-based recommendations for patient diagnosis, treatment and management. Knowledge of the biophysical aspects of PDT is important for improving dosimetry protocols. Fluorescence in clinical PDT may be used to detect and diagnose pre-malignant and malignant conditions, while photobleaching can monitor changes in fluorescence during treatment. Combining empirical fluorescence photobleaching clinical data with computational modelling enables clinical PDT dosimetry protocols to be investigated with a view to optimising treatment regimes. We will discuss how Monte Carlo radiation transfer (MCRT) modelling has been intercalated in the field of fluorescence detection and PDT. In this paper we highlight important aspects of basic research in PDT by reporting on the current utilisation of fluorescence in clinical PDT from both a clinical and theoretical perspective. Understanding and knowledge of light propagation in biological tissue from these perspectives should have a positive impact on treatment planning.

The risk to normal and photosensitive individuals from exposure to light from compact fluorescent lamps.

BACKGROUND/PURPOSE: The incandescent electric light bulb has been in widespread use since the early part of the 20th century. There is now a strong move underway to improve lighting efficiency to cut carbon dioxide emissions. As a result, many countries have introduced legislation to phase out the use of incandescent bulbs, and these are largely being replaced with compact fluorescent lamps (CFLs). The rate at which CFLs are replacing the traditional bulbs has caused alarm among patients with light-sensitive skin disorders as there has been very little informed discussion regarding the safety of these new lamps for this group of patients. The purpose of the present paper is to review the available literature to assess the likely impact of CFLs on the skin of normal and photosensitive individuals. METHODS: All data sources were identified through searches of MEDLINE and a manual literature search. RESULTS: The spectrum of light emitted by CFLs is different from incandescent light. In particular, some CFLs emit short wavelength UV radiation at 253.7 nm. Most published reports show that the short wavelengths can be eliminated by the use of a double envelope. There are very little data examining directly the risk to photosensitive individuals. In one study, a patient with chronic actinic dermatitis had a severe erythematous reaction from an exposure of only 2.5min' duration. CONCLUSION: CFLs present a low level of risk to individuals of normal sensitivity but they are potentially harmful to photosensitive patients. We recommend the use of double envelope lamps, and consideration given to the adoption of a 'UV-safe' classification scheme.

Intraoperative optical identification of pituitary adenomas.

INTRODUCTION: The main goals of transsphenoidal pituitary surgery are total removal of pituitary adenomas (PAs) and preservation of normal pituitary functions. Achieving these goals is dependent upon the precise localisation of PAs during surgery, particularly secreting microadenomas. However, some microadenomas are invisible on preoperative imaging and during surgery, leading some surgeons to perform total hypophysectomy in many patients to achieve cure at the expense of panhypopituitrism. We have examined optical detection systems to identify PAs intraoperatively. This paper reports our preliminary findings. METHODS: A prospective observational study design. TECHNIQUE: Patients were given 20 mg/kg body weight 5-aminolevulinic acid (ALA) mixed in 30 ml of orange juice, orally 3 h before surgery. Surgery was performed in the supine position, under image guidance, through the right nostril using Storz 0 degree endoscope assisted with microsurgery as required. The endoscope was attached to photodiagnostic filters (PD) allowing switching the light from white to blue at the flick of a foot pedal. After the dura of the floor of the sella was incised a laser probe was inserted into the pituitary gland to identify the ALA-induced protoporphyrin IX spectroscopy at 632 nm, using an optical biopsy system (OBS). Once the adenoma was identified by the OBS it was exposed and examined by the PD system to detect fluorescence. The PA was removed and its type was confirmed by histopathology and correlated to the OBS and PD system findings. PATIENTS: Thirty consecutive patients were studied: 14 were non-functioning macroadenomas (NFA), 12 were secreting PAs and 4 pituitary cysts. The secreting PAs were GH (2), ACTH (3), prolactin (2) and gonadotrophins (5). Six were microadenomas (3 ACTH, 1 GH, 2 prolactin) and 20 were macroadenomas, of which 12 were invading macroadenomas. Twenty-four of these were examined by the OBS and the PD systems and six were examined by the PD system only. The true positive (sensitivity) of the PD and OBS systems were 80.8% (21/26) and 95.5% (21/22) respectively. The true negative (specificity) of PD and OBS were 75% (3/4) and 100% (2/2) respectively. The false negative rate of PD was 19.2% (5/26) and for OBS was 4.5% (1/22), while the false positive rate for PD was 25% (1/4) and for OBS was 0. CONCLUSION: Intraoperative optical identification of pituitary adenomas is a feasible and reliable way to localize pituitary adenomas during transsphenoidal surgery and it may lead to improved cure rate and preservation of normal pituitary functions.

