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Women with post-menopausal osteoporosis (bone loss) absorb less calcium from their diets, although their absorption of other dietary nutrients seems to be normal. Calcitriol, the active form of vitamin D, controls absorption of calcium by intestinal cells. In women with post-menopausal osteoporosis calcitriol levels tend to be low. It is unclear whether low calcitriol levels cause poor calcium absorption, or whether interactions between calcitriol and other calcium-regulating hormones lead to osteoporosis. Small doses of synthetic calcitriol have little long-term effect on calcium balance; high doses stimulate bone formation, but may cause toxicity if dietary calcium is not low. The effects of moderately high doses of calcitriol and moderate dietary calcium intake on bone density and calcium absorption were studied over a two-year period in 50 post-menopausal women with osteoporosis. Forty women completed the study. Half the women were given placebo, and this group had a decreased spinal bone density and total body calcium after two years. The calcitriol-treated group had increased spinal bone density and total body calcium, indicating an increase in calcium balance. Other measurements indicated that calcitriol improved the rate of bone formation. However, the incidence of new fractures was similar in both groups, but this may have been related to patients having rather mild osteoporosis, avoiding exercise, or other factors. No toxicity was observed among the calcitriol-treated women. Further research on calcitriol treatment for post-menopausal osteoporosis is needed. (Consumer Summary produced by Reliance Medical Information, Inc.)

AbstractObjectives: Discrete blocks of low haplotype diversity exist within the human genome. The non-redundant subset of ‘haplotype tagging’ single nucleotide polymorphisms (htSNPs) in such blocks can distinguish a majority of the haplotypes. Several approaches have been proposed to determine htSNPs, ranging from visual inspection to formal analytic procedures. Optimal htSNPs can be estimated using a small subgroup of an association study population that have been genotyped for a dense SNP map, and it is just these htSNPs that are genotyped in the remainder of the samples. We investigated by simulation how the size of the subsample affects the power of association studies, and what type of subjects it should include. Methods: We used the program tagSNPs [Stram et al., Hum Hered 2003;55:27–36], which selects htSNPs to minimize the uncertainty in predicting common haplotypes for individuals with unphased genotype data. Results: On average, 27% of the SNPs were designated as htSNPs. Genotyping as few as 25 unphased individuals to select the htSNPs did not appear to reduce the power of an association study, as compared with using all SNPs. For the disease models considered, selecting htSNPs based on cases, controls, or a mixture of both gave similar results. Conclusions: These results suggest that the genotyping effort in an association study can be substantially reduced with little loss of power by identifying htSNPs in a small subsample of individuals.Copyright © 2003 S. Karger AG, Basel

Introduction: While the association between family history of colorectal cancer in first-degree relatives and risk of developing colon cancer has been well defined, the association with rectal cancer is much less clear. The purpose of this study is to define rectal cancer risk associated with family history of colorectal cancer in first-degree relatives. We also evaluate diet and lifestyle factors associated with developing colorectal cancer among participants with a positive family history. Methods: Data were available from two population-based case–control studies of colon and rectal cancer. Participants were members of the Kaiser Permanente Medical Care Program (KPMCP) or residents of the state of Utah. Cases were first primary colon cancer diagnosed between 1991 and 1994 (n = 1308 cases and 1544 controls) or rectal cancer diagnosed between 1997 and 2001 (n = 952 cases and 1205 controls). Results: A family history of colorectal cancer in any first-degree relatives slightly increased risk of rectal cancer (OR: 1.37 95% CI: 1.02–1.85). Family history of colorectal cancer was associated with the greatest risk among those diagnosed at age 50 or younger (OR: 2.09 95% CI: 0.94–4.65 for rectal tumors; OR: 3.00 95% CI: 0.98–9.20 for distal colon tumors; and OR: 7.88 95% CI: 2.62–23.7 for proximal colon tumors). Factors significantly associated with cancer risk among those with a family history of colorectal cancer, included not having a sigmoidoscopy (OR: 2.81 95% CI: 1.86–4.24); a diet not Prudent, i.e.high in fruits, vegetables, whole grains, fish and poultry, (OR: 2.79 95% CI: 1.40–5.56); smoking cigarettes (OR: 1.68 95% CI: 1.12–2.53), and eating a Western diet, i.e.a diet high in meat, refined grains, high-fat foods, and fast foods, (OR: 2.15 95% CI: 1.06–4.35). Physical inactivity was not associated with increased cancer risk among those with a positive family history of colorectal cancer. Summary: These results confirm observations reported by others that a family history of colorectal cancer increases risk of cancer among those diagnosed at a younger age. Associations with family history are weakest for rectal cancer and strongest for proximal colonic tumors. Since several diet and lifestyle factors influence development of cancer among those with a family history of the disease, there appears to be practical approaches for individuals with a family history of colorectal cancer to reduce their cancer risk.

