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Christian Meier

Publications and source records attributed to Christian Meier.

At least 19 recordsLinked to original sources
PubMed2006

Repeated measurement of pregnancy-associated plasma protein-A (PAPP-A) in Down syndrome screening: a validation study.

OBJECTIVES: To confirm that measuring pregnancy-associated plasma protein-A (PAPP-A) in both first- and second-trimester serum samples improves Down syndrome screening. METHODS: We selected paired first- and second-trimester stored serum samples from 34 Down syndrome pregnancies (cases) and 514 unaffected pregnancies (controls) and tested the second-trimester samples for PAPP-A and dimeric inhibin-A (DIA). First-trimester PAPP-A measurements were already available, as were second-trimester measurements of alpha-fetoprotein, unconjugated estriol (uE3), and human chorionic gonadotrophin (hCG). RESULTS: PAPP-A was lower among cases than controls (0.47 MoM) in the first trimester (at an average of 12.5 weeks); in the second trimester, it was not different (0.91 MoM). Using repeated measures of PAPP-A alone, 21 of 34 cases were detected (62%, 95%CI 44% to 78%) with 5% false positives. At an observed 2% false-positive rate, the detection rates (DR) for the quadruple (69%) and serum integrated (69%) tests were lower than for the repeated measures test (75%). Modelled performance at 12 weeks was similar to these observed findings (70, 75, and 82%, respectively). If the first-trimester samples were collected at 10 weeks, however, DR would be higher (70, 81, and 91%, respectively). CONCLUSIONS: Adding a repeated measure of PAPP-A to existing serum markers improves Down syndrome screening to levels that are currently obtainable only by including ultrasound measurement of nuchal translucency (NT). Serum-based screening has the advantages of higher availability and reliability at a lower cost, resulting in a more effective screening strategy. A serum-based repeated measures test has a place in routine Down syndrome screening.

Adult↗
PubMed2006

Use of recombinant human thyroid-stimulating hormone in the management of well-differentiated thyroid cancer.

Recombinant human (rh) thyroid-stimulating hormone (TSH) has changed the care of patients with well-differentiated thyroid cancer (DTC). Traditionally, thyroid hormone withdrawal has been used to increase TSH concentrations for optimising trapping and retention of radioiodine for thyroid remnant ablation and for diagnostic procedures (measurement of thyroglobulin and whole body scan) used in the follow-up of patients with DTC. The resulting hypothyroidism is, however, accompanied by substantial morbidity. rhTSH is an effective and safe alternative to thyroid hormone withdrawal for follow-up of DTC. Its ability to detect persistent or recurrent disease is similar to that of thyroid hormone withdrawal. At the present time, rhTSH is approved for diagnostic monitoring of patients with DTC as well as for pretherapeutic stimulation in low-risk patients for remnant ablation with 100 mCi (131)I (in the EU). In addition, rhTSH has potential for use in facilitating the treatment of metastasis in patients with DTC and in patients with non-toxic nodular goiter; however, more clinical trials are needed to confirm its use in these situations.

Animals↗
PubMed2006

Serum cathepsin K concentrations reflect osteoclastic activity in women with postmenopausal osteoporosis and patients with Paget's disease.

INTRODUCTION: Cathepsin K, a cysteine protease, plays an essential role in osteoclast-mediated collagen degradation. Recently, an immunoassay to quantify cathepsin K in serum has been developed. We assessed the usefulness of serum cathepsin K as a marker of bone turnover in cross-sectional and longitudinal studies of patients with metabolic bone disease. METHODS: The study cohort consisted of 40 healthy subjects, 21 women with postmenopausal osteoporosis [66.1 +/- 7.9 yrs] and 10 patients with Paget's disease of bone [67.1 +/- 11.6 yrs]. All patients were started on oral or intravenous bisphosphonate treatment and were followed prospectively over 6 months. Circulating cathepsin K levels were determined by a specific sandwich enzyme immunoassay (Biomedica, Vienna, Austria). In addition, serum carboxyterminal cross-linked telopeptide of type I collagen (betaCTX-I) and bone-specific alkaline phosphatase (BALP) were measured for comparison. RESULTS: When compared to healthy subjects, mean serum cathepsin K levels were significantly elevated in women with postmenopausal osteoporosis (3.1 +/- 1.9 vs. 11.3 +/- 13.1 pmol/L, p = 0.01) and in patients with Paget's disease of bone (6.2 +/- 4.4 pmol/L, p = 0.04). In postmenopausal osteoporotic women, both oral and intravenous bisphosphonate treatment resulted in a significant reduction in serum cathepsin K levels (p = 0.03) with most of the effect occurring after one month (mean% change: -33%). In patients with mild Paget's disease, serum cathepsin K levels decreased during bisphosphonate treatment. CONCLUSIONS: Serum concentrations of cathepsin K appear to reflect osteoclastic activity in patients with postmenopausal osteoporosis and Paget's disease of bone and may hold promise as a marker of osteoclast activity.

