Relationship between climate change and skin cancer and implications for prevention and management: a scoping review.

OBJECTIVES: This study aimed to explore the published research on the relationship between climate change and skin cancer and the implications for prevention, management and further research. STUDY DESIGN: Scoping review. METHODS: This scoping review following JBI methodology reviewed English articles identified in searches of MEDLINE, Embase, CINAHL, Web of Science and Scopus on 14 April 2023. The screening of articles was completed by two independent reviewers. Data were extracted by a single reviewer and checked by another. A causal pathway diagram was iteratively developed throughout the review and was used to categorise the findings. RESULTS: The search identified 1376 papers, of which 45 were included in the final review. Nine papers reported primary research, and 36 papers were reviews, perspectives, commentaries, editorials, or essays. The papers examined climate change influencing behaviours related to ultraviolet exposure (30 papers), ambient temperature (21 papers) and air pollution (five papers) as possible risk factors; occupational, rural, and contextual factors affecting skin cancer (11 papers); and prevention and access to health care in the context of climate change (seven papers). Most papers were published in journals in subject areas other than health. CONCLUSIONS: This review identified ultraviolet radiation, occupation, rising temperature, individual behaviour and air pollution as possible influences on skin cancer rates. Furthermore, it highlights the complexity and uncertainties in the relationship between climate change and skin cancer and the need for further research on this relationship, including primary epidemiological research and reviews that follow recognised review guidelines and include assessment of health services and social determinants in the causal pathways of this relationship.

Linking Patient-Centered Outcomes to Neuropsychological Practice: A Conceptual Framework and Opportunities for Research.

In the current healthcare climate, reimbursement for services is increasingly linked to the ability to demonstrate beneficial patient outcomes. Neuropsychology faces some unique challenges in outcomes research, namely, that neuropsychologists often do not follow patients over time and the effect of neuropsychological services on patient outcomes may not be fully realized until under another provider's care. Yet there is an urgent need for empirical evidence linking neuropsychological practice to positive patient outcomes. To provide a framework for this research, we define a core set of patient-centered outcomes and neuropsychological processes that apply across practice settings and patient populations. Within each area, we review the available existing literature on neuropsychological outcomes, identifying substantial gaps in the literature for future research. This work will be critical for the field to demonstrate the benefit of neuropsychological services, to continue to advocate effectively for reimbursement, and to ensure high-quality patient care.

Methodological pluralism for better evaluations of complex interventions: lessons from evaluating an innovation platform in Australia.

Complex interventions, such as innovation platforms, pose challenges for evaluators. A variety of methodological approaches are often required to build a more complete and comprehensive understanding of how complex interventions work. In this paper, we outline and critically appraise a methodologically pluralist evaluation of an innovation platform to strengthen primary care for Aboriginal and Torres Strait Islander Australians. In doing so, we aim to identify lessons learned from the approach taken and add to existing literature on implementing evaluations in complex settings, such as innovation platforms. The pluralist design used four evaluation approaches-developmental evaluation, principles-focused evaluation, network analysis, and framework analysis-with differing strengths and challenges. Taken together, the multiple evaluation approaches yielded a detailed description and nuanced understanding of the formation, functioning and outcomes of the innovation platform that would be difficult to achieve with any single evaluation method. While a methodologically pluralist design may place additional pressure on logistical and analytic resources available, it enables a deeper understanding of the mechanisms that underlie complex interventions.

Daily, monthly and seasonal variation in PSA levels and the association with weather parameters.

PSA levels have shown daily and seasonal variation, although data are conflicting regarding the season with higher PSA levels and the clinical relevance of this. We assessed the correlation of total PSA levels with meteorological data on a daily, weekly, monthly and seasonal basis. Data from 53,224 men aged 45-74 years, with an initial PSA <10.0 ng ml(-1) were correlated with temperature (°C), duration of bright sunshine (hours) and rainfall (mm). There was seasonal variation in PSA levels, with median PSA being higher in spring compared with other seasons (1.18 vs 1.10 ng ml(-1), P = 0.004). Seasonal variation was not apparent when PSA levels were age-adjusted (P = 0.112). Total PSA was not correlated with daily, weekly or monthly hours of sunshine, rainfall or mean temperature. In contrast, age-adjusted PSA varied with weekday, with higher PSA levels on Thursday and Friday compared with other days (1.16 vs 1.10 ng ml(-1), respectively). On multivariate analysis, only age predicted for PSA levels >3.0 ng ml(-1). In conclusion, PSA levels did show seasonal variation, although there was no direct correlation between PSA and any meteorological parameter. The degree of seasonal variation is small and the decision to proceed to prostate biopsy should be independent of season or weather parameters.

