Serum levels of sclerostin, Dickkopf-1, and secreted frizzled-related protein-4 are not changed in individuals with high bone mass causing mutations in LRP5.

SUMMARY: We compared circulating levels of Wnt inhibitors among patients with high bone mass mutations in LRP5, unaffected kindred, and unrelated normal controls. Inhibitors were unchanged in affected and unaffected kindred. We saw no meaningful differences between controls and affected individuals. LRP5 signaling may not influence circulating levels of these inhibitors. INTRODUCTION: It is thought that gain-of-function mutations in LRP5 result in high bone mass syndromes because these allelic variants confer resistance to the actions of endogenous inhibitors of Wnt signaling. We therefore attempted to determine if circulating levels of Wnt inhibitors are altered in patients with gain-of-function mutations in LRP5. METHODS: This is a cross-sectional study in a university research center. Serum was collected from consented volunteers known to have either the G171V or N198S gain-of-function mutations in LRP5, kindred members affected with either mutation, unrelated kindred, and unrelated normal age-matched controls. BMD was provided or measured on site. RESULTS: There were no significant differences found in the serum levels of sclerostin (SOST), Dickkopf-1 (Dkk-1), or secreted frizzled-related protein-4 (SFRP-4) in affected vs. unaffected individuals from different kindreds or when compared to age-matched unrelated normal individuals. Mean serum SOST values in affected and unaffected kindred members and unrelated normal controls were 52.7 ± 6.1, 36.5 ± 9.6, and 54.8 ± 5.4, respectively. For Dkk-1, the values were 25.9 ± 3.4, 25.7 ± 3.0, and 17.3 ± 2.3 and for SFRP-4, 38.1 ± 2.3, 39.8 ± 3.6, and 28.5 ± 1.7. Serum levels of RANKL and osteoprotegerin (OPG) were not different in the three groups. CONCLUSIONS: Circulating levels of endogenous Wnt inhibitors do not change in patients with gain-of-function mutations in LRP5 including Dkk1, which is suppressed by Wnt signaling. It may be that circulating levels of Wnt inhibitors do not reflect changes in target tissues. It is also possible that other mechanisms besides or in addition to resistance in Wnt inhibitors explains the skeletal effects of these mutations.

Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3.

INTRODUCTION: Array comparative genomic hybridisation (array CGH) is a powerful method that detects alteration of gene copy number with greater resolution and efficiency than traditional methods. However, its ability to detect disease causing duplications in constitutional genomic DNA has not been shown. We developed an array CGH assay for X linked hypopituitarism, which is associated with duplication of Xq26-q27. METHODS: We generated custom BAC/PAC arrays that spanned the 7.3 Mb critical region at Xq26.1-q27.3, and used them to search for duplications in three previously uncharacterised families with X linked hypopituitarism. RESULTS: Validation experiments clearly identified Xq26-q27 duplications that we had previously mapped by fluorescence in situ hybridisation. Array CGH analysis of novel XH families identified three different Xq26-q27 duplications, which together refine the critical region to a 3.9 Mb interval at Xq27.2-q27.3. Expression analysis of six orthologous mouse genes from this region revealed that the transcription factor Sox3 is expressed at 11.5 and 12.5 days after conception in the infundibulum of the developing pituitary and the presumptive hypothalamus. DISCUSSION: Array CGH is a robust and sensitive method for identifying X chromosome duplications. The existence of different, overlapping Xq duplications in five kindreds indicates that X linked hypopituitarism is caused by increased gene dosage. Interestingly, all X linked hypopituitarism duplications contain SOX3. As mutation of this gene in human beings and mice results in hypopituitarism, we hypothesise that increased dosage of Sox3 causes perturbation of pituitary and hypothalamic development and may be the causative mechanism for X linked hypopituitarism.

The effects of self-hypnosis for children with cystic fibrosis: a pilot study.

This pilot study assessed the effects of self-hypnosis on psychological and physiological functioning of children ages 7 to 18 with Cystic Fibrosis (N = 12). The study used a pre- and posttest design, repeated measures, and control group. Control and experimental groups were matched for age and clinical severity. The experimental group demonstrated significant changes in locus of control, health locus of control, and self-concept. State anxiety scores did not differ significantly, but changes in trait anxiety distinguished the experimental group from the control group. The experimental group also demonstrated significant increase in peak expiratory flow rates using an air flow meter immediately after self-hypnosis when compared to the control group. Generalizability of the results is discussed in terms of the small sample size. Recommendations are offered for future studies with larger samples and variations in procedure.

Parathyroid adenomas and hyperplasia. Dual radionuclide scintigraphy and bone densitometry studies.

