Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.

Primary lymphoedema is a rare, autosomal dominant disorder that leads to a disabling and disfiguring swelling of the extremities and, when untreated, tends to worsen with time. Here we link primary human lymphoedema to the FLT4 locus, encoding vascular endothelial growth factor receptor-3 (VEGFR-3), in several families. All disease-associated alleles analysed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation. Our study establishes that VEGFR-3 is important for normal lymphatic vascular function and that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.

Bone health-related factors and the use of bisphosphonates in community setting--15-year follow-up study.

UNLABELLED: The present study investigated the bone health related factors that were associated with the use of bisphosphonates (BP) among 2,050 postmenopausal Finnish women. Low BMD + low trauma energy fracture was the strongest determinant of BP use, while other secondary causes of osteoporosis were less strongly related with BP use. BP use was associated with reduced femoral neck (FN) and lumbar spine (LS) bone loss rate. INTRODUCTION: The aim was to identify bone health related factors associated with the use of BP in a community setting. METHODS: A population-based sample of 2,050 Finnish postmenopausal women was measured with dual X-ray absorptiometry at the FN and LS in 1989, 1994, 1999 and 2004, and information on osteoporosis risk factors, including low-trauma energy fractures, were collected with postal inquiries. Self-reported use of BP in 2004 was considered as the end point variable. RESULTS: Among BP users, 12% had T-score > -2.0 SD and no fracture during follow-up (FU). In women without any bone medication, 26% had T-score < -2.0 SD or low-trauma energy fracture or both during the FU. In BP users, a significant reduction in FN and LS bone loss rate, cumulative with duration of use, was observed in ANCOVA (p < 0.001). Among BP users, there was a significantly higher proportion of women with several independent risk factors for osteoporosis and more spine and humerus fractures but less ankle fractures. T-score < -2 SD combined with low-trauma energy fracture was significantly related to the use of BPs (p < 0.001, OR = 15.96) and T-score < -2 SD was a stronger predictor of BP use (p < 0.001, OR = 13.29) than fracture (p > 0.05, OR = 1.35) in multivariate logistic regression. Other factors related with BP use were vitamin D use (p = 0.001, OR = 2.27), high number of medications (p < 0.001, OR = 1.26) and rheumatoid arthritis (p < 0.05, OR 2.55). CONCLUSIONS: These findings reveal the recent bone health-related indications for BP prescription.

Effect of calcium and vitamin D supplementation on bone mineral density in women aged 65-71 years: a 3-year randomized population-based trial (OSTPRE-FPS).

SUMMARY: The Osteoporosis Risk Factor and Prevention-Fracture Prevention Study (OSTPRE-FPS) was a randomized population-based open trial (n = 593). The supplementation group (n = 287) received daily cholecalciferol 800 IU + calcium 1,000 mg for 3 years while the control group (n = 306) received neither supplementation nor placebo. Daily vitamin D and calcium supplementation have a positive effect on the skeleton in ambulatory postmenopausal women. INTRODUCTION: vitamin D deficiency is common in the elderly, and vitamin D levels are associated with low bone mineral density (BMD). The working hypothesis was that vitamin D and calcium supplementation could prevent bone loss in ambulatory postmenopausal women. METHODS: the OSTPRE-FPS was a randomized population-based open trial with a 3-year follow-up in 3,432 women (aged 66 to 71 years). A randomly selected subsample of 593 subjects underwent BMD measurements. The supplementation group (n = 287) received daily cholecalciferol 800 IU + calcium 1,000 mg for 3 years while the control group (n = 306) received neither supplementation nor placebo. RESULTS: in the intention-to-treat analysis, total body BMD (n = 362) increased significantly more in the intervention group than in the control group (0.84% vs. 0.19%, p = 0.011). The BMD change differences at the lumbar spine (p = 0.372), femoral neck (p = 0.188), trochanter (p = 0.085), and total proximal femur (p = 0.070) were statistically nonsignificant. Analyses in compliant women (≥ 80% of use) resulted in stronger and statistically significant effects at the total body and femoral regions. CONCLUSION: daily vitamin D and calcium supplementation have a positive effect on the skeleton in ambulatory postmenopausal women with adequate nutritional calcium intake.