Algorithms for digital image processing in diabetic retinopathy.

This work examined recent literature on digital image processing in the field of diabetic retinopathy. Algorithms were categorized into 5 steps (preprocessing; localization and segmentation of the optic disk; segmentation of the retinal vasculature; localization of the macula and fovea; localization and segmentation of retinopathy). The variety of outcome measures, use of a gold standard or ground truth, data sample sizes and the use of image databases is discussed. It is intended that our classification of algorithms into a small number of categories, definition of terms and discussion of evolving techniques will provide guidance to algorithm designers for diabetic retinopathy.

Retinal pericytes control expression of nitric oxide synthase and endothelin-1 in microvascular endothelial cells.

Pericytes are known to communicate with endothelial cells by direct contact and by releasing cytokines such as TGF-beta. There is also strong evidence that pericytes act as regulators of endothelial cell proliferation and differentiation. We have investigated the effect of pericyte-conditioned medium (PCM) on proliferation of human microvascular endothelial cells in vitro, together with the expression of the vasoregulatory molecules, constitutive and inducible nitric oxide synthases (ecNOS and iNOS), and endothelin-1 (ET-1). Expression was measured at the mRNA level using semiquantitative RT-PCR for all three genes and at the protein level for ecNOS and iNOS using Western blotting. Growth curves for HMECs showed that PCM inhibits proliferation, eventually leading to cell death. Exposure to PCM repressed iNOS mRNA expression fivefold after 6 h. A similar, though delayed, reduction in protein levels was observed. ecNOS mRNA was slightly induced at 6 h, though there was no significant change in ecNOS protein. By contrast, ET-1 mRNA was induced 2.3-fold after 6 h exposure to PCM. We conclude that pericytes release a soluble factor or factors that are potent inhibitors of endothelial cell growth and promote vasoconstriction by up-regulating endothelin-1 and down-regulating iNOS.

Receptor binding and biologic activity of synthetic ET-1 peptides in the retinal pericyte.

PURPOSE: The purpose of this study was to examine the effect of synthetic endothelin (ET)-1 peptides with antigenic potential for binding and biologic activity using an in vitro model of microvascular pericytes. METHODS: All possible sequential hexapeptide fragments of endothelins -1, -2, and -3 were synthesized on polyethylene rods and tested for reactivity with antibodies for ET-1 and ET-3. The most highly antigenic peptide ET-1[3-8] and the least antigenic ET-1[1-6], which gave low reactivity in the enzyme-linked immunosorbent assay (ELISA), were synthesized. The C-terminal hexapeptide ET-1[16-21], which has been reported as an ETB receptor agonist but which gave no reactivity in the ELISA, also was investigated. The synthesized ET analogues were tested for receptor binding, inositol phosphate generation, and mitogenesis in bovine retinal pericytes. RESULTS: ET-1[16-21] partially inhibited both [125I]-ET-3 binding at high concentrations, as did ET-1[1-6]. In contrast, ET-1[3-8] displaced labeled ET-1 binding but not labeled ET-3 binding. None of the peptides had any significant mitogenic or second-messenger responses when compared to those elicited by the full ET-1 molecule. CONCLUSIONS: The result of the current work shows that the sequence, ET[3-8], is involved in isopeptide-specific binding to ETA receptors, but it suggests that other regions of the molecule are necessary for full bioactivity in microvascular pericytes.

Murine epidermal growth factor (EGF) fragment (33-42) inhibits both EGF- and laminin-dependent endothelial cell motility and angiogenesis.

Laminin, murine epidermal growth factor (mEGF), and the synthetic laminin peptide Lam.B1(925-933) (a linear peptide from the B1 chain of murine laminin, CDPGY1GSR-amide) all stimulate endothelial cell motility above basal rates, whereas a synthetic mEGF fragment, mEGF33-42 (a linear peptide from the C-loop of mEGF, acetyl-C-[S-Acm]-VIGYSGDR-C-[S-Acm]-amide), inhibits motility. In both human SK HEP-1 and embryonic chick endothelial cells, mEGF33-42 blocks both EGF- and laminin-stimulated locomotion of endothelial cells. In vivo, mEGF33-42 also blocks both laminin- and mEGF-induced angiogenesis in the chick. In the human cell line. Lam.B1(925-933) has an additive effect in coincubation with either laminin or mEGF, but it blocks their effects in the chick cells. Lam.B1(925-933) alone stimulates angiogenesis in the chick but blocks laminin-induced angiogenesis. Thus, mEGF33-42 acts as a general laminin antagonist, whereas Lam.B1(925-933) acts as a laminin agonist in human cells, but in chick cells it acts as a partial antagonist. We propose that the presence of an anionic group at the eighth residue of mEGF33-42 may be the source of the antagonistic effects seen with this peptide as compared with the laminin fragment. These findings have important implications in the design of human antiangiogenic agents, and also in the use of chick models in the study of human disease.