Aged↗
PubMed2005

On the role of methacrylic acid copolymers in the intracellular delivery of antisense oligonucleotides.

The delivery of active biomacromolecules to the cytoplasm is a major challenge as it is generally hindered by the endosomal/lysosomal barrier. Synthetic titratable polyanions can overcome this barrier by destabilizing membrane bilayers at pH values typically found in endosomes. This study investigates how anionic polyelectrolytes can enhance the cytoplasmic delivery of an antisense oligonucleotide (ODN). Novel methacrylic acid (MAA) copolymers were examined for their pH-sensitive properties and ability to destabilize cell membranes in a pH-dependent manner. Ternary complex formulations prepared with the ODN, a cationic lipid and a MAA copolymer were systematically characterized with respect to their size, zeta potential, antisense activity, cytotoxicity and cellular uptake using the A549 human lung carcinoma cell line. The MAA copolymer substantially increased the activity of the antisense ODN in inhibiting the expression of protein kinase C-alpha. Uptake, cytotoxicity and antisense activity were strongly dependent on copolymer concentration. Metabolic inhibitors demonstrated that endocytosis was the major internalization pathway of the complexes, and that endosomal acidification was essential for ODN activity. Confocal microscopy analysis of cells incubated with fluorescently-labeled complexes revealed selective delivery of the ODN, but not of the copolymer, to the cytoplasm/nucleus. This study provides new insight into the mechanisms of intracellular delivery of macromolecular drugs, using synthetic anionic polyelectrolytes.

Active Transport, Cell Nucleus↗
PubMed2005

L -Carnitine and the recovery from exhaustive endurance exercise: a randomised, double-blind, placebo-controlled trial.

We hypothesised that L: -carnitine could accelerate recovery from exhaustive exercise since increased blood L: -carnitine concentrations elicit a vasodilation in isolated animal vessels as well as in patients with peripheral vascular or coronary artery disease during exercise. Twelve subjects received either 2 g L: -carnitine or a placebo in a study which was double-blind and crossover in design. Two hours after administration, the subjects performed a constant-load exercise test (CET(1)) cycling at their individual anaerobic threshold to exhaustion. Three hours later this test was repeated (CET(2)). After 4-14 days, each subject performed the same cycling tests after having taken the other substance. Exercise times of the 12 subjects were identical with L: -carnitine (CET(1): 21.3+/-5.7 min; CET(2): 21.4+/-5.3 min) and placebo (CET(1): 21.9+/-6.2 min; CET(2): 20.4+/-4.8 min). Also, heart rate, oxygen consumption, respiratory exchange ratio, and blood lactate concentration were identical. In conclusion, 2 g of L-carnitine taken 2 h before a first of two constant-load exercise tests had no influence on the second tests performed 3 h after the first test compared with placebo.

Adult↗
PubMed2005

Serum estradiol after single dose hCG administration correlates with Leydig cell reserve in hypogonadal men: reassessment of the hCG stimulation test.

The hCG stimulation test with assessment of serum testosterone (T) is used for evaluation of testicular function. This retrospective study was undertaken to estimate the diagnostic value of stimulated estradiol (E2) levels in the assessment of Leydig cell function. Serum T and E2 before and after repeated daily hCG injections in 23 adult men with clinically suspected or established primary hypogonadism were studied. After hCG administration serum T increased gradually with peak levels after 72 hours (delta84%, p=0.003). In contrast, serum E2 concentrations reached their maximal levels 24 hours after the first injection (delta168%, p=0.001). Serum T and E2 responses were more attenuated in men with LH > or =17 IU/L as compared to men with lower LH levels. Peak E2 levels after 24 hours correlated significantly with peak T levels after 3 days. We conclude that the increase in serum E2 levels 24 hours after a single hCG injection is an useful additional measure of Leydig cell function. Assessment of E2 increments would render the test procedure more practical, less time-consuming and more cost-effective than assessing peak T levels after 72 hours.