Dual radionuclide imaging of the neck (Tc-99m pertechnetate and TI-201 thallous chloride) was performed in 22 patients with chemical evidence of hyperparathyroidism (elevated blood calcium and parathormone [PTH] levels). Of these, 19 of 22 had localization of a TI-201 "excess" area on radiothallium-radiotechnetium subtraction images. In 13 patients who have had operative confirmation at this writing, the dual radionuclide imaging was positive in 12 (12/13 = 92.3%). One patient had two parathyroid adenomas, both of which were seen on the images; thus, overall detection was 13 out of 14 or 92.8%. The parathyroid adenomas visualized weighed from 0.06 to 3.0 g; the one not detected weighed 0.25 g. In three patients with parathyroid hyperplasia secondary to renal disease, the subtraction imaging detected eight of 12 glands (66.7%). The forearm bone mineral content and bone density were determined in eight patients with parathyroid adenomas; results were abnormally low in five of these eight. One of the three patients with secondary hyperparathyroidism had an abnormally low radial bone mass. The combination of dual radionuclide imaging and radial bone mass determination may present a useful approach in both localizing abnormal parathyroid tissue and in examining its functional consequences.

Cushing's syndrome due to ectopic production of corticotropin-releasing factor.

A patient with Cushing's syndrome is described who had a metastatic medullary carcinoma of the thyroid which contained corticotropin-releasing factor. ACTH was found by an immunohistochemical method in the patient's pituitary, but not in the thyroid tumor. This is the second report demonstrating corticotropin-releasing factor in tumor tissue in this syndrome. Wider use of immunohistological methods can help distinguish this variety from other tumors associated with the ectopic ACTH syndrome when bioassays are not available.

Photon absorptiometry for non-invasive measurement of bone mineral content.

Bone mineral content of the distal radius was determined in 106 patients by single photon absorptiometry using iodine-125 monochromatic source. The technique provided a reliable means to assess the degree of mineral loss in conditions such as osteoporosis, renal osteodystrophy in patients on chronic maintenance dialysis, subjects on long-term steroid therapy, and those with diabetes mellitus. It is more sensitive than conventional radiography and completely noninvasive compared to bone biopsy. It is suggested that photon absorptiometry is a simple, sensitive, and reliable technique for assessment and follow-up of the bone mineral content in a host of disorders associated with bone demineralization.

Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California. Coronary heart disease risk factors in Japan and Hawaii.

Various risk factors were evaluated to explain a significantly greater incidence of coronary heart disease in men of Japanese ancestry resident in Hawaii compared with men resident in Japan. The independent predictors of incidence of coronary heart disease in both Japan and Hawaii were systolic blood pressure, serum cholesterol, relative weight and age. These factors appeared to influence incidence similarly in both areas because in each case the correlation coefficients for Japan and Hawaii did not differ significantly. The hypothesis that the greater incidence in Hawaii could be attributed to differences in levels of these risk factors was tested with the Walker-Duncan method. The four variable multiple logistic function describing the probability of coronary heart disease in Japan was applied to the cohort characteristics observed in Hawaii. The estimated incidence thus obtained was not significantly different from that actually observed in the men resident in Hawaii. Therefore the increased coronary risk profile in Hawaii compared with Japan can account for the greater incidence of coronary heart disease in the former. Current cigarette smoking was significantly related to the risk of coronary heart disease in Hawaii but not in Japan. This difference requires further investigation.

Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: prevalence of coronary and hypertensive heart disease and associated risk factors.

A study of coronary heart disease (CHD) among Japanese migrants compared with Japanese living in Japan provided the opportunity to study factors possibly responsible for the high rates of CHD in America as compared with Japan. Comparable methods were employed in examining 11,900 men of Japanese ancestry aged 45--69 living in Japan, Hawaii and California. The age-adjusted prevalence rates for definite CHD as determined by ECG were: Japan 5.3, Hawaii 5.2 and California 10.8/1000. For definite plus possible CHD the rates were 25.4, 34.7 and 44.6. The prevalence of angina pectoris and pain of possible myocardial infarction, determined by questionnaire, showed a similar gradient. Elevated serum cholesterol showed a Japan-Hawaii-California gradient, but the prevalence of hypertension in Japan was intermediate between the prevalence in Hawaii and the higher prevalence in California. The three geographic locations were compared as to prevalence of CHD at comparable levels of blood pressure and cholesterol. At each blood pressure level and at each cholesterol level, the greater prevalence of CHD in California persisted. These facts, plus the near universality of smoking in Japan, suggest that conventional risk factors only partly explain the observed gradient in CHD.

Salivary gland neoplasms following atomic radiation: additional cases and reanalysis of combined data in a fixed population, 1957-1970.

A reappraisal was made of the relationship between exposure to atomic radiation in 1945 and the occurrence of salivary gland tumors in heavily exposed survivors. This was made possible by the discovery of 8 additional patients; the total now reported consists of 30 cases. In those exposed to 300+ rads, the number of cases was significantly (p less than .01) greater than expected. This was found for the combined group and for malignant types, but not for histologically benign tumors. Our prior conclusion regarding the high-dose radiation effect upon salivary gland neoplasia remains unchanged in the reanalysis; however, our suggestion that younger persons were at significantly greater risk is weakened.