Characterization of endothelin A (ETA) and endothelin B (ETB) receptors in cultured bovine retinal pericytes.

PURPOSE: The endothelins are a family of structurally similar vasoactive peptides. It has been shown recently that cultured retinal microvascular endothelial cells secrete endothelin-1 (ET-1) and that corresponding pericytes bear receptors and are responsive to this peptide. These findings suggest a role for ET-1 in the autoregulation of retinal blood flow. There are at least two known subtypes of ET receptors, ETA and ETB. The purpose of this study was to characterize endothelin receptor subtypes on cultured bovine retinal pericytes (BRP). METHODS: To characterize the specific binding sites for ET-1 and ET-3 on monolayers of BRP, a radioligand binding assay was performed using [125I] ET-1 and [125I] ET-3. Competition binding studies with ET-1 and ET-3 were used to assess the heterogeneity of the ET-receptor population on BRP. Also, [125I] ET-1 and ET-3 were covalently linked to their corresponding receptors and analyzed on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by autoradiography. RESULTS: [125I] ET-1 and [125I] ET-3 showed specific binding to BRP and subsequent Scatchard analysis for both labels showed upward concavity, implying two-site ligand binding. Unlabeled ET-1 was found to displace [125I] ET-1 with greater efficiency than ET-3, indicating the presence of the ETA receptor subtype. Conversely, [125I] ET-3 was displaced by ET-1 and ET-3 with equal potency, indicating a component of ETB in the receptor population. Preincubation with BQ123, an ETA selective antagonist, decreased the binding of [125I] ET-1 but had no effect on [125I] ET-3 binding curves. Affinity cross-linking of the receptors showed two distinct protein bands on SDS-PAGE of 66 and 45 kd, corresponding to ETA and ETB. CONCLUSIONS: These results show that BRP possess ETA and ETB receptor subtypes. The function of ETB on BRP may be to modulate the vasoconstrictive effect of ET-1 caused through ETA.

Nitric oxide synthase activity and expression in retinal capillary endothelial cells and pericytes.

The purpose of this study was to examine nitric oxide synthase (NOS) expression in the retinal vasculature in vivo and to study nitric oxide (NO) synthesis in vitro in retinal microvascular endothelial cells and pericytes. Immunoreactivity was examined using a polyclonal antibody raised against porcine cerebellar nitric oxide synthase on frozen sections cut from postmortem human retina and trypsin digests of rat retinal vasculature. The synthesis of nitrite, a stable end product from the interaction of NO with molecular oxygen, was measured in culture supernatants of retinal microvascular cells under basal and stimulated conditions. Expression of constitutive NOS (cNOS) in these cells was examined using the polymerase chain reaction (PCR). Strong NOS immunoreactivity was seen in the endothelium of choroidal and retinal vessels. Nitrite synthesis was documented in supernatants from cultured microvascular endothelial cells which increased significantly following exposure to A23187 and cytokines. Nitrite synthesis by pericytes was not detectable under basal conditions or following stimulation with A23187. Bacterial lipopolysaccharide (LPS), a potent inducer of NOS, caused an increase in nitrite concentrations in pericyte supernatants 24 h after stimulation suggesting the presence of inducible NOS (iNOS). PCR amplification confirmed the presence of the cNOS gene in endothelial cells but not in pericytes. Retinal vascular endothelial cells express significant amounts of NOS constitutively in vivo and in vitro which is activated by Ca++. Also, endothelial cells can be stimulated to synthesize iNOS by cytokines. Retinal pericytes too show iNOS activity following exposure to bacterial LPS. These results suggest that the nitric oxide synthase/nitric oxide pathway may be involved in the regulation of microcirculatory haemodynamics in the retina.

Molecular characterization of endothelin receptors and the effect of insulin on their expression in retinal microvascular pericytes.