Adult↗
PubMed2004

Bone resorption and osteoporotic fractures in elderly men: the dubbo osteoporosis epidemiology study.

UNLABELLED: Among the potential risk factors for fragility fractures, bone turnover is considered an important determinant. In a case-cohort control study of 151 elderly men followed prospectively over 6.3 years, high bone resorption as assessed by S-ICTP was associated with increased risk of osteoporotic fracture, independent of BMD. Combining measurements of BMD and bone turnover may improve fracture prediction in elderly men. INTRODUCTION: Approximately one-third of osteoporotic fractures occur in men. Among the potential risk factors for fragility fractures, bone turnover is considered an important determinant. The association between fracture risk and rates of bone turnover has not been well established in men. We examined this relationship in elderly community-dwelling men. MATERIALS AND METHODS: This case-cohort control study included 50 men with incident low-trauma fractures (cases; age, 72.3 +/- 6.7 years) and 101 men without fracture (controls; age, 70.4 +/- 4.1 years), who have been prospectively followed in the Dubbo Osteoporosis Epidemiology Study for a median of 6.3 years (range, 2-13 years). BMD at the lumbar spine (LSBMD) and at the femoral neck (FNBMD) and markers of bone turnover were measured at baseline. Bone resorption was assessed by measuring nonfasting serum concentrations of the carboxyterminal cross-linked telopeptide of type I collagen (S-ICTP) and of a linear octapeptide derived from the carboxyterminal type I collagen telopeptide (S-CTX). Bone formation was assessed by measuring the serum levels of the aminoterminal propeptide of type I procollagen (S-PINP). RESULTS: Men with subsequent fractures had lower BMD at baseline, both at the femoral neck and the spine, lower dietary calcium intake, and higher S-ICTP levels than age-and weight-matched controls. Smoking habits, S-CTX, and S-PINP did not differ between groups. Based on univariate regression analyses, S-ICTP (relative risk [RR] for 1 SD change: 1.8; 95% CI, 1.4-2.3) and serum creatinine levels (RR, 1.4; 95% CI, 1.1-1.7) were associated with increased risk of fracture. In multivariate regression analyses, S-ICTP (RR, 1.4; 95% CI, 1.0-1.9) and FNBMD (RR, 1.8; 95% CI, 1.4-2.3) remained independent predictors of fracture risk. Men within the highest quartile of S-ICTP had a 2.8-fold (95% CI 1.4-5.4) increased risk of fracture compared with those in the lowest quartile. The incidence of osteoporotic fractures was 10 times higher in men with high S-ICTP and low FNBMD compared with men with low S-ICTP and high FNBMD. Of the fracture risk in the population, 20% was attributable to high S-ICTP and low FNBMD, and S-ICTP contributed 17% to this increased risk. CONCLUSION: High bone resorption is associated with an increased risk of osteoporotic fracture in elderly men, independent of BMD. Combining measurements of BMD and bone turnover, which correlated with fracture in this cohort, could improve fracture risk prediction in elderly men.

Aged↗
PubMed2004

Ubiquitin-associated domain mutations of SQSTM1 in Paget's disease of bone: evidence for a founder effect in patients of British descent.

UNLABELLED: Mutations in the UBA domain of SQSTM1 are a common cause of Paget's disease of bone. Here we show that the most common disease-causing mutation (P392L) is carried on a shared haplotype, consistent with a founder effect and a common ancestral origin. INTRODUCTION: Paget's disease of bone (PDB) is a common condition with a strong genetic component. Mutations affecting the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1) have recently been shown to be an important cause of PDB. The most common mutation results in a proline to leucine amino acid change at codon 392 (P392L), and evidence has been presented to suggest that there may be a recurrent mutation rather than a founder mutation on an ancestral chromosome. Because marked geographical differences exist in the prevalence of PDB, we have investigated the frequency of SQSTM1 mutations in different populations and looked for a founder effect on chromosomes bearing SQSTM1 UBA domain mutations. MATERIALS AND METHODS: We conducted mutation screening of SQSTM1 and performed haplotype analysis using the PHASE software program in 83 kindreds with familial PDB, recruited mainly through clinic referrals in the United Kingdom, Australia, and New Zealand. Similar studies were conducted in 311 individuals with PDB who did not have a family history and 375 age- and sex-matched controls from the United Kingdom. RESULTS: The proportion of patients with familial PDB who had SQSTM1 UBA domain mutations varied somewhat between referral centers from 7.1% (Sydney, Australia) to 50% (Perth, Australia), but the difference between centers was not statistically significant. Haplotype analysis in 311 British patients with PDB who did not have a family history and 375 age- and sex-matched British controls showed that two common haplotypes accounted for about 90% of alleles at the SQSTM1 locus, as defined by common single nucleotide polymorphisms (SNPs) in exon 6 (C916T, G976A) and the 3'UTR (C2503T, T2687G). These were H1 (916T-976A-2503C-2687T) and H2 (916C-976G-2503T-2687G). There was no significant difference in haplotype distribution in PDB cases and controls, but the P392L mutation was found on the H2 haplotype in 25/27 cases (93%), which is significantly more often than expected given the allele frequencies in the normal population (odds ratio, 13.2; 95% CI, 3.1-56.4; p < 0.0001). Similar findings were observed in familial PDB, where 12/13 (92%) of P392L mutations were carried on H2 (odds ratio 17.2; 95% CI, 2.2-138; p = 0.001). CONCLUSIONS: These results provide strong evidence for a founder effect of the SQSTM1 P392L mutation in PDB patients of British descent, irrespective of family history. Our results imply that these individuals share a common ancestor and that the true rate of de novo mutations may be lower than previously suspected.

