First published as an Advance ArticleSince publication of the 1998 UNEP Assessment, there has been continued rapid expansion of the literature on UV-B radiation. Many measurements have demonstrated the inverse relationship between column ozone amount and UV radiation, and in a few cases long-term increases due to ozone decreases have been identified. The quantity, quality and availability of ground-based UV measurements relevant to assessing the environmental impacts of ozone changes continue to improve. Recent studies have contributed to delineating regional and temporal differences due to aerosols, clouds, and ozone. Improvements in radiative transfer modelling capability now enable more accurate characterization of clouds, snow-cover, and topographical effects.A standardized scale for reporting UV to the public has gained wide acceptance. There has been increased use of satellite data to estimate geographic variability and trends in UV. Progress has been made in assessing the utility of satellite retrievals of UV radiation by comparison with measurements at the Earth's surface. Global climatologies of UV radiation are now available on the Internet.Anthropogenic aerosols play a more important role in attenuating UV irradiances than has been assumed previously, and this will have implications for the accuracy of UV retrievals from satellite data. Progress has been made inferring historical levels of UV radiation using measurements of ozone (from satellites or from ground-based networks) in conjunction with measurements of total solar radiation obtained from extensive meteorological networks.We cannot yet be sure whether global ozone has reached a minimum. Atmospheric chlorine concentrations are beginning to decrease. However, bromine concentrations are still increasing. While these halogen concentrations remain high, the ozone layer remains vulnerable to further depletion from events such as volcanic eruptions that inject material into the stratosphere. Interactions between global warming and ozone depletion could delay ozone recovery by several years, and this topic remains an area of intense research interest.Future changes in greenhouse gases will affect the future evolution of ozone through chemical, radiative, and dynamic processes. In this highly coupled system, an evaluation of the relative importance of these processes is difficult; studies are ongoing. A reliable assessment of these effects on total column ozone is limited by uncertainties in lower stratospheric response to these changes.At several sites, changes in UV differ from those expected from ozone changes alone, possibly as a result of long-term changes in aerosols, snow cover, or clouds. This indicates a possible interaction between climate change and UV radiation. Cloud reflectance measured by satellite has shown a long-term increase at some locations, especially in the Antarctic region, but also in Central Europe, which would tend to reduce the UV radiation.Even with the expected decreases in atmospheric chlorine, it will be several years b...

We assess the importance of factors that determine the intensity of UV radiation at the Earth's surface. Among these, atmospheric ozone, which absorbs UV radiation, is of considerable importance, but other constituents of the atmosphere, as well as certain consequences of climate change, can also be major influences. Further, we assess the variations of UV radiation observed in the past and present, and provide projections for the future. Of particular interest are methods to measure or estimate UV radiation at the Earth's surface. These are needed for scientific understanding and, when they are sufficiently sensitive, they can serve as monitors of the effectiveness of the Montreal Protocol and its amendments. Also assessed are several aspects of UV radiation related to biological effects and health. The implications for ozone and UV radiation from two types of geoengineering methods that have been proposed to combat climate change are also discussed. In addition to ozone effects, the UV changes in the last two decades, derived from measurements, have been influenced by changes in aerosols, clouds, surface reflectivity, and, possibly, by solar activity. The positive trends of UV radiation observed after the mid-1990s over northern mid-latitudes are mainly due to decreases in clouds and aerosols. Despite some indications from measurements at a few stations, no statistically significant decreases in UV-B radiation attributable to the beginning of the ozone recovery have yet been detected. Projections for erythemal irradiance (UVery) suggest the following changes by the end of the 21(st) century (2090-2100) relative to the present time (2010-2020): (1) Ozone recovery (due to decreasing ozone-depleting substances and increasing greenhouse gases) would cause decreases in UVery, which will be highest (up to 40%) over Antarctica. Decreases would be small (less than 10%) outside the southern Polar Regions. A possible decline of solar activity during the 21(st) century might affect UV-B radiation at the surface indirectly through changes induced in stratospheric ozone. (2) The projected changes in cloud cover would lead to relatively small effects (less than 3%), except at northern high latitudes where increases in cloud cover could lead to decreases in UVery by up to 7%. (3) Reductions in reflectivity due to the melting of sea-ice in the Arctic would lead to decreases of UVery by up to 10%, while at the margins of the Antarctic the decreases would be smaller (2-3%). The melting of the sea-ice would expose the ocean surface formerly covered by ice to UV-B radiation up to 10 times stronger than before. (4) The expected improvement of air-quality and reductions of aerosols over the most populated areas of the northern hemisphere may result in 10-20% increases in UVery, except over China where even larger increases are projected. The projected aerosol effect for the southern hemisphere is generally very small. Aerosols are possibly the most important factor for future UV levels over heavily populated areas, but their project...