Overexpression of VEGF in testis and epididymis causes infertility in transgenic mice: evidence for nonendothelial targets for VEGF.

Vascular endothelial growth factor (VEGF) is a key regulator of endothelial growth and permeability. However, VEGF may also target nonendothelial cells, as VEGF receptors and responsiveness have been detected for example in monocytes, and high concentrations of VEGF have been reported in human semen. In this work we present evidence that overexpression of VEGF in the testis and epididymis of transgenic mice under the mouse mammary tumor virus (MMTV) LTR promoter causes infertility. The testes of the transgenic mice exhibited spermatogenic arrest and increased capillary density. The ductus epididymidis was dilated, containing areas of epithelial hyperplasia. The number of subepithelial capillaries in the epididymis was also increased and these vessels were highly permeable as judged by the detection of extravasated fibrinogen products. Intriguingly, the expression of VEGF receptor-1 (VEGFR-1) was detected in certain spermatogenic cells in addition to vascular endothelium, and both VEGFR-1 and VEGFR-2 were also found in the Leydig cells of the testis. The infertility of the MMTV-VEGF male mice could thus result from VEGF acting on both endothelial and nonendothelial cells of the male genital tract. Taken together, these findings suggest that the VEGF transgene has nonendothelial target cells in the testis and that VEGF may regulate male fertility.

Effects of a low-frequency sound wave therapy programme on functional capacity, blood circulation and bone metabolism in frail old men and women.

OBJECTIVE: To evaluate the effects of a low-frequency sound wave therapy programme on functional capacity, blood circulation and bone metabolism of the frail elderly. DESIGN: Single-blind, randomized, controlled trial. SETTING: Two senior service centres. SUBJECTS: Forty-nine volunteers (14 males and 35 females) aged 62-93 years with up to 12 diagnosed diseases were allocated in either the intervention group (n = 30) or control group (n = 19). INTERVENTION: The intervention group underwent sound wave therapy, 3-5 times a week for 30 minutes per session over a period of 6 months. The control group received no intervention. MAIN MEASUREMENTS: Blood pressure, functional capacity, mobility, bone density, biochemical markers, isometric muscle strength, balance, and skin surface temperature. RESULTS: Compared with the control group, the intervention group's mobility and the amount of self-reported kilometres walked per week increased by 3 km (P<0.05), while levels of cholesterol (4.97 (0.72) to 4.52 (0.65) mmol/L, P =0.019), low-density lipoprotein (2.82 (0.72) to 2.45 (0.61) mmol/L, P =0.022), bone markers of total osteocalcin (11.0 (6.5) to 10.3 (5.9) ng/mL, P =0.048)) and tartrate-resistant acid phosphatase isoform 5b (2.50 (1.0) to 2.41 (1.1) IU/L, P =0.021)) decreased. The average skin surface temperature was significantly higher during active sessions at the end of the intervention than in the beginning (P = 0.004). No change was found during placebo sessions. CONCLUSIONS: Low-frequency sound wave therapy may have the potential to promote well-being of frail elderly subjects via improved functional capacity, especially in subjects who are too frail to undertake exercise.

Selenium speciation and bioavailability in biofortified products using species-unspecific isotope dilution and reverse phase ion pairing-inductively coupled plasma-mass spectrometry.