3' Untranslated Regions↗
PubMed2004

Supplementation with oral vitamin D3 and calcium during winter prevents seasonal bone loss: a randomized controlled open-label prospective trial.

UNLABELLED: Bone metabolism follows a seasonal pattern with high bone turnover and bone loss during the winter. In a randomized, open-label 2-year sequential follow-up study of 55 healthy adults, we found that supplementation with oral vitamin D3 and calcium during winter abolished seasonal changes in calciotropic hormones and markers of bone turnover and led to an increase in BMD. Supplementation with oral vitamin D3 and calcium during the winter months seems to counteract the effects of seasonal changes in vitamin D and thus may be beneficial as a primary prevention strategy for age-related bone loss. INTRODUCTION: Bone metabolism follows a seasonal pattern characterized by high bone turnover and bone loss during winter. We investigated whether wintertime supplementation with oral vitamin D3 and calcium had beneficial effects on the circannual changes in bone turnover and bone mass. MATERIALS AND METHODS: This prospective study comprised an initial observation period of 12 months ("year 1"), followed by an intervention during parts of year 2. Fifty-five healthy subjects living in southwestern Germany (latitude, 49.5 degrees N) were randomized into two groups: 30 subjects were assigned to the treatment group and received oral cholecalciferol (500 IU/day) and calcium (500 mg/day) during the winter months of year 2 (October-April), while 25 subjects assigned to the control group obtained no supplements. Primary endpoints were changes in calciotropic hormones [serum 25(OH)D, 1,25(OH)2D, and parathyroid hormone], markers of bone formation (serum bone-specific alkaline phosphatase) and of bone resorption (urinary pyridinoline and deoxypyridinoline), and changes in lumbar spine and femoral neck BMD. RESULTS: Forty-three subjects completed the study. During year 1, calciotropic hormones, markers of bone turnover, and BMD varied by season in both groups. During the winter months of year 1, bone turnover was significantly accelerated, and lumbar spine and femoral BMD declined by 0.3-0.9%. In year 2, seasonal changes in calciotropic hormones and markers of bone turnover were either reversed or abolished in the intervention group while unchanged in the control cohort. In the subjects receiving oral vitamin D3 and calcium, lumbar and femoral BMD increased significantly (lumbar spine: +0.8%, p = 0.04 versus year 1; femoral neck: +0.1%, p = 0.05 versus year 1), whereas controls continued to lose bone (intervention group versus control group: lumbar spine, p = 0.03; femoral neck, p = 0.05). CONCLUSIONS: Supplementation with oral vitamin D3 and calcium during winter prevents seasonal changes in bone turnover and bone loss in healthy adults. It seems conceivable that annually recurring cycles of low vitamin D and mild secondary hyperparathyroidism during the winter months contributes, at least in part and over many years, to age-related bone loss. Supplementation with low-dose oral vitamin D3 and calcium during winter may be an efficient and inexpensive strategy for the primary prevention of bone loss in northern latitudes.

Absorptiometry, Photon↗
PubMed2004

Restoration of euthyroidism accelerates bone turnover in patients with subclinical hypothyroidism: a randomized controlled trial.

