Low bone mineral density for age/osteoporosis in triple A syndrome-an overlooked symptom of unexplained etiology.

UNLABELLED: Triple A syndrome (alacrima, achalasia, adrenal failure, progressive neurodegenerative disease) is caused by mutations in the AAAS gene which encodes the protein alacrima achalasia adrenal insufficiency neurologic disorder (ALADIN). Our investigation suggests that low bone mineral density (BMD) for age/osteoporosis could be a common but overlooked symptom of unexplained etiology in this rare multisystemic disease. INTRODUCTION: The purpose of this study is to evaluate incidence and etiology of BMD for age/osteoporosis, a possibly overlooked symptom in triple A syndrome. METHODS: Dual-energy X-ray absorptiometry (DXA) of the femoral neck, total hip, lumbar spine, and radius, bone turnover markers, minerals, total alkaline phosphatase (ALP), 25-hydroxy vitamin D (25-OHD), 1,25-dihydroxy vitamin D (1,25-OH2D), intact parathyroid hormone (PTH), and adrenal androgens (dehydroepiandrosterone sulfate (DHEAS) and androstenedione) were measured in five male and four female patients. RESULTS: At time of diagnosis, low BMD for age was suspected on X-ray in seven of nine patients aged 2-11 years (not performed in two patients); normal levels of minerals and ALP were found in nine patients and low levels of adrenal androgens in eight patients (not measured in one patient). Reevaluation 5-35 years after introduction of 12 mg/m(2)/day hydrocortisone showed low BMD for age in two children, osteopenia in one, and osteoporosis in six adults. Normal levels of minerals, ALP, PTH, 1,25-OH2D, procollagen type 1, crosslaps, and osteocalcin were found in all patients. Low levels of adrenal androgens were found in all and 25OHD deficiency in six patients. Body mass index was <25 % for age and sex in eight of nine patients. CONCLUSION: Low BMD for age/osteoporosis in our patients probably is not a result of glucocorticoid therapy but could be the consequence of low level of adrenal androgens, neurological impairment causing physical inactivity, inadequate sun exposure, and protein malnutrition secondary to achalasia. Considering ubiquitous ALADIN expression, low BMD/osteoporosis may be a primary phenotypic feature of the disease. Besides optimizing glucocorticoid dose, physical activity, adequate sun exposure, appropriate nutrition, and vitamin D supplementation, therapy with DHEA should be considered.

TP53 mutational status is predictive of pazopanib response in advanced sarcomas.

BACKGROUND: To investigate whether TP53 DNA mutational status impacts progression-free survival (PFS) in patients with advanced sarcomas (soft tissue sarcoma) treated with vascular endothelial growth factor receptors (VEGFR) inhibition. PATIENTS AND METHODS: We retrospectively reviewed 19 cases of patients treated at the Ohio State James Comprehensive Cancer Center with advanced sarcoma treated with VEGFR inhibition who also had next-generation sequencing of their tumors (via FoundationOne Heme panel). We evaluated TP53 as well as mutations that were observed in at least 20% of patients and evaluated its contribution to PFS using the Kaplan-Meier survival analysis of available radiology end points. RESULTS: Mutations that were observed in at least 20% of patients included TP53 and Rb1. Only TP53 was predictive of PFS in the context of VEGFR inhibition. The PFS of patients with TP53 mutations was significantly greater than TP53 wild-type tumors with the median PFS of 208 versus 136 days, respectively [P = 0.036, hazards ratio 0.38 (95% confidence interval 0.09-0.83)]. CONCLUSIONS: Mutations in TP53 may serve as a predictive biomarker of response to VEGFR inhibition in patients with advanced sarcoma. Larger, prospective studies are necessary to confirm these findings.

Serum testosterone and urinary excretion of steroid hormone metabolites after administration of a high-dose zinc supplement.

OBJECTIVES: To investigate whether the administration of the zinc-containing nutritional supplement ZMA causes an increase of serum testosterone levels, which is an often claimed effect in advertising for such products; to monitor the urinary excretion of testosterone and selected steroid hormone metabolites to detect potential changes in the excretion patterns of ZMA users. SUBJECTS: Fourteen healthy, regularly exercising men aged 22-33 years with a baseline zinc intake between 11.9 and 23.2 mg day(-1) prior to the study. RESULTS: Supplementation of ZMA significantly increased serum zinc (P=0.031) and urinary zinc excretion (P=0.035). Urinary pH (P=0.011) and urine flow (P=0.045) were also elevated in the subjects using ZMA. No significant changes in serum total and serum free testosterone were observed in response to ZMA use. Also, the urinary excretion pattern of testosterone metabolites was not significantly altered in ZMA users. CONCLUSIONS: The present data suggest that the use of ZMA has no significant effects regarding serum testosterone levels and the metabolism of testosterone in subjects who consume a zinc-sufficient diet.

Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use.

BACKGROUND: The serum total homocysteine concentration (tHcy), an indicator of folate status and a possible risk factor for vascular disease, is elevated with impaired renal function and poor vitamin B-12 status, which are common in the elderly. OBJECTIVE: Our objective was to determine the association between tHcy, folate intake, alcohol consumption, and other lifestyle factors in elderly persons. DESIGN: This cross-sectional study used linear regression to model changes in tHcy. Subjects were 278 men and women aged 66-94 y studied in 1993. RESULTS: Total folate intake was negatively associated with tHcy in models adjusted for age, sex, serum creatinine, and serum albumin. We found an interaction between food folate intake and supplement use. Food folate intake had an inverse dose-response relation with tHcy that was limited to nonusers of supplements. Predicted tHcy was 1.5 micromol/L lower in users of supplements containing folate and vitamin B-12 than in nonusers and was independent of food folate intake. We found a positive dose-response relation of coffee and tea intake with tHcy, a positive association for alcohol intake of > or = 60 drinks/mo compared with low intake, and an interaction of alcohol use with folate intake and supplement use. Compared with alcohol users, nonusers had higher predicted tHcy and a lower inverse dose-response relation of food folate intake with tHcy. CONCLUSIONS: The inverse association between folate intake and tHcy was strongest among nonusers of supplements and among alcohol drinkers. Identifying modifiable factors related to tHcy, a possible risk factor for vascular disease, is especially important in elderly persons.

9 clinical cases of nonhealing pressure ulcers in patients with spinal cord injury treated with an anabolic agent: a therapeutic trial.

Anabolic steroid agents may potentially promote wound healing in individuals with spinal cord injury who have long-standing wounds. Nine patients hospitalized on the Spinal Cord Injury Service of the VA Medical Center, Bronx, NY, received treatment with an anabolic agent and amino acid supplement. Selection of patients was based on having at least 1 of the following criteria: (1) nonhealing pressure ulcer of at least 2 months' duration with no change or worsening status, and/or (2) full-thickness pressure ulcer through fascia into muscle, tendon, or bone. Previous and current pressure ulcer histories were determined by review of the hospital records when available and/or self-reporting by the patient. Eight of 9 patients had nonhealing wounds of 2 months' to 5 years' duration. One patient was included because of having a large, full-thickness pressure ulcer of reportedly 2 weeks' duration. Except for 1 Stage III pressure ulcer, all others had Stage IV pressure ulcers.Three patients had documented weight loss (>10% of total body weight), 3 had no recent weight loss, and 3 refused to be weighed. Patients were treated from 1 to 12 months with oxandrolone (20 mg/day) and glutamine (20 g/day). Eight of 9 patients completely healed: 3 after 3 months, 2 after 4 months, 1 after 6 months, and 2 after 12 months of treatment. One patient was discharged against medical advice after 1 month of treatment with a healing wound and was lost to follow-up. Although clinical case studies have limited usefulness for determining effectiveness of drug therapy on wound healing, these initial observations of successful treatment with an anabolic agent and amino acid supplement have been encouraging.

Serum vitamin B12, C and folate concentrations in the New Mexico elder health survey: correlations with cognitive and affective functions.

OBJECTIVES: 1) To compare serum vitamin B12, C and folate concentrations in a randomly selected sample of elderly (age 65 years or older) male and female Hispanics and nonHispanic whites (NHW) and 2) to examine associations between serum B12, C and folate concentrations compared to measures of cognitive and affective (depression) functions. METHODS: Equal numbers of male and female Hispanics and NHW were randomly sampled from the Health Care Financing Administration (Medicare) registrant list for Bernalillo County, New Mexico, and asked to volunteer for a paid home interview followed by a paid comprehensive interview/examination covering health and health-related issues. In addition to serum determinations of B12, C and folate, associations were examined between these vitamins and measures of cognitive and affective functions. RESULTS: Males and Hispanics had lower serum vitamin B12, C and folate concentrations than females and NHW respectively. Participants taking a multivitamin supplement (MVI) had higher serum vitamin concentrations than those not taking MVI. There were significant associations between serum folate concentrations and measures of cognitive function, not seen with B12 or C, nor between any of the vitamins and affective function. CONCLUSIONS: Hispanics, even after adjustments for gender, age, vitamin supplementation, vitamin content of dietary foods, education and household income, had lower serum concentrations of B12, C and folate than NHW. The most significant associations observed were those between serum folate and various measures of cognitive function, even after adjusting for presence of depression.

Folate nutrition and older adults: challenges and opportunities.