In some regions of the world, where the bioavailability of selenium (Se) in soil is low and/or declining (e.g., due to use of high-sulfur fertilizers), there is increased risk of adverse affects on animals and human health. In recent years, increased research attention has focused on understanding the relationships between Se contents in foods and supplements and their nutritional benefits for animal and humans. The objective of this study was to use a species-unspecific isotope dilution and reverse phase ion pairing-inductively coupled plasma-mass spectrometry techniques for the identification and quantification of Se species in biofortified grains (i.e., wheat and triticale), flour, and wheat biscuits. The information on Se species was used to gain an understanding of the bioavailability of Se in biofortified and process-fortified wheat biscuits used in a clinical trail. The major Se species identified in biofortified and process-fortified samples were selenomethionine (76-85%) and selenomethionine selenoxide (51-60%), respectively. Total plasma Se concentrations in the biofortified Se exposure group were found to increase throughout the 6 month trial period (mean=122 microg L(-1) at 0 months to 194 microg L(-1) at 6 months). In contrast, the trial group exposed to process-fortified Se biscuits showed little increase in mean total Se plasma concentrations until 4 months of exposure (mean=122 microg L(-1) at 0 months to 140 microg L(-1) at 4 months) that remained constant until the end of the trial period (mean=140 microg L(-1) at 4 months to 138 microg L(-1) at 6 months). The difference in total Se plasma concentrations may be due to the presence and bioavailability of different Se species in biofortified and process-fortified biscuits. An understanding of Se speciation in foods enables better understanding of pathways and their potential benefits for animals and humans.

Primary reconstruction of orbital fractures using patient-specific titanium milled implants: the Helsinki protocol.

Preoperative virtual planning and the use of patient-specific implants enable exact reconstruction of orbital fractures. We present our results and experience of reconstruction of isolated orbital fractures with patient-specific implants, according to the Helsinki protocol, in 15 patients who were followed up for at least three months postoperatively. The mean (range) difference between the positions of virtually planned, and postoperative, implants was 1.9 (0.5-5.6) mm. The postoperative volume of the fractured orbit was 1.34ml less than that of the non-fractured side, but this was not clinically relevant. None of the patients required reoperation and none had any implant-related complications during follow up. We conclude that patient-specific implants are an adaptable and reliable treatment for primary orbital trauma, and that the Helsinki protocol may have wider applications in the treatment of facial fractures.

Safety aspects and cholesterol-lowering efficacy of low fat dairy products containing plant sterols.

OBJECTIVE: The aim of this study was to investigate whether a plant sterol mixture would reduce serum cholesterol when added to low fat dairy products in subjects with hypercholesterolaemia, and to examine the effects of the mixture on the serum plant sterol and fat-soluble vitamin levels. DESIGN: A parallel, double-blind study. SETTING: The study was performed in three different locations in Finland. SUBJECTS: In total, 164 mildly or moderately hypercholesterolaemic subjects participated in the study. METHODS: The subjects were randomly divided into two groups: a plant sterol group and a control group. The subjects consumed the products for 6 weeks after a 3-week run-in period. The targeted plant sterol intake was 2 g/day in the sterol group. RESULTS: During the treatment period, there was a 6.5% reduction in serum total cholesterol in the sterol group while no change was observed in the control group (P<0.0005). Serum low-density lipoprotein (LDL) cholesterol was reduced by 10.4% in the sterol group and by 0.6% in the control group (P<0.00005). There was no change during the trial in serum high-density lipoprotein (HDL) cholesterol or triacylglycerol concentrations. The HDL/LDL cholesterol ratio increased by 16.1% in the sterol group and by 4.3% in the control group (P=0.0001). Serum plant sterol levels increased significantly (P=0.0001) in the sterol group. None of the fat-soluble vitamin levels decreased significantly when changes in serum total cholesterol were taken into account. The hypocholesterolaemic effect of sterol administration was not influenced by apolipoprotein E phenotype. CONCLUSIONS: Yoghurt, low-fat hard cheese and low-fat fresh cheese enriched with a plant sterol mixture reduced serum cholesterol in hypercholesterolaemic subjects and no adverse effects were noted in the dietary control of hypercholesterolaemia.

Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth.

Many solid tumors produce vascular endothelial growth factor C (VEGF-C), and its receptor, VEGFR-3, is expressed in tumor blood vessels. To study the role of VEGF-C in tumorigenesis, we implanted MCF-7 human breast carcinoma cells overexpressing recombinant VEGF-C orthotopically into severe combined immunodeficient mice. VEGF-C increased tumor growth, but unlike VEGF, it had little effect on tumor angiogenesis. Instead, VEGF-C strongly promoted the growth of tumor-associated lymphatic vessels, which in the tumor periphery were commonly infiltrated with the tumor cells. These effects of VEGF-C were inhibited by a soluble VEGFR-3 fusion protein. Our data suggest that VEGF-C facilitates tumor metastasis via the lymphatic vessels and that tumor spread can be inhibited by blocking the interaction between VEGF-C and its receptor.

Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis.

VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR-3 (Flt4) are endothelial specific receptor tyrosine kinases, regulated by members of the vascular endothelial growth factor family. VEGFRs are indispensable for embryonic vascular development, and are involved in the regulation of many aspects of physiological and pathological angiogenesis. VEGF-C and VEGF-D, as ligands for VEGFR-3 are also capable of stimulating lymphangiogenesis and at least VEGF-C can enhance lymphatic metastasis. Recent studies have shown that missense mutations within the VEGFR-3 tyrosine kinase domain are associated with human hereditary lymphedema, suggesting an important role for this receptor in the development of the lymphatic vasculature.

Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response.

Endothelial receptor tyrosine kinases (RTKs) and their signaling mechanisms are of interest because they may control tumor angiogenesis and thereby tumor growth. In this report we have examined activation of the signal transducers and activators of transcription (STATs) by the three known vascular endothelial growth factor receptors (VEGFR1-3), as well as by the endothelial Tie-1 and -2 receptors. We also studied signaling by the R849W mutant of Tie-2 (MTie-2), which has been shown to cause venous malformations. When overexpressed in 293T cells, MTie-2 activated STAT1 while the other endothelial RTKs failed to do so. In contrast, the three VEGFRs were strong activators of STAT3 and STAT5, suggesting that they activate only a specific subset of these signal transducers. STAT3 and STAT5 were also activated by Tie-2 and, more so, by MTie-2. Tyrosine phosphorylation and DNA binding of STATs correlated with their ability to activate transcription as judged by luciferase assays. When co-expressed with STAT5, VEGFR-1 as well as both the Tie-2 receptor forms increased expression of the cell cycle inhibitor p21. Interestingly, co-expression of the Tie-2 receptors with STAT1 resulted in appearance of a novel, p21 related transcript. Taken together, these findings identify STAT proteins as novel targets for signal transduction by the endothelial RTKs, suggesting that they may be involved in the regulation of endothelial function.

Molecular regulation of lymphangiogenesis and targets for tissue oedema.

New insight has recently been obtained into the molecular mechanisms regulating the function of lymphatic endothelial cells. Vascular endothelial growth factors-C and -D have been shown to stimulate lymphangiogenesis, and their receptor VEGFR-3 has been linked to human hereditary lymphoedema, although there is evidence that other genes are also involved. These data suggest that it may become possible to stimulate lymphatic growth and function and to treat tissue oedema involved in many diseases.

A 7-week reduction in salt intake does not contribute to markers of bone metabolism in young healthy subjects.

BACKGROUND: Sodium intake increases urinary calcium excretion and may thus lead to negative calcium balance and bone loss. OBJECTIVE: We hypothesised that reducing sodium intake would reduce urinary calcium excretion and have a beneficial influence in bone metabolism. DESIGN: A total of 29 subjects, 14 males and 15 females, were divided into two study groups. One group (low-sodium group (LS)) reduced sodium intake for 7 weeks by substituting low-salt alternatives for the most important dietary sources of sodium. The other group, serving as a control group (C), was given the same food items in the form of normally salted alternatives. Fasting serum samples as well as 24-h urine samples were obtained in the beginning and at the end of the study. Urinary sodium, urinary calcium, urinary creatinine, serum calcium, serum phosphate, serum creatinine, serum parathyroid hormone (s-PTH), serum C-terminal telopeptides of Type-I collagen and serum bone alkaline phosphatase (s-B-ALP) were analysed. RESULTS: The LS group showed a significant decline (P = 0.001) in urinary sodium/creatinine ratio without a significant effect on urinary calcium/creatinine ratio. In the LS group, s-PTH increased (P = 0.03). The C group showed an increase in s-PTH (P = 0.05) and in s-B-ALP, but no differences were observed between the study groups in the changes of serum markers of calcium and bone metabolism. CONCLUSIONS: We have shown that reducing the sodium intake of young, healthy people with adequate calcium intake over a 7-week period does not affect the markers of bone metabolism.

