The UK Food Standards Agency (FSA) convened an international group of scientific experts to review three Agency-funded projects commissioned to provide evidence for the relative contributions of two sources, dietary vitamin D intake and skin exposure to UVB rays from sunlight, to vitamin D status. This review and other emerging evidence are intended to inform any future risk assessment undertaken by the Scientific Advisory Committee on Nutrition. Evidence was presented from randomised controlled trials to quantify the amount of vitamin D required to maintain a serum 25-hydroxy vitamin D (25OHD) concentration .25 nmol/l, a threshold that is regarded internationally as defining the risk of rickets and osteomalacia. Longitudinal evidence was also provided on summer sunlight exposure required to maintain 25OHD levels above this threshold in people living in the British Isles (latitude 518-578N). Data obtained from multi-level modelling of these longitudinal datasets showed that UVB exposure (i.e. season) was the major contributor to changes in 25OHD levels; this was a consistent finding in two Caucasian groups in the north and south of the UK, but was less apparent in the one group of British women of South Asian origin living in the south of the UK. The FSA-funded research suggested that the typical daily intake of vitamin D from food contributed less than UVB exposure to average year-round 25OHD levels in both Caucasian and Asian women. The low vitamin D status of Asian women has been acknowledged for some time, but the limited seasonal variation in Asian women is a novel finding. The Workshop also considered the dilemma of balancing the risks of vitamin D deficiency (from lack of skin exposure to sunlight in summer) and skin cancer (from excessive exposure to sunlight with concomitant sunburn and erythema). Cancer Research UK advises that individuals should stay below their personal sunburn threshold to minimise their skin cancer risk. The evidence suggests that vitamin D can be produced in summer at the latitude of the UK, with minimal risk of erythema and cell damage, by exposing the skin to sunlight for a short period at midday, when the intensity of UVB is at its daily peak. The implications of the new data were discussed in the context of dietary reference values for vitamin D for the general population aged 4-64 years. Future research suggestions included further analysis of the three FSA-funded studies as well as new research.
The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25 nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations > 75 nmol/l). Any discussion of 'optimal' concentration of serum 25(OH)D needs to define 'optimal' with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population; this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations. Keywords
Interindividual differences in susceptibility to hematologic malignancies may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs) have been implicated as susceptibility genes in this context for a number of cancers. The aim of this study was to examine whether polymorphic variation in GSTs confers susceptibility to chronic lymphocytic leukemia (CLL). GSTM1, GSTT1, and GSTP1 genotypes were determined in 138 patients and 280 healthy individuals. The frequency of both GSTM1 and GSTT1 null genotypes and the GSTP1-Ile allele was higher in cases than in controls. There was evidence of a trend in increasing risk with the number of putative "high-risk" alleles of the GST family carried (P ؍ .04). The risk of CLL associated with possession of all 3 "high-risk" genotypes was increased 2.8-fold (OR ؍ 2.8, 95% confidence interval: 1.1-6.9). Our findings suggest that heritable GST status may influence the risk of developing CLL. IntroductionB-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia, accounting for around 30% of all cases. 1 There is increasing evidence that predisposition to CLL involves both inherited and environmental factors. 2,3 It is likely that part of the inherited susceptibility to CLL may be determined by interindividual differences in the bioactivation of procarcinogens and detoxification of carcinogens.The glutathione S-transferases (GSTs) are a superfamily of genes whose products are phase II enzymes, catalyzing the conjugation of reactive intermediates to soluble glutathione. 4 GSTM1 and GSTP1 detoxify carcinogenic polycyclic aromatic hydrocarbons such as benzo-(a)pyrene, whereas GSTT1 is responsible for the detoxification of smaller reactive hydrocarbons, such as ethylene oxide. 4 Differences in the activities of some GSTs are determined by genetic polymorphisms. 4 GSTM1 activity is absent in ϳ50% of whites as a consequence of the inheritance of 2 null alleles (deletion of the gene). Similarly, GSTT1 activity is deficient in ϳ20% of whites, resulting from homozygous deletion. The GSTP subfamily comprises only GSTP1. The 1578AϾG substitution in GSTP1 creates the Ile105Val polymorphism that leads to expression of an enzyme with reduced activity. 4 There is epidemiologic evidence that exposure to aliphatic hydrocarbons and chlorinated hydrocarbons plays a role in the etiology of CLL. 3,[5][6][7][8] This, coupled with the proposed role of GSTs in the etiology of a number of common cancers 9 provides a strong rationale for evaluating GSTM1, GSTT1, and GSTP1 polymorphisms as risk factors for CLL. Study design PatientsBlood samples were obtained from 138 white patients (62% male; 38% female; mean age at presentation 54 years, SD: 12) with B-cell CLL referred to the Royal Marsden Hospital NHS Trust. The diagnosis of CLL was based on standard hematologic and immunologic criteria. The proportion of patients with Binet stages A, B, and C were 58%, 14%, and 28%, respectively. Median white c...
TCL1 is an oncogene activated by recurrent reciprocal translocations at chromosome segment 14q32.1 in the most common of the mature T-cell malignancies, T-cell prolymphocytic leukemia. It acts to transport Akt1 to the nucleus and enhance Akt1's serine-threonine kinase activity. TCL1 is also expressed in the B-cell malignancy, Burkitt's lymphoma (BL). However, 14q32.1 breakpoints have not been detected in BL, and we therefore investigated in more detail how expression was activated. No evidence for rearrangement near TCL1 was found in BL. Instead, a NotI site adjacent to the TATA box in the TCL1 promoter was found to be unmethylated. By contrast, tumor cell lines not expressing TCL1 were fully methylated at this NotI site, while normal somatic cells were hemimethylated. We also found that TCL1 was expressed in B-cell chronic lymphocytic leukemia (CLL) and the related disorder splenic lymphoma with villous lymphocytes (unlike in normal mature B-cells), and that the NotI site was unmethylated on both alleles. This correlation of repression and methylation was tested in vitro. When cells with both alleles methylated at the NotI site were demethylated, TCL1 expression was induced. These data provide evidence that in mature B-cell malignancies there is an alternative mechanism of TCL1 activation that apparently involves loss of methylation of one promoter allele. We discuss the significance of this for CLL tumorigenesis and for genomewide hypomethylation in CLL.
The authors report on the morphological features of a pituitary adenoma that produced growth hormone (GH) and adrenocorticotropic hormone (ACTH). This hormone combination produced by a single adenoma is extremely rare; a review of the available literature showed that only one previous case has been published. The tumor, which was removed from a 62-year-old man with acromegaly, was studied by histological and immunocytochemical analyses, transmission electron microscopy, immunoelectron microscopy, and in situ hybridization. When the authors used light microscopy, the tumor appeared to be a bimorphous mixed pituitary adenoma composed of two separate cell types: one cell population synthesized GH and the other ACTH. The cytogenesis of pituitary adenomas that produce more than one hormone is obscure. It may be that two separate cells--one somatotroph and one corticotroph--transformed into neoplastic cells, or that the adenoma arose in a common stem cell that differentiated into two separate cell types. In this case immunoelectron microscopy conclusively demonstrated ACTH in the secretory granules of several somatotrophs. This was associated with a change in the morphological characteristics of secretory granules. Thus it is possible that the tumor was originally a somatotropic adenoma that began to produce ACTH as a result of mutations that occurred during tumor progression.
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