Distribution and quantitation of skin iron in primary haemochromatosis: correlation with total body iron stores in patients undergoing phlebotomy.

Measurement of the concentration of iron in the skin, if correlated with total body iron stores, may enable better informed decisions on when to initiate, change or stop therapy in hereditary heamochromatosis. Naïve haemochromatosis patients with iron overload and with C282Y and/or H63D HFE mutations were evaluated at the following time-points: disease diagnosis, end of the therapy programme, and 6 months after the end of therapy. The distribution and concentration of iron in the skin were assessed by quantitative nuclear microscopy methods, in parallel with serum and plasma iron concentration. Iron content in the liver was determined by nuclear magnetic resonance. Iron accumulated in the epidermis; its concentration increased from outer to inner layers, being maximal in the basal layer (7.33 ± 0.98 µmol/g). At all 3 time-points, most of the iron was associated with the extracellular space. During the phlebotomy programme the iron content of the skin and the liver decreased by a factor of 2. These data suggest that measurements of iron concentration in the epidermis, which is a readily accessible tissue, reflect iron overload in the liver.

Cost-Effectiveness of Inpatient Continuous Glucose Monitoring.

Introduction Our department conducted a retrospective cohort study to compare the efficacy of continuous glucose monitoring devices versus capillary blood glucose in the glycemic control of inpatient type 2 diabetes on intensive insulin therapy in a Portuguese hospital. The use of continuous glucose monitoring devices was associated with improved glycemic control, including an increased number of glucose readings within target range and reduced hyperglycemic events, being safe concerning hypoglycemias. This is the cost-effectiveness analysis associated with these results. Aim The primary objective was to compare the cost-effectiveness of achieving glycemic control, defined as the number of patients within glycemic goals, between groups. Secondary endpoints included cost-effectiveness analyses of each time in range goal, and each percentual increment in time in range. Methods We defined each glycemic goal as: "readings within range (70-180 mg/dL) >70%", "readings below range (below 70 mg/dL) <4%", "severe hypoglycemia (below 54 mg/dL) <1%", "readings above range (above 180 mg/dL) <25%", "very high glycemic readings (above 250 mg/dL) <5%". Results Continuous glucose monitoring showed lower median cost per effect for the primary outcome (€11.1 vs. €34.9/patient), with lower cost for readings in range (€7.8 vs. €11.6/patient) and for both readings above range goals ("above 180mg/dL": €7.4 vs. €9.9/patient, and "above 250mg/dL": €6.9 vs. €17.4/patient). Conclusions There are no published data regarding the cost-effectiveness of continuous glucose monitoring devices in inpatient settings. Our results show that continuous glucose monitoring devices were associated with an improved glycemic control, at a lower cost, and endorse the feasibility of incorporating these devices into hospital settings, presenting a favorable cost-effective option compared to capillary blood glucose.

Long-term follow-up of treatment outcomes in Graves' disease and toxic nodular disease.

PURPOSE: Hyperthyroidism guidelines have not been updated over the past five years, despite numerous data on the subject, and recent studies providing a wide variation in treatment success rates. We aim to compare the effectiveness and safety of treatment modalities in patients with Graves' disease or toxic nodular disease. METHODS: Single center retrospective cohort study of Graves' disease and toxic nodular disease patients treated between 1983 and 2023. RESULTS: A total of 411 patients were treated for hyperthyroidism, 245 due to Graves' disease and 166 due to or toxic nodular disease, followed for a median of 7 years. In Graves' disease, 90.2% were treated with antithyroid drugs over 250 cycles, achieving 41.7% cumulative remission. Half of all relapses (50.9%) occurred in the first year, 76.3% in the first three years, and 98.3% within nine years. Treatment periods of 12-24 months showed higher remission and lower relapse rates than longer periods. I-131 was used in 103 cycles with 82.5% remission and 7.1% relapse. A total of 29 thyroidectomies resulted in 100% remission, with no relapse. In toxic nodular disease, surgery was the most frequently used treatment (54.5%), followed by I-131 (37.1%). CONCLUSION: Our findings support antithyroid drugs as the preferential first-line treatment for Graves' disease, allowing for euthyroidism with minimal adverse effects. Given the propensity for relapse, we suggest a rigorous monitoring, particularly within the first three years. In toxic nodular disease, surgery should be the preferred option, with I-131 being reserved for single adenomas and small goiters.