This study evaluated the effect of physiological l-thyroxine (L-T4) treatment on bone metabolism in patients with subclinical hypothyroidism. Sixty-six women with subclinical hypothyroidism (TSH 11.7 +/- 0.8 mIU/l) were randomly assigned to receive L-T4 or placebo for 48 weeks. Sixty-one of 66 patients completed the study. Individual L-T4 replacement (mean dosage 85.5 +/- 4.3 microg/day) was performed targeting euthyroid thyroid-stimulating hormone (TSH) levels. The primary outcome measure was 24- and 48-week change in markers of bone formation (total and bone alkaline phosphatase [ALP, bone ALP], osteocalcin [OC]) and resorption (pyridinoline [PYD] and deoxypyridinoline [DPD], C-terminal cross-linking telopeptide type I [CTX]). Secondary outcomes were 48-week changes in bone mineral density (BMD) of the lumbar spine and hip, measured by dual-energy X-ray absorptiometry. Compared with placebo, l-thyroxine ( n=31) resulted in significant activation of bone turnover. Overall, a significant treatment effect was observed for DPD (between-group difference 16.0%; 95%CI, 10.9 to 21.1), CTX (29.9%; 95%CI, 23.3 to 36.5), and bone ALP (13.2%; 95%CI, 6.6 to 19.7) after 24 weeks. At the end of the study, lumbar BMD in the both treatment groups differed by 1.3% (95%CI, -2.9 to 0.5) with lower levels in l-thyroxine treated women. Significant difference in BMD between groups was also observed at the trochanter. We conclude that physiological l-thyroxine treatment accelerates bone turnover reflecting early activation of bone remodeling units in the initial replacement of subclinical hypothyroidism. The observed bone loss could be interpreted as an adaptive mechanism on decreased bone turnover in preexistent hypothyroidism, and not as l-thyroxine-induced clinically important bone loss. However, long-term studies are needed to confirm this assumption.

Alkaline Phosphatase↗
PubMed2004

Is there a clinical relevance of partial androgen deficiency of the aging male?

PURPOSE: Aging in men is characterized by a progressive, generally moderate decrease in plasma testosterone (T) levels and T substitution is increasingly prescribed. However, the association of partial androgen deficiency of the aging male with clinical symptoms and the ideal screening test are controversial. We investigate the association between various T measures and clinical and biochemical parameters of the aging male. MATERIALS AND METHODS: We investigated the association between total (TT), calculated free (FTcalc) and bioavailable (BT) testosterone, and various clinical and biochemical parameters in 51 healthy community living male volunteers, 55 and 75 years old. The parameters included serum levels of sex hormone-binding globulin, estradiol and lipid profile after an overnight fast; questionnaires assessing clinical symptoms, erectile function and mood; bone mineral density and body composition. RESULTS: TT correlated with FTcalc (r2 = 0.71, p <0.001) but not with BT (r2 = 0.04, p not significant) and FTcalc correlated moderately with BT (r2 = 0.23, p <0.001). Testicular volume correlated with TT levels (r2 = 0.17, p <0.001) and FTcalc (r2 = 0.17, p <0.001) but not with BT. There was neither a correlation of TT, FTcalc nor BT values with clinical symptoms nor with biochemical and radiological parameters, ie affective symptoms and sexual interest, circulating estradiol, lipid levels, bone mineral density or lean body mass. CONCLUSIONS: T values in our study sample did not correlate with clinical signs and symptoms of hypogonadism. Thus, according to our data, symptoms of the aging male could be rather multifactorial and should not be indiscriminately assigned to the age associated decrease in T levels.

Aged↗
PubMed2004

Development and evaluation of a quality-controlled ribosomal sequence database for 16S ribosomal DNA-based identification of Staphylococcus species.