Folate fortification of bread and grains has been directed to prevent neural tube birth defects. Research has also challenged previous concepts of folate nutritional status and suggested that folate may play a role in reducing the risk of vascular disease. Although folate status of many elderly people is adequate according to traditional, hematologic criteria, some elderly persons have elevated blood concentrations of the metabolite homocysteine, which indicates subclinical deficiency of folate or vitamin B-12. Higher homocysteine concentrations, even within the normal range, are associated with increased risk of vascular disease. Elderly people with better folate and vitamin B-12 status have lower homocysteine concentrations and may have lower risk for vascular disease. Although the new folate fortification rules provide the benefit of increasing folate in the food supply, they could be a risk for the elderly because excess folate intake can mask vitamin B-12 deficiency, thereby delaying diagnosis. Elderly people have a higher prevalence of vitamin B-12 deficiency as a result of absorption problems. Those deficient in vitamin B-12 should be treated to prevent irreversible neurologic damage. Modern approaches to screening the elderly include using higher cutoff points for serum vitamin B-12 and obtaining blood concentrations of the metabolite methylmalonic acid, which is elevated in deficiency of vitamin B-12 but not folate. To examine current folate intake and food sources, food frequency questionnaires were administered to 308 elderly volunteers aged 65 to 94 years. Mean (+/-standard error) folate intake from food was 299.6+/-5.8 microg/day. Supplements (median dose=400 microg/day) were consumed by 47% of participants. Only 3.2% of the sample had total folate intake greater than 1,000 microg/day, the recommended upper limit, and these were taking high-dose folate supplements (> or = 800 microg/day). Breakfast cereals provided 25.6% of folate intake; vegetables, 23.2%; fruit, 20.8%; refined breads/grains, 6.7%; dark bread, 5.0%; legumes/nuts, 5.9%; dairy products, 5.8%; meat/poultry/fish/eggs, 5.1%; other, 1.9%. Mean folate intake would increase 16.5% if enriched bread and grains were fortified. Such fortification could help some persons to lower serum homocysteine concentration and vascular disease risk. Dietitians should be aware of modern protocols for screening the elderly for vitamin B-12 deficiency.

Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessment.

Associations between nutritional status and cognitive performance were examined in 137 elderly (aged 66-90 y) community residents. Participants were well-educated, adequately nourished, and free of significant cognitive impairment. Performance on cognitive tests in 1986 was related to both past (1980) and concurrent (1986) nutritional status. Several significant associations (P < 0.05) were observed between cognition and concurrent vitamin status, including better abstraction performance with higher biochemical status and dietary intake of thiamine, riboflavin, niacin, and folate (rs = 0.19-0.29) and better visuospatial performance with higher plasma ascorbate (r = 0.22). Concurrent dietary protein in 1986 correlated significantly (rs = 0.25-0.26) with memory scores, and serum albumin or transferrin with memory, visuospatial, or abstraction scores (rs = 0.18-0.22). Higher past intake of vitamins E, A, B-6, and B-12 was related to better performance on visuospatial recall and/or abstraction tests (rs = 0.19-0.28). Use of self-selected vitamin supplements was associated with better performance on a difficult visuospatial test and an abstraction test. Although associations were relatively weak in this well-nourished and cognitively intact sample, the pattern of outcomes suggests some direction for further research on cognition-nutrition associations in aging.

Vitamin supplementation and other variables affecting serum homocysteine and methylmalonic acid concentrations in elderly men and women.

OBJECTIVE: An elevated serum concentration of the metabolite, homocysteine (Hcys): 1) can indicate folate or vitamin B12 deficiency, 2) is an independent risk factor for vascular disease. The metabolite, methylmalonic acid (MMA), is elevated in deficiency of vitamin B12, but not folate. The purpose of this study was to determine the effect of self-selected vitamin supplementation and other variables on serum Hcys and MMA concentrations in elderly men and women. METHODS: Serum concentrations of Hcys, MMA, folate and vitamin B12 were measured for elderly volunteers, age 68-96 years, and compared for those consuming (26 men, 25 women) and not consuming (24 men, 25 women) self-selected vitamin supplements. RESULTS: Compared with the nonsupplemented group, the supplemented group had lower mean serum MMA (208 +/- 162 vs. 241 +/- 98 nmol/L [+/- SD]) and Hcys (9.5 +/- 2.6 vs. 11.2 +/- 2.7 mumol/L); and higher serum vitamin B12 (391 +/- 174 vs 292 +/- 107 pmol/L), and serum folate (46 +/- 15 vs. 24 +/- 10 nmol/L) p < 0.05. Among all 100 subjects, the prevalence of serum vitamin B12 < 221 pmol/L (300 pg/mL) was 18; MMA > 271 nmol/L, 16; Hcys > 16.2 mumol/L, 3; folate < 5.0 nmol/L, none. Based on serum vitamin B12 < 221 nmol/L with elevated serum MMA, vitamin B12 deficiency was probable in seven subjects, of whom two were supplemented. All three subjects with elevated serum Hcys had elevated serum MMA as well, suggesting vitamin B12 deficiency or renal insufficiency. A stepwise linear regression model for serum Hcys explained 61.7% of the variance, and included (in order) serum creatinine, folate, vitamin B12, albumin, age and body mass index (BMI). A model with serum MMA replacing serum vitamin B12 explained 64.1% of the variance in serum Hcys. Folate did not enter the model for supplemented subjects, supporting a "threshold effect": serum Hcys was inversely related to serum folate at lower serum folate (nonsupplemented subjects), but at higher serum folate (supplemented subjects), the relationship was flat. In supplemented subjects, serum Hcys was still related to vitamin B12 status, confirming that tissue deficiency of the vitamin was present. CONCLUSIONS: Results showed potential usefulness of serum MMA and Hcys in identifying subclinical or tissue deficiency of vitamin B12. Clinicians should be aware of the risk of vitamin B12 deficiency in older people and of current screening algorithms using serum metabolites. These elderly volunteers had generally good folate status; nevertheless, some subjects seemed likely to benefit from an improvement in folate status that would reduce their serum Hcys within the normal range. The role of serum creatinine in the normal range in predicting serum Hcys, a vascular disease risk factor, remains unexplained.