A time course investigation of the fluorescence induced by topical application of 5-aminolevulinic acid and methyl aminolevulinate on normal human skin.

BACKGROUND: Treatment of non-melanoma skin cancers (NMSC) with topical photodynamic therapy (PDT) is a treatment of choice for many clinicians. The two most commonly used PDT photosensitizer precursors are 5-aminolevulinic acid (ALA) and methyl aminolevulinate (MAL). Current PDT treatment regimes advise longer (4-6 h) application times for ALA and shorter times (3 h) for MAL. AIMS: To establish the time course characteristics of protoporphyrin IX (PpIX) fluorescence following the application of ALA and MAL in normal skin. METHODS: A total of 17 healthy volunteers were recruited, and both ALA and MAL were applied to the inner forearm for varying times (1-6 h). PpIX fluorescence was detected using a non-invasive spectroscopy system. RESULTS AND CONCLUSION: PpIX fluorescence (following the application of either ALA or MAL) is dependent on duration of application. Following the application of ALA for 1-3 h peak fluorescence was noted at 7 h. Longer duration times (4-6 h) resulted in sustained fluorescence, which peaked at 24 h. MAL-induced fluorescence peaked at 7 h and was significantly decreased by 24 h for all application times. ALA induced fluorescence was shown to be significantly greater than MAL. The findings from this study have shown that potentially it would be more beneficial to apply ALA for shorter periods of time and MAL for longer than current practice.

Population reference intervals for minimal erythemal doses in monochromator phototesting.

BACKGROUND/PURPOSE: Monochromator phototesting, to measure the minimal erythemal dose (MED), is useful in investigating patients with abnormal photosensitivity at different wavelengths. It relies on access to reliable, up-to-date data on the MED in normal individuals. The purpose of this study was to determine MED in normal subjects at different wavebands and compare these with historical controls. METHODS: The study group consisted of 415 normal individuals (349 males) of skin types I-III living in Scotland. Age range was 18-83 years (median 31 years). Phototesting was performed using a monochromator at prescribed wavelengths from 295 to 430 nm. All calibrations were traceable to the National Physical Laboratory. Quality systems were maintained to ISO 9001 and ISO 17025 international standards and ultraviolet (UV) measurements accredited by the United Kingdom Accreditation Service (UKAS). RESULTS: The 95% reference interval (99% confidence interval for this) ranged from 6.8 to 27 mJ/cm(2) at 295 nm to >82,000 mJ/cm(2) at 430 nm. CONCLUSIONS: Results of the current investigation are broadly in agreement with values published 25 years ago by this centre. This validates the phototesting process based on the use of monochromators with attention to careful control of conditions during UV exposure and MED reading, supported by dosimetric calibration.

Assessment of the optical radiation hazard from a home-use intense pulsed light (IPL) source.

BACKGROUND AND OBJECTIVES: Intense pulsed light (IPL) systems have evolved and crossed over from the clinic to the home. Studies have shown home-use IPLs to be clinically effective but there has been no published data on ocular safety. It was our aim to measure the spectral and temporal optical radiation output from a home-use IPL and assess the ocular hazard. MATERIALS AND METHODS: The iPulse Personal is a new home-use IPL hair reduction system. We measured its optical radiation spectral output using a calibrated diode array spectrometer that was traceable to national standards. Pulse duration was determined by measurement with a fast photodiode. The results from these measurements were used to assess the optical radiation hazard to the human eye. Retinal thermal hazard (RTH), blue light hazard (BLH), and infrared radiation hazard to the cornea and lens were assessed in accordance with IEC TR 60825-9 and the International Committee on Non-Ionizing Radiation Protection (ICNIRP) Guidelines on Limits of Exposure to Broad-band Incoherent Optical Radiation, as there are no specific international IPL standards. RESULTS: Neither the BLH radiance dose nor the infrared radiation hazard to the cornea and lens irradiance exceeded the exposure limit values (ELVs) set by the ICNIRP. The RTH radiance, however, was exceeded at a fluence of 11 J cm(-2) and pulse duration of 16 milliseconds. Following these results the settings on the IPL were adjusted and the RTH was no longer exceeded at a new fluence of 10 J cm(-2) and pulse duration of 26 milliseconds. CONCLUSIONS: The home-use device that we assessed does not present an optical hazard according to currently available international standards.