Background: In renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown. Methods: We clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical and cell-biologic investigations of renal proximal tubular cells, studies in knockout mice, and functional evaluations of mitochondria. Urine was studied with the use of proton nuclear magnetic resonance (1H-NMR) spectroscopy. Results: We linked the phenotype of this family's Fanconi's syndrome to a single locus on chromosome 3q27, where a heterozygous missense mutation in EHHADH segregated with the disease. The p.E3K mutation created a new mitochondrial targeting motif in the N-terminal portion of EHHADH, an enzyme that is involved in peroxisomal oxidation of fatty acids and is expressed in the proximal tubule. Immunocytofluorescence studies showed mistargeting of the mutant EHHADH to mitochondria. Studies of proximal tubular cells revealed impaired mitochondrial oxidative phosphorylation and defects in the transport of fluids and a glucose analogue across the epithelium. 1H-NMR spectroscopy showed elevated levels of mitochondrial metabolites in urine from affected family members. Ehhadh knockout mice showed no abnormalities in renal tubular cells, a finding that indicates a dominant negative nature of the mutation rather than haploinsufficiency. Conclusions: Mistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome; this indicates a central role of mitochondria in proximal tubular function. The dominant negative effect of the mistargeted protein adds to the spectrum of monogenic mechanisms of Fanconi's syndrome. (Funded by the European Commission Seventh Framework Programme and others.)

CDC4/FBXW7 is part of a ubiquitin ligase complex which targets molecules such as cyclin E, c-myc, and c-jun for destruction. CDC4 mutations occur in several cancer types and are best described in colorectal tumors. Knockout of CDC4 in vitro in colorectal cancer cells causes changes suggestive of chromosomal instability (CIN). In p53 +/À mice, radiation-induced lymphomas show deletion or mutation of one copy of CDC4 and knockdown of CDC4 leads to increased aneuploidy in mouse fibroblasts. We screened 244 colorectal tumors and 40 cell lines for CDC4 mutations and allelic loss. Six percent (18 of 284) of tumors, including near-diploid (CINÀ) lesions, harbored CDC4 mutations and there was no association between mutation and CIN (polyploidy). The CDC4 mutation spectrum in colorectal tumors was heavily biased towards C:G>T:A changes, either missense mutations at critical arginine residues or nonsense changes in the 5V half of the gene. The reasons for this odd mutation spectrum were unclear but C:G>T:A changes were not found more often than expected at APC, K-ras, or p53 in the same tumors and we found no specific defects in DNA repair to account for the observations. No colorectal tumor was found to carry two CDC4 mutations predicted to abolish protein function; partial loss of CDC4 function may therefore cause tumorigenesis. The in vitro studies, therefore, did not assess the functional effects of mutant alleles which are found in vivo. CDC4 mutations may be selected primarily to drive progression through the cell cycle although CIN might be an important secondary effect in some cancers. (Cancer Res 2005; 65(24): 11361-6)

Level III retrospective study.

No abstract

Colorectal cancer (CRC) is one of the best characterised cancers, with extensive data documenting the sequential g e n e m u t a t i o n s t h a t u n d e r l i e i t s d e v e l o p m e n t . Complementary datasets are also being generated describing changes in protein and RNA expression, tumour biology and clinical outcome. Both the quantity and the variety of information are inexorably increasing and there is now an accompanying need to integrate these highly disparate datasets. In this article we aim to explain why we believe that mathematical modelling represents a natural tool or language with which to integrate these data and, in so doing, to provide insight into CRC.

The objective of this study was to review the epidemiological patterns of acute post-streptococcal glomerulonephritis (APSGN) in a pediatric population. We compared incidence, pathogenesis, clinical presentation and outcomes in two APSGN pediatric patient cohorts in northeastern Florida. Retrospective medical records were reviewed of children who were admitted to our institution with a diagnosis of APSGN. Patients admitted between 1999 and 2006 (recent cohort) were compared with a previously reported cohort of patients admitted between 1957 and 1973 (earlier cohort). The recent cohort comprised 45 children with APSGN of whom 87% were male and 13% were female; the median age was 7 years, and there was an average incidence of 6.4 patients per year. The earlier cohort comprised 153 children with APSGN of whom 62% were male and 38% were female; the median age 4.25 years, and there was an average incidence of 10.9 patients per year. The recent cohort was predominantly White-American (62%) and the earlier cohort predominately African American (87%). In the recent cohort, 64% of patients had antecedent pharyngitis, and in the earlier cohort, 66% of patients had antecedent pyoderma. In the recent cohort, 11% of APSGN cases occurred between August to October, and in the earlier cohort, 50% occurred during these months. In the recent cohort, symptoms of APSGN at presentation were milder and all cases recovered, but in the earlier cohort two deaths (1.3% mortality) were reported. In conclusion, there has been a decline in the incidence and severity of APSGN at our institute in recent decades. Pharyngitis has replaced impetigo as the predominant cause of APSGN. The etiological agent for impetigo has changed over the last decade, which has impacted the incidence, racial distribution, seasonal variation and severity of APSGN.