To establish an improved ribosomal gene sequence database as part of the Ribosomal Differentiation of Microorganisms (RIDOM) project and to overcome the drawbacks of phenotypic identification systems and publicly accessible sequence databases, both strands of the 5' end of the 16S ribosomal DNA (rDNA) of 81 type and reference strains comprising all validly described staphylococcal (sub)species were sequenced. Assuming a normal distribution for pairwise distances of all unique staphylococcal sequences and choosing a reporting criterion of > or =98.7% similarity for a "distinct species," a statistical error probability of 1.0% was calculated. To evaluate this database, a 16S rDNA fragment (corresponding to Escherichia coli positions 54 to 510) of 55 clinical Staphylococcus isolates (including those of the small-colony variant phenotype) were sequenced and analyzed by the RIDOM approach. Of these isolates, 54 (98.2%) had a similarity score above the proposed threshold using RIDOM; 48 (87.3%) of the sequences gave a perfect match, whereas 83.6% were found by searching National Center for Biotechnology Information (NCBI) database entries. In contrast to RIDOM, which showed four ambiguities at the species level (mainly concerning Staphylococcus intermedius versus Staphylococcus delphini), the NCBI database search yielded 18 taxon-related ambiguities and showed numerous matches exhibiting redundant or unspecified entries. Comparing molecular results with those of biochemical procedures, ID 32 Staph (bioMerieux, Marcy I'Etoile, France) and VITEK 2 (bioMerieux) failed to identify 13 (23.6%) and 19 (34.5%) isolates, respectively, due to incorrect identification and/or categorization below acceptable values. In contrast to phenotypic methods and the NCBI database, the novel high-quality RIDOM sequence database provides excellent identification of staphylococci, including rarely isolated species and phenotypic variants.

Bacterial Typing Techniques↗
PubMed2004

Recombinant human chorionic gonadotropin but not dihydrotestosterone alone stimulates osteoblastic collagen synthesis in older men with partial age-related androgen deficiency.

Several randomized trials of androgen supplementation in older men have been undertaken. However, the relative contributions of testosterone (T) and estrogens on bone metabolism in aging men are controversial. Within the setting of two double-blind, placebo-controlled studies, we evaluated the effect of dihydrotestosterone (DHT) and recombinant human chorionic gonadotropin (rhCG) on bone turnover in healthy, community-dwelling older men with partial androgen deficiency (total T < or = 15 nmol/liter). In the first study, 35 men (age 68.3 +/- 6.8 yr; baseline T, 13.9 +/- 3.3 nmol/liter) were randomized to receive either daily transdermal DHT (n = 17) or placebo for 3 months. In the second study, 40 men (age 67.4 +/- 5.4 yr; baseline T, 11.4 +/- 2.2 nmol/liter) were randomized to receive either rhCG s.c. (n = 20), two injections weekly, or placebo for 3 months. The following parameters were measured before, monthly during, and 1 month after treatment: serum T, estradiol (E2), and LH; markers of bone formation, serum amino-terminal propeptide of type I procollagen (S-PINP) and osteocalcin; markers of bone resorption, serum carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline. Compared with placebo, treatment with DHT significantly increased serum DHT and suppressed LH and T levels, whereas E2 concentrations and markers of bone turnover did not change. In contrast, rhCG therapy significantly increased both T and E2, with the increases in E2 being supraphysiological. At the same time, rhCG significantly increased S-PINP concentrations with peak levels after 1 month (Delta40%; P = 0.02 compared with placebo). In contrast, serum osteocalcin and carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline levels did not change. The change in S-PINP levels correlated with the change in E2 levels (r = 0.59; P = 0.02) but not with a change in T. We conclude that in older men with partial age-related androgen deficiency, rhCG treatment stimulates osteoblastic collagen formation proportionally to increased E2 concentrations but does not alter markers of mature osteoblastic function or bone resorption. In contrast, treatment with a pure, nonaromatizable androgen (DHT) has no effect on bone turnover despite a 20-fold increase in serum levels. Bone resorption was not accelerated during unchanged (DHT) or increased (rhCG) E2 levels, suggesting that minimal E2 levels are needed to maintain stable resorption, although direct androgen receptor-mediated effects cannot be excluded. If androgen supplementation is required for aging men, aromatizable androgens with sufficient endogenous estrogenic activity may have the most beneficial effects on bone.

Aged↗
PubMed2003

Characterization of the membrane-destabilizing properties of different pH-sensitive methacrylic acid copolymers.

The intracellular delivery of active biomacromolecules from endosomes into the cytoplasm generally requires a membrane-disrupting agent. Since endosomes have a slightly acidic pH, anionic carboxylated polymers could be potentially useful for this purpose since they can destabilize membrane bilayers by pH-triggered conformational change. In this study, five different pH-sensitive methacrylic acid (MAA) copolymers were characterized with respect to their physicochemical and membrane lytic properties as a function of pH. pH-dependent conformational changes were studied in aqueous solution by turbidimetry and spectrofluorimetry. The hydrophobic domains that formed upon a decrease in pH were found to be dependent on copolymer's composition. Hemolysis and cytotoxicity assays demonstrated that the presence of the hydrophobic ethyl