Teenage girls and elderly women living in northern Europe have low winter vitamin D status.

OBJECTIVE: To determine the vitamin D status (serum 25-hydroxyvitamin D; S-25OHD) in adolescent girls and elderly community-dwelling women living in four countries of northern Europe and to explain differences in S-25OHD concentrations between and within the countries. DESIGN: A cross-sectional observational study conducted in a standardised way during February-March. S-25OHD was analysed by high-performance liquid chromatography. Vitamin D and calcium intake was calculated using a standardised food composition database. SETTING: Denmark, Finland, Ireland, and Poland. SUBJECTS: A total of 199 girls (mean (s.d.) age 12.6 (0.5) y) and 221 women (mean (s.d.) age 71.8 (1.4) y). RESULTS: The median (inter quartiles) concentration of S-25OHD was 29.4 (20.3, 38.3) nmol/l for the girls and 40.7 (28.0, 54.2) nmol/l for the women. S-25OHD below 25 nmol/l was found in 37% of the girls and 17% of the women, and S-25OHD below 50 nmol/l was found in 92% of the girls and 37% of the women. Positive significant determinants for S-25OHD in girls were use of vitamin D supplements, and in women sun habits, dietary vitamin D intake, use of vitamin D and calcium supplements. Body mass index and smoking were negative determinants in women. For women predictors could explain the differences between countries (P(country) = 0.09, R(2) = 0.39), but for girls the difference remained significant even after including predictors (P(country) = 0.03, R(2) = 0.15). CONCLUSION: Vitamin D status is low in northern Europe during winter. More than one-third of the adolescent girls have vitamin D status below 25 nmol/l and almost all are below 50 nmol/l. Two-thirds of the elderly community-dwelling women have vitamin D status below 50 nmol/l. Use of vitamin D supplements is a significant positive determinant for S-25OHD for both girls and women (P = 0.001). SPONSORSHIP: The European Fifth Framework Programme (Contract No. QLK1-CT-2000-00623).

Vascular endothelial growth factor-C: a growth factor for lymphatic and blood vascular endothelial cells.

The endothelial cells lining all vessels of the circulatory system have been recognized as key players in a variety of physiological and pathological settings. They act as regulators of vascular tone via the inducible nitric oxide system and in angiogenesis, the formation of blood vessels de novo. Aberrant regulation of endothelial cells contributes to tumor formation, atherosclerosis, and diseases such as psoriasis and rheumatoid arthritis. Among the most recently discovered growth factors for endothelial cells are newly isolated members of the platelet-derived growth factor/vascular endothelial growth factor (VEGF) family, VEGF-B, VEGF-C, and VEGF-D. VEGF-C is the ligand for the receptor tyrosine kinase VEGFR-3 (also known as Flt4), which is expressed predominantly in lymphatic endothelium of adult tissues, but a proteolytically processed form of VEGF-C can also activate VEGFR-2 of blood vessels. The lymphatic vessels have been known since the 17th century, but their specific roles in health and disease are still poorly understood. With the discovery of VEGF-C and its cognate receptor VEGFR-3, the regulation and functions of this important component of the circulatory system can be investigated.

An acute intake of phosphate increases parathyroid hormone secretion and inhibits bone formation in young women.