Photodynamic therapy: Dermatology and ophthalmology as main fields of current applications in clinic.

Photodynamic therapy (PDT) of skin tumors or pre-cancerous lesions and of age-related macular degeneration combines the administration of porphyrins or porphyrin precursors and illumination with red light at the diseased sites. Photosensitizers absorbing light beyond 630 nm where tissues have the highest transmittance produce singlet oxygen, a highly reactive activated oxygen species and a major cytotoxin. The PDT of age-related macular degeneration is performed with red laser light after i.v. injection of verteporfin (Visudyne) a hydrophobic porphyrin carried by serum lipoproteins whose endocytosis leads to accumulation of the porphyrin in endothelial cells of choroidal neo-vessels. In the PDT of skin cancers, local synthesis of the photosensitizer occurs after topical application of the natural protoporphyrin IX precursor delta-aminolevulinic acid (or its ester forms) on the lesions. In all the cases, the photosensitizers should be rapidly excreted to avoid a long lasting skin photosensitivity.

Sun protection behaviour and skin cancer literacy among outdoor runners.

Outdoor runners have an increased risk of melanoma and non-melanoma skin cancer. The purpose of this study was to assess skin cancer literacy and sun exposure and protection behaviour among outdoor runners during training. A cross-sectional survey-based study was conducted. All athletes registered for four consecutive running events in Porto: the Porto Marathon (November 2014), the Fathers' Day 10-km race (March 2015), the Saint John's Day 15-km race (June 2015), and the Porto half-marathon (September 2015). Athletes were invited to answer an online survey with 23 questions on the following items: sociodemographic and constitutional factors, skin cancer literacy, and sun exposure and protection behaviour. A scoring system was devised to analyse behaviour. Multivariate analysis was performed. The survey was completed by 2,445 runners, 2,159 of whom trained outdoors. Only 23.5% had adequate sun exposure and protection behaviour. A higher proportion of women than men had adequate behaviour (33% versus 17%; P < 0.001). Athletes with a university, or higher degree were more knowledgeable about skin cancer than those with a lower level of education, however, their behaviour in relation to sun exposure and protection was the same. Based on multivariate analysis, gender, skin type, marital status, and average number of hours spent training significantly affected attitude score. Investment in more targeted campaigns, aimed particularly at high-risk groups such as outdoor athletes, is essential to modify attitudes and behaviour regarding sun exposure and protection. Outdoor sports event organisers and sport associations also need to engage.

Targeting TNFα in severe psoriasis-mass spectrometry reveals a time-dependent specific inhibition of Factor H in responding patients.

Drugs targeting TNFα (eg, Etanercept®) provide effective control of severe psoriasis. In absence of validated biological parameters of inflammation in psoriasis most decisions on therapeutics have relied mostly on clinical criteria, namely the "Psoriasis Area and Severity Index" (PASI). The purpose of this study was to assess by mass spectrometry alterations in concentrations of serum proteins that specifically correlated with effectiveness of Etanercept treatment. This prospective study enrolled 10 patients suffering from moderate to severe psoriasis (PASI score > 10 and < 17) and treated with Etanercept over a period of 24 weeks; 10 healthy, age-matched volunteers provided controls. Serum proteins sensitive to Etanercept treatment were identified using SELDI-TOF (surface-enhanced laser desorption and ionization - time of flight) coupled to nano LC-ESI/MS (nano liquid chromatography-electrospray ionization/tandem mass spectrometry) technologies. For comparisons between groups of individuals p-values (considered significant when < 0.01) were estimated with non-parametric tests, namely Mann-Whitney (for unpaired data) and Wilcoxon signed-rank (for paired data). In responding patients it could be shown using SELDI-TOF spectrometry that two proteins (134 kDa and 4.3 kDa) return to control levels by 24 weeks of treatment. Using nano LC-ESI/MS the 134 kDa species was identified as complement Factor H. These observations deserve further analyses utilizing larger cohorts of patients. Determination of Factor H levels may become a complementary tool to follow remission or predict the onset of relapse in the follow-up of patients under treatment with Etanercept.