Iron stores and iron absorption: effects of repeated blood donations.

We assessed changes in iron stores and iron absorption after repeat blood donations using a combination of biochemical measures of iron status: ferritin, hemoglobin, and transferrin saturation. Thirty-six volunteers with a mean (+/- SD) age of 67.7 +/- 3.7 y donated an average of 15 units of blood over 3.5 y. Initial iron stores were 12.45 +/- 3.09 mg/kg for men and 12.53 +/- 3.24 mg/kg for women. Of the 20 men and 16 women who completed the study, 6 men and 10 women were taking a self-selected supplement providing approximately 20 mg Fe/d. Dietary iron intake was determined to be approximately 20 mg/d for men and approximately 18 mg/d for women. Decreases in iron stores in supplemented men were not significantly different from those in nonsupplemented men: 9.52 +/- 2.57 and 11.31 +/- 2.74 mg/kg, respectively. Nonsupplemented women showed a significantly (P < 0.05) greater decline in iron stores than did supplemented women: 13.09 +/- 2.46 and 10.60 +/- 4.15 mg/kg, respectively. Mean maximal iron absorption was approximately 4.10 mg/d for men and approximately 3.55 mg/d for women regardless of iron intake.

A prospective study of blood donations in healthy elderly persons.

Iron stores were observed in 57 healthy elderly volunteers, between 63 and 77 years of age, who donated 5 units of blood over approximately 1 year. An equal number of nondonors who contributed approximately 7 mL of blood at each visit for iron status measurements only were seen at the same frequency as the donor population. At entrance to the study, iron stores in women and men averaged 724 and 875 mg, respectively. After five donations, mean iron stores dropped to 67 mg in women (n = 27) and 362 mg in men (n = 30); four women (15%) became iron deficient, while two (7%) developed iron deficiency anemia. Three men (10%) developed iron deficiency, but none were found to be anemic. Mean intakes of iron were 23.3 and 22.5 mg per day, respectively, for women and men. Iron intakes were adequate to meet iron requirements of nondonors, but they were not sufficient to halt the steady decrease in iron stores among the donor population, in whom iron absorption increased from approximately 5 percent at entrance to 14 percent at the time of the fifth donation. In summary, healthy elderly persons may contribute to the national blood resource; however, donations should probably be limited to less than five per year or donors should regularly take an iron supplement to preserve reasonable amounts of iron reserves.

Lycanthropy and demonomania: some psychopathological issues.

Modern reports on lycanthropy mainly concentrate on the content of patients' beliefs in being transformed into an animal. By contrast, an interest in the form of the symptomatology is usually minimal. This paper draws on Karl Jaspers' phenomenological views and focuses on some important albeit neglected psychopathological issues related to form which are relevant to any comprehensive consideration of lycanthropic phenomena.

Calcium and magnesium binding to gamma-carboxyglutamic acid-containing peptides via metal ion nuclear magnetic resonance.

The determination of binding constants of metal ions to biomolecules is approachable via many techniques. Metal ion NMR spectroscopy is an alternative to more traditional techniques and is complementary to them, particularly in investigations of the interactions of metal ions with relatively small peptides containing multiple ionizing groups. The method requires relatively small amounts of material, is fairly fast, and is carried out at equilibrium. Our study has been of calcium and magnesium ion binding to gamma-carboxyglutamic acid (Gla)-containing peptides. Dissociation constants of approximately 0.6 mM for the binding of either metal ion to Z-D-Gla-D-Gla-OMe have been obtained. The procedure for determination of these constants via metal ion NMR is discussed.