We studied the effects of a single oral phosphate (Pi) dose as well as those of three consecutive oral phosphate doses on calcium and bone metabolism. In the first part of the study (P1 study) 10 female volunteers were given orally 1500 mg of Pi in water, as a single dose, or plain water in randomized order at two different sessions. In the second part of the study (P3 study), 10 female volunteers were given orally 1500 mg of Pi, as three separate 500 mg doses in water, or plain water in randomized order. Calcium and bone metabolism was monitored for 24 h by measuring the concentrations of serum ionized calcium (S-iCa), urinary calcium, serum phosphate (S-P), urinary P, serum intact parathyroid hormone (PTH), serum carboxy-terminal propeptide of type I collagen (PICP), serum osteocalcin (BGP), serum carboxy-terminal telopeptide of type I collagen (ICTP), urine deoxypyridinoline (DPD) and bone-specific alkaline phosphatase activity (B-ALP). The S-P increased (p = 0.00005 and p = 0.0005, in the P1 and P3 studies, respectively), the S-iCa concentration declined significantly only in the P1 study (p = 0.0014), the urinary calcium excretion decreased (p = 0.02 and 0.013, in the P1 and P3 studies, respectively), and the PTH concentration rose (p = 0.0083 and p = 0.014, in the P1 and P3 studies, respectively) during the phosphate experiment as compared with the control session. Of the three markers of bone formation studied, PICP declined in the P1 study (p = 0.04), and B-ALP declined in both parts of the study (p = 0.027, p = 0.026, in the P1 and P3 studies, respectively) after phosphate administration, whereas there was no significant change in BGP in either of the studies. The markers of bone resorption, ICTP and DPD, were unaffected by the phosphate load in both studies. In conclusion, acute ingestion of phosphate leads to an increase in S-P, a decrease in S-iCa, and an increase in intact PTH secretion. Our results indicate that these events may lead to an acute inactivation of the early phases of bone formation. In this setting, there was no indication of enhanced bone resorption despite the increase in PTH secretion, which could be due to the combined effect of phosphate and PTH on bone resorption.

Vitamin D deficiency and bone health in healthy adults in Finland: could this be a concern in other parts of Europe?

A low vitamin D status could be a concern not only in children and the elderly in Europe, but also in adults. We do not know the effect of mild vitamin D deficiency on bone in this age group. The aim of this study was to detect the prevalence of low serum 25-hydroxyvitamin D [S-25(OH)D] and elevated serum intact parathyroid hormone (S-iPTH) concentrations in healthy young adults in the winter in northern Europe and to characterize the determinants of these variables. In addition, we studied the association between vitamin D status and forearm bone mineral density (BMD) in this population group. Three hundred and twenty-eight healthy adults (202 women and 126 men, 31-43 years) from southern Finland (60 degrees N) participated in this study conducted in February through March 1998. Fasting overnight blood samples were collected in the morning. Forearm BMD was measured by dual-energy X-ray absorptiometry (DXA). The mean daily vitamin D intake met the recommendations in the men (5.6 +/- 3.2 microg) and almost met it in the women (4.7 +/- 2.5 microg). The mean S-25(OH)D concentrations did not differ between genders (women, 47 +/- 34 nM; men, 45 +/- 35 nM; mean +/- SD), but the women had significantly higher mean S-iPTH levels than the men (women, 30 +/- 13 ng/liter; men, 24 +/- 12 ng/liter; p < 0.001). Low S-25(OH)D concentrations (<25 nM) were found in 26.2% of the women (53 women) and 28.6% of the men (36 men), respectively. Based on nonlinear regression analysis between S-25(OH)D and S-iPTH concentration, the S-iPTH concentration started to increase with S-25(OH)D concentrations lower than approximately 80 nM in the women and lower than approximately 40 nM in the men. Based on this relation between S-25(OH)D and S-iPTH concentrations, 86% of the women and 56% of the men had an insufficient vitamin D status. In linear regression analysis, the main positive determinants of S-25(OH)D were dietary vitamin D intake (p < 0.02), the use of supplements (p < 0.005), alcohol intake (p < 0.05), and age (p < 0.005). Smoking associated negatively with the S-25(OH)D concentration (p < 0.03). The main determinants of S-iPTH were S-25(OH)D (p < 0.01), dietary calcium intake (p < 0.02), and body mass index (BMI; p < 0.01). In addition, female gender was associated with higher S-iPTH concentration. The mean daily dietary calcium intake was 1,037 +/- 489 mg and 962 +/- 423 mg, in the men and women, respectively. Significantly lower forearm BMD was found in the men (p = 0.01) but not in the women (p = 0.14) with higher S-iPTH concentrations. Low vitamin D status was prevalent in these young adults in northern Europe in winter, although the vitamin D intake met the recommendation. This probably is not a local problem for northern Europe, because the natural sources of vitamin D are scarce and fortification is not very common in Europe, and with the exception of the southern part of Europe, sunshine is not very abundant in this part of the world. Thus, the results of this study indicate that more attention should be focused on vitamin D status and the sources of vitamin D in these countries.

Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs.

In patients on antiepileptic drugs, bone loss has been mainly demonstrated at radial sites using old technology and has been ascribed to drug-induced vitamin D deficiency rather than to any direct effects of the treatment on bone cells. We examined 38 epileptic patients (24 women and 14 men) aged 20-49 years who were using either carbamazepine or phenytoin or both. Bone mineral density (BMD) at the lumbar spine and three femoral sites was measured by dual-energy x-ray absorptiometry (DXA) and serum and urine markers of bone and mineral metabolism were determined. The latter included the C-terminal extension peptide of type I procollagen (PICP), a putative serum marker of bone formation, and the cross-linked carboxyl-terminal telopeptide of human type I collagen (ICTP), a novel serum marker of bone matrix degradation. In female patients on phenytoin, weight- and height-adjusted BMD was reduced at the femoral neck and the Ward's triangle (p < 0.05) but was at the control level in the other patient groups at all four measurement sites. Compared with controls, the serum concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were reduced by 26% (p < 0.01) and by 27% (p < 0.001) in female patients. These changes were independent of the therapy used. They were not present in male patients. For both genders the serum levels of vitamin D binding protein were normal. Both female and male patients had hypocalcemia, but women only showed hypocalciuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Postprandial parathyroid hormone response to four calcium-rich foodstuffs.

We studied the effects of four calcium-rich foodstuffs on postprandial parathyroid hormone secretion. Four hundred milligrams calcium from either Emmental cheese, milk, sesame seeds, spinach, or calcium salt (calcium lactate gluconate + calcium carbonate) or no additional calcium (control session) were given to nine female volunteers immediately after a first blood sample (at 0900) in random order with a light standardized meal containing 37 mg Ca. Blood samples were taken at 0900 (before the calcium load), 1000, 1100, 1300, and 1500 at every study session. Urine was collected during the sessions. Serum ionized calcium, phosphate, magnesium, intact parathyroid hormone, and urinary calcium excretion were measured. The serum ionized calcium concentration increased significantly after ingesting cheese (P = 0.004, contrast analysis) or calcium salt (P = 0.05, contrast analysis) compared with the control session. Compared with the control session, the serum phosphate concentration increased after the cheese session (P = 0.004, contrast analysis) and after the milk session (P = 0.02, contrast analysis). Calcium salt (P = 0.007, contrast analysis) and cheese (P = 0.002, contrast analysis) caused a significant decline in serum intact parathyroid hormone compared with the control session. The urinary calcium excretion with cheese was 141% (P = 0.001), with milk was 107% (P = 0.004), and with calcium salt was 75% (P = 0.02) above that of the control session. Our results show that calcium from sesame seeds and spinach does not cause an acute response in calcium metabolism. Our results indicate that fermented cheese could be a better dietary source of calcium than milk when the metabolic effects of the foodstuffs are considered.

Low serum 25-hydroxyvitamin D concentrations and secondary hyperparathyroidism in middle-aged white strict vegetarians.

The vitamin D status of vegetarians was studied in the winter. The groups studied were strict vegetarians (G1), lactovegetarians (G2), lactoovovegetarians eating some fish (G3), and vegetarians who were taking vitamin D supplements or who had been exposed to abundant sunlight during the last 6 mo (G4). A group of healthy women served as control subjects (C). The serum 25-hydroxyvitamin D [25(OH)D] concentration was significantly lower, the serum intact parathyroid hormone (S-iPTH) concentration significantly higher, and the dietary vitamin D intake significantly lower in G1 than in C. S-iPTH correlated negatively with serum 25(OH)D and dietary calcium intake. In conclusion, white strict vegetarians are at risk of vitamin D deficiency, at least in the winter, primarily because of a low dietary vitamin D intake, despite a normal sunlight exposure in summer. Low serum 25(OH)D concentrations are accompanied by high S-iPTH concentrations, which also are affected by a low calcium intake. The effect of these changes on bone health remains to be evaluated.