Nuclear microscopy: a tool for imaging elemental distribution and percutaneous absorption in vivo.

Nuclear microscopy is a technique based on a focused beam of accelerated particles that has the ability of imaging the morphology of the tissue in vivo and of producing the correspondent elemental maps, whether in major, minor, or trace concentrations. These characteristics constitute a strong advantage in studying the morphology of human skin, its elemental distributions and the permeation mechanisms of chemical compounds. In this study, nuclear microscopy techniques such as scanning transmission ion microscopy and particle induced X-ray emission were applied simultaneously, to cryopreserved human skin samples with the purpose of obtaining high-resolution images of cells and tissue morphology. In addition, quantitative elemental profiling and mapping of phosphorus, calcium, chlorine, and potassium in skin cross-sections were obtained. This procedure accurately distinguishes the epidermal strata and dermis by overlapping in real time the elemental information with density images obtained from the transmitted beam. A validation procedure for elemental distributions in human skin based on differential density of epidermal strata and dermis was established. As demonstrated, this procedure can be used in future studies as a tool for the in vivo examination of trans-epidermal and -dermal delivery of products.

Photodynamic therapies: principles and present medical applications.

Photodynamic therapy (PDT) by porphyrins and related tetrapyrrole derivatives is an emerging new treatment modality of tumors of lung, eosophagus and skin and of age-related macular degeneration. Phase III clinical trials for other applications such as re-stenosis after angioplasty are also underway. Under systemic conditions, the transport of porphyrin photosensitizers by serum low density lipoproteins and their specific delivery to tumor cells and vasculature is a determinant of treatment effectiveness. However, this effectiveness can be improved by increasing the selectivity of the photosensitizer uptake by tumors and by using photosensitizers absorbing light in the 660-800 nm range where tissues have the highest transmittance. Another treatment showing great promise is the PDT of skin cancers after topical application of the protoporphyrin IX precursor delta-aminolevulinic acid (or its ester forms). In all the cases, the photosensitizers should be rapidly excreted to avoid a long lasting skin photosensitivity.

Polyhydroxylated 2-styrylchromones as potent antioxidants.

Four polyhydroxylated 2-styrylchromones, structurally related to flavones and cinnamic acid, have been studied. An SC derivative with OH groups only at positions 3' and 4' on the styryl moiety and another SC bearing an additional OH group at position 5 on the benzopyrone ring were more potent inhibitors of the Cu2+-induced peroxidation of LDL than the flavonoid quercetin. Fluorescence and absorption spectroscopies suggested that one LDL particle may bind 40 SC molecules. A pulse radiolysis study in pH 7 buffered micellar solutions of neutral TX100 and positively charged CTAB demonstrated that one-electron oxidation by *Br2-, *O2- and tryptophan radicals (8Trp) depends strongly on the micellar microenvironment. All SCs were readily oxidized by *O2- in CTAB micelles (rate constants: 6-18 x 10(6) M(-1) s(-1)). In TX100 micelles only the SC derivative with OH groups in position 3' and 4' reacted with *O2- (rate constant: 1.1 x 10(6) M(-1)s(-1)). In CTAB, electron transfer to *Trp radicals was observed for all SCs with rate constants > or =3.2 x 10(7) M(-1) s(-1). In TX100 micelles, this reaction occurred solely with the derivative bearing OH groups only at positions 3' and 4'.

Plasma lipoproteins as mediators of the oxidative stress induced by UV light in human skin: a review of biochemical and biophysical studies on mechanisms of apolipoprotein alteration, lipid peroxidation, and associated skin cell responses.