Microvascular pericytes contain predominantly endothelin A (ET(A))-like binding sites and also a smaller number of ETB binding sites. In this study we verified the expression of both receptors in these cells. We then examined the effect of insulin, a potent mediator of vasodilatation, on the expression of these receptors in pericytes by Northern hybridization. Northern hybridization studies showed that ET(A) mRNA levels were not influenced by exposure to insulin (1 x 10(-7) M). By contrast, ETB receptor mRNA, which was minimal under basal conditions, was significantly increased by 4 h after exposure to insulin.

Receptor-mediated endocytosis and intracellular trafficking of insulin and low-density lipoprotein by retinal vascular endothelial cells.

PURPOSE: The authors investigated the receptor-mediated endocytosis (RME) and intracellular trafficking of insulin and low-density lipoprotein (LDL) in cultured retinal vascular endothelial cells (RVECs). METHODS: Low-density lipoprotein and insulin were conjugated to 10 nm colloidal gold, and these ligands were added to cultured bovine RVECs for 20 minutes at 4 degrees C. The cultures were then warmed to 37 degrees C and fixed after incubation times between 30 seconds and 1 hour. Control cells were incubated with unconjugated gold colloid at times and concentrations similar to those of the ligands. Additional control cells were exposed to several concentrations of anti-insulin receptor antibody or a saturating solution of unconjugated insulin before incubation with gold insulin. RESULTS: Using transmission electron microscopy, insulin gold and LDL gold were both observed at various stages of RME. Insulin-gold particles were first seen to bind to the apical plasma membrane (PM) before clustering in clathrin-coated pits and internalization in coated vesicles. Gold was later visualized in uncoated cytoplasmic vesicles, corresponding to early endosomes and multivesicular bodies (MVBs) or late endosomes. In several instances, localized regions of the limiting membrane of the MVBs appeared coated, a feature of endosomal membranes not previously described. After RME at the apical PM and passage through the endosomal system, the greater part of both insulin- and LDL-gold conjugates was seen to accumulate in large lysosome-like compartments. However, a small but significant proportion of the internalized ligands was transcytosed and released as discrete membrane-associated quanta at the basal cell surface. The uptake of LDL gold was greatly increased in highly vacuolated, late-passage RVECs. In controls, anti-insulin receptor antibody and excess unconjugated insulin caused up to 89% inhibition in gold-insulin binding and internalization. CONCLUSION: These results illustrate the internalization and intracellular trafficking by RVECs of insulin and LDL through highly efficient RME, and they provide evidence for at least two possible fates for the endocytosed ligands. This study outlines a route by which vital macromolecules may cross the inner blood-retinal barrier.

Immunoreactive endothelin distribution in ocular tissues.

PURPOSE: To study the distribution of the endothelins in the eye using ocular tissues of human, rat, and porcine origin. METHODS: Extracts of ocular tissues were examined for immunoreactivity to endothelin 1 and 3 and pro-endothelin 1 using radioimmunoassay. Characterization of immunoreactivity was verified using high-performance liquid chromatography. RESULTS: Immunoreactivity to endothelin 1 and endothelin 3 was found in all ocular tissues except the cornea, which contained no immunoreactivity to endothelin 3. Highest levels were found in the choroid, although species-related differences were present. Immunoreactivity to endothelin 3 was generally twofold to threefold higher than immunoreactivity to endothelin 1. The majority of endothelin-like-immunoreactivity in the retina was blood vessel-associated. High-pressure liquid chromatography (HPLC) confirmed that immunoreactive endothelin 1 and endothelin 3 in the tissue extracts eluted in identical positions to their respective standard synthetic peptides. CONCLUSIONS: The endothelins are abundantly distributed in the eye. Endothelin 1 is present in its mature, 21 amino acid form, and only minimal amounts of the precursor pro-endothelin is found in ocular tissues. The wide distribution patterns point to complex roles for these peptides in blood vessel physiology and in such other functions as regulation of aqueous outflow, and in neurotransmission or modulation.

Synthesis of a cyclic analogue of the C-loop region of epidermal growth factor, containing 1-aminocyclopropane-1-carboxylic acid.

We report the synthesis of a cyclic analogue of epidermal growth factor sequence 33-42 with substitution of 1-aminocyclopropane-1-carboxylic acid for glycine at position 39 (N-acetyl-Cys-Val-Ile-Gly-Tyr-Ser-ACPCA-Asp-Arg-Cys-NH2). The analogue was synthesised by solid-phase methods, using t-Boc chemistry and acid-labile side-chain protecting groups. The use of the 4-methoxybenzyl protecting group for C- and N-terminal cysteine residues resulted in the spontaneous formation of the desired intramolecular disulfide bond after HF deprotection.