Malabsorption of calcium is a common finding in patients with postmenopausal osteoporosis (1, 2). In a number of studies serum 1,25 dihydroxyvitamin D levels were found to be significantly lower in osteoporotic patients, which could account for the calcium absorptive defect (3–6). Based on these findings, we studied the effects of synthetic calcitriol (Rocaltrol) in women with osteoporosis. We showed that calcitriol, 0.25 μg twice daily, improved and normalized the absorption of calcium in all patients and improved calcium balance (7). Urine hydroxyproline, which is a measure of bone resorption, decreased significantly after 2 years of treatment with Rocaltrol. Because of these preliminary findings, further clinical studies were carried out at two centers using a variable dose of Rocaltrol. In these studies we focused on the effectiveness of Rocaltrol in preventing vertebral fractures in patients with spinal osteoporosis.MethodsThe results from two centers have been analyzed both as separate groups and as one combined group. One study was performed at the Mayo Clinic (Protocol 861) and the other at Creighton University (Protocol 860). In both centers the studies performed were double blind and randomized, and compared the effect of placebo against Rocaltrol for a period of 1 year. At the end of 1 year all patients on placebo were crossed over to treatment with Rocaltrol and followed for 2 more years. Patients initially treated with Rocaltrol were followed for an additional 2 years, thus yielding treatment data extending to 3 years in a number of patients. In the study design, patients were given Rocaltrol at a starting dose of 0.25 μg twice daily, if hypercalcemia and hypercalciuria did not occur the dose then was increased to 0.75 μg or 1.0 μg daily at the discretion of the investigator.

Bone density in different regions of the skeleton was measured in 392 normal women aged 20–80 years by dual photon absorpiometry. In premenopausal women, aged 25–50 years, multiple regression analysis of regional bone density on age, height, and weight showed a small significant decrease in total bone density (<0.01) but no significant change in other regions of the skeleton. In postmenopausal women there were highly significant decreases in all regions of the skeleton (p< 0.001), and bone density in these areas decreased as a logarithmic function of years since menopause.Based on multiple regression analyses, the decrease in spine density and total bone calcium was 2.5–3.0 times greater in the 25 years after menopause than the 25 years before menopause. The largest change, however, occurred in the first five years after menopause. During this time the estimated annual change in spine density and total bone calcium was about 10 times greater than that in the premenopausal period. These results demonstrate the important effect of the menopause in determining bone mass in later life.

Women who carry mutations in the BRCA1 gene on chromosome 17q have an 85% lifetime risk of breast cancer, and a 60% risk of ovarian cancer. We have identified BRCA1 mutations in 12 of 30 (40%) Canadian families with breast and/or ovarian cancer, including six of the eight families (75%) that contained two cases of early-onset breast cancer and two cases of ovarian cancer. Six frameshift mutations account for all 12 mutant alleles, including nucleotide insertions (two mutations) and deletions (four mutations). Four independent families carried the same 1 basepair (bp) insertion mutation in codon 1755 and four other families shared a 2 bp deletion mutation in codons 22–23. These families were not known to be related, but haplotype analysis suggests that the carriers of each of these mutations have common ancestors.

A locus for familial melanoma, MLM, has been mapped within the same interval on chromosome 9p21 as the gene for a putative cell cycle regulator, p16INK4(CDKN2) MTS1. This gene is homozygously deleted from many tumour cell lines including melanomas, suggesting that CDKN2 is a good candidate for MLM. We have analysed CDKN2 coding sequences in pedigrees segregating 9p melanoma susceptibility and 38 other melanoma-prone families. In only two families were potential predisposing mutations identified. No evidence was found for heterozygous deletions of CDKN2 in the germline of melanoma-prone individuals. The low frequency of potential predisposing mutations detected suggests that either the majority of mutations fall outside the CDKN2 coding sequence or that CDKN2 is not MLM.

Abstract A recent report based on 68 families, including 17 with mutations in BRCA1, suggested that there was an excess of female offspring born to BRCA1 mutation carriers. We have examined the gender ratio among offspring of 511 mutation carriers from 116 BRCA1 families, 77 and 39 from Australia and the United States, respectively. We found no evidence for a significant deviation from the expected proportion of female offspring in the Australian pedigrees, but there was an excess of female offspring in pedigrees from the USA. Ascertainment bias probably explains this bias, rather than a link with X-chromosome inactivation as previously suggested, because the families from the USA were ascertained for the purposes of linkage studies whereas those from Australia were ascertained through Familial Cancer Clinics to which they had been referred for clinical genetic counseling and mutation testing.

Previous studies of the genetics of melanoma have focused on the dysplastic nevus syndrome (DNS). The variability in clinical and histopathological expression of affected individuals, however, has made definition and diagnosis of the syndrome difficult and subjective. Independent of the DNS, case-control studies have demonstrated the total number of nevi to be a significant risk factor for melanoma. In this article, we report results of genetic analyses of two quantitative nevus phenotypes that can be measured objectively in all subjects: the total number of nevi on an individual (TNN) and total nevus density (TND), a derived phenotype which incorporates both number and size of nevi. Ten kindreds ascertained for multiple cases of DNS-melanoma (multiplex ascertainment) and 16 kindreds and 19 solitary cases ascertained from a sequential list of melanoma cases without regard for family history (simplex ascertainment) were studied. Both phenotypes exhibited increased levels in relatives of probands compared with those in spouse controls. While neither TNN nor TND exhibited evidence for a major factor in the simplex pedigrees, a major factor was strongly indicated in the multiplex kindreds for TND. When both phenotypes were examined in more detail in the multiplex kindreds, the phenotype incorporating nevus size, TND, fit a mendelian pattern of inheritance better than the TNN. Significant residual familial correlations were found for both phenotypes. Parameter estimates from the best fitting genetic model indicated that a major gene may be responsible for 55% of the phenotypic variability of TND in the multiplex kindreds. [J Natl Cancer Inst 83:1726–1733, 1991]