There are numerous studies concerning the effect of UVB light on skin cells but fewer on other skin components such as the interstitial fluid. This review highlights high-density lipoprotein (HDL) and low-density lipoprotein (LDL) as important targets of UVB in interstitial fluid. Tryptophan residues are the sole apolipoprotein residues absorbing solar UVB. The UVB-induced one-electron oxidation of Trp produces (•)Trp and (•)O2 (-) radicals which trigger lipid peroxidation. Immunoblots from buffered solutions or suction blister fluid reveal that propagation of photooxidative damage to other residues such as Tyr or disulfide bonds produces intra- and intermolecular bonds in apolipoproteins A-I, A-II, and B100. Partial repair of phenoxyl tyrosyl radicals (TyrO(•)) by α -tocopherol is observed with LDL and HDL on millisecond or second time scales, whereas limited repair of α -tocopherol by carotenoids occurs in only HDL. More effective repair of Tyr and α -tocopherol is observed with the flavonoid, quercetin, bound to serum albumin, but quercetin is less potent than new synthetic polyphenols in inhibiting LDL lipid peroxidation or restoring α -tocopherol. The systemic consequences of HDL and LDL oxidation and the activation and/or inhibition of signalling pathways by oxidized LDL and their ability to enhance transcription factor DNA binding activity are also reviewed.

The alkyl chain length of 3-alkyl-3',4',5,7-tetrahydroxyflavones modulates effective inhibition of oxidative damage in biological systems: illustration with LDL, red blood cells and human skin keratinocytes.

It is shown that the relationship between the alkyl chain length of 3-alkyl-3',4',5,7 tetrahydroxyflavones (FnH) bearing alkyl chains of n=1, 4, 6, 10 carbons and their capacity to counter oxidative damage varies markedly with the nature of the biological system. In Cu(2+)-induced lipid peroxidation of low-density lipoprotein (LDL), the less hydrophobic short-chain F1H and F4H are probably located in the outer layer of LDL and parallel the reference flavonoid antioxidant, quercetin (Q) as effective inhibitors of lipid peroxidation. A marked inhibition of haemolysis induced in red blood cells (RBC) suspensions by the membrane-permeant oxidant, tert-butylhydroperoxide (t-BuOOH), is observed with F4H and F6H present at concentration in the micromolar range. However, F10H the most hydrophobic FnH is even more effective than Q against both haemolysis and lipid peroxidation as measured by malondialdehyde (MDA) equivalents. In oxidation of RBC by H(2)O(2,) at least 50 times more F6H and F10H than by t-BuOOH are required to only partly inhibit haemolysis and MDA production. The F1H, F4H and Q are found rather inactive under these conditions. At concentrations in the micromolar range, a marked protection against the cytotoxic effects of the t-BuOOH-induced oxidative stress in human skin NCTC 2544 keratinocytes is also exhibited by the four FnH antioxidants and is comparable to that of Q. Thus, the four FnH species under study may be considered as potent antioxidants which manifest complementary anti-oxidative actions in biological systems of markedly different complexity.

Contrasting action of flavonoids on phototoxic effects induced in human skin fibroblasts by UVA alone or UVA plus cyamemazine, a phototoxic neuroleptic.

The potential protective effects of the flavanol catechin, the flavonol quercetin, the flavones, luteolin and rutin, and the isoflavones, genistein and daidzein, against the photo-oxidative stress induced by ultraviolet A radiation (UVA) and by phototoxic reactions resulting from the interaction of UVA with drugs and chemicals, has been assessed with cultured human skin fibroblasts. Lipid peroxidation and cell death have been chosen as model photobiological damage induced by UVA alone or photosensitized by cyamemazine (CMZ) and its photoproduct possessing phototoxic properties. Contrasting effects of flavonoids are observed. The flavanol, the flavonol and the flavones may protect against lipid peroxidation and cell death induced by 30 J cm(-2) of UVA alone or CMZ plus 10 J cm(-2) UVA. On the other hand, an amplification of the photodamage may be observed with isoflavones. A concentration-dependence study demonstrates that among the protective flavonoids, quercetin is the most efficient. The very effective protection brought by quercetin may result from its ability to scavenge reactive oxygen species produced by the photo-oxidative stress. However, the modification of membrane properties and the alteration of the lysosomal function by quercetin may not be neglected in these protective effects. The amplification of the photodamage by isoflavones is in sharp contrast with previous literature data demonstrating photoprotection by genistein. As a consequence, it may be concluded that an eventual antioxidant action of genistein may strongly depend on cells and photosensitizers. Furthermore such contrasting pro-versus anti-oxidant effects have to be taken into account when using flavonoid mixtures of plant extracts.