Randomized comparison of Mohs micrographic surgery and surgical excision for small nodular basal cell carcinoma: tissue-sparing outcome.

BACKGROUND: Mohs micrographic surgery (MMS) is recognized globally as the criterion standard for high-risk basal cell carcinoma (BCC). The main advantage of MMS over conventional surgery is the chance of complete tumor removal, but it is also thought, based on experience, to be tissue sparing. OBJECTIVE: To determine whether MMS leaves smaller surgical defects than standard surgery. METHODS AND MATERIALS: This was a randomized trial involving 30 patients with a clinical diagnosis of BCC. Patients were randomly assigned to MMS or standard surgery. In the standard surgery group the BCCs were excised with 4-mm margins. In the MMS group, tumors were excised with 2-mm margins and subsequent stages of MMS until the tumor was completely removed. An observer unaware of the treatment allocation calculated the defect size. The main outcome measure was defect size in mm(2). RESULTS: The median area of the surgical defects in the MMS group was 116.6 mm(2), versus 187.7 mm(2) in the standard surgery group (95% confidence interval for difference=61-126, p<.001). CONCLUSIONS: This is the first randomized trial demonstrating that MMS is a tissue-sparing treatment. TRIAL REGISTRATION: http://www.clinicaltrials.gov Identifier: NCT00571363. The authors have indicated no significant interest with commercial supporters.

Does surface preparation alter ALA uptake in superficial non-melanoma skin cancer in vivo?

BACKGROUND/PURPOSE: Photodynamic therapy (PDT) using aminolaevulinic acid (ALA) is widely used in the treatment of non-melanoma skin cancer. Surface preparation of the lesion is commonly performed before application of ALA but the extent of the preparation varies from centre to centre and there has been no study of its effects. The purpose of this study was to examine the effects of surface preparation on the local uptake of ALA by recording fluorescence from accumulated protoporphyrin IX (PPIX). METHODS: The study was performed on 16 lesions, either superficial basal cell carcinoma (BCC) or Bowen's disease (BD). Each half of the lesion was randomly assigned to (a) no surface preparation or (b) surface preparation (randomly allocated to gentle curettage or abrasion with a spatula). ALA was left for 4 h (BCC) or 6 h (BD). PPIX fluorescence was measured using an excitation wavelength of 405+/-5 nm and emission spectrum recorded using a photodiode array. Spectra were measured (a) before and (b) after surface preparation, (c) immediately before and (d) after laser irradiation at 630 nm. RESULTS: The ratio of fluorescence after incubation to that before incubation was 6.1+/-1.2 in the non-prepared section. This increased slightly but not significantly to 6.8 +/-1.8 in the prepared section (P<0.1). There was no significant difference between curettage and abrasion. There was also no significant difference in outcome after PDT. CONCLUSIONS: The clinical assessment agrees with the fluorescence data as no significant difference was seen between prepared and unprepared halves of the lesion 12 months after PDT. Overall our data seem to suggest that for most BCC and BD lesions, surface preparation did not increase ALA uptake.

Quantifying Direct DNA Damage in the Basal Layer of Skin Exposed to UV Radiation from Sunbeds.

Nonmelanoma and melanoma skin cancers are attributable to DNA damage caused by ultraviolet (UV) radiation exposure. One DNA photoproduct, the cyclobutane pyrimidine dimer (CPD), is believed to lead to DNA mutations caused by UV radiation. Using radiative transfer simulations, we compare the number of CPDs directly induced by UV irradiation from artificial and natural UV sources (a standard sunbed and the midday summer Mediterranean sun) for skin types I and II on the Fitzpatrick scale. We use Monte Carlo radiative transfer (MCRT) modeling to track the progression of UV photons through a multilayered three dimensional (3D) grid that simulates the upper layers of the skin. By recording the energy deposited in the DNA-containing cells of the basal layer, the number of CPDs formed can be quantified. The aim of this work was to compare the number of CPDs formed in the basal layer of the skin and by implication the risk of developing cancer, as a consequence of irradiation by artificial and natural sources. Our simulations show that the number of CPDs formed per second during sunbed irradiation is almost three times that formed during solar irradiation.