The synthesis, kinetic characterization and application of biotinylated aminoacylchloromethanes for the detection of chymotrypsin and trypsin-like serine proteinases.

The synthesis of two biotinylated affinity labels for chymotrypsin and trypsin-like serine proteinases is described, along with their kinetic characterization and application to the detection of these proteinases after PAGE and Western blotting. Thus the chloromethane analogues biotinylphenylalanylchloromethane (Bio-Phe-CH2Cl; reagent 1) and biotinylarginylchloromethane (Bio-Arg-CH2Cl, reagent 2), have been shown to be potent active-site-directed inactivators of chymotrypsin and trypsin respectively. The apparent overall second-order rate constants (kobs./[I]) for the inactivation of chymotrypsin and trypsin by reagent 1 (approximately 4.9 x 10(3) M-1.min-1) and reagent 2 (approximately 1.0 x 10(5) M-1.min-1) respectively are comparable with those obtained by other workers with simple urethane-protected analogues and demonstrates that the presence of the bulky biotinyl moiety is compatible with inhibitor effectiveness. Samples of chymotrypsin and trypsin that have been inactivated by reagents 1 and 2 respectively and which have been subjected to SDS/PAGE and Western blotting can be revealed with a streptavidin/alkaline phosphatase label. We can presently detect down to 20 ng of inactivated proteinase by using this system. The utility of the arginine derivative for the detection of the plasma trypsin-like proteinases plasmin and thrombin has also been demonstrated, thus holding out the possibility that this reagent may find general application as an active-site-directed label for this class of proteinase.

Synthetic murine epidermal growth factor sequence 20-31 is mitogenic and angiogenic.

Epidermal growth factor (EGF) and its homologue, transforming growth factor alpha (TGF alpha), are mitogenic, angiogenic and tumour-promoting polypeptides. Much effort has therefore been directed towards the development of EGF/TGF alpha antagonists as a potential cancer therapy. Initial reports that some EGF/TGF alpha synthetic fragments possess EGF-receptor binding activity have not been confirmed in subsequent studies. We have found, however, that the murine EGF B-loop sequence: Ac-[(S-acetamidomethyl)-Cys20,31]-EGF-(20-31)-NH2 [(mEGF-(20-31)] produces biological effects consistent with the parent molecule in bovine, murine, chick and human, but not rat, model systems. In parallel experiments, both mEGF and mEGF-(20-31) elicit migratory, cytoprotective, growth-stimulatory, growth-inhibitory and angiogenic responses. The reverse B-loop sequence, mEGF-(31-20), is also mitogenic and angiogenic. The C-loop sequence, mEGF-(33-42), has no mitogenic or angiogenic activity when applied alone, does not block the mitogenic effect of mEGF, but does block the angiogenic effect of mEGF. It has not been established that the EGF receptor is the target for these fragments, but the results suggest that the residual biological activities of EGF fragments merit further investigation.

Dose-response relationship of tetronasin administered to grazing steers.

Two grazing experiments were conducted to evaluate the dose-response relationship of steers to the ionophore tetronasin. Bermudagrass-based pastures were grazed 126 d in Exp. 1, and annual ryegrass or an annual ryegrass-berseem clover mixture was grazed 112 d in Exp. 2. Tetronasin was administered in ground corn (.91 kg/hd) fed daily to provide dosages of 0, 7.5, 15, 30, 60 or 90 mg. One hundred forty-four steers (220 kg, Exp. 1; 196 kg, Exp. 2) were allocated to treatment groups of six steers within four initial weight blocks in Exp. 1 and within two initial weight blocks, assigned to two forage types in Exp. 2. Initial weight blocks were confounded with four pasture blocks, divided in six 1.35-ha paddocks. Treatment groups were rotated among paddocks within pasture block every 2 wk. Stepwise tetronasin addition resulted in a linear increase (P less than .05) in the proportion of propionic acid and a linear decrease (P less than .05) in the proportion of acetic acid and the acetic to propionic acid ratio in both experiments. Total VFA concentrations were not altered in Exp. 1 but they decreased linearly in Exp. 2 with tetronasin addition. Maximal observed improvement in daily gain (.1 kg) occurred at a dosage of 30 mg.hd-1.d-1 in Exp. 1 and 90 mg.hd-1.d-1 in Exp. 2. Daily gain increased linearly (P less than .06) with tetronasin level in both experiments.(ABSTRACT TRUNCATED AT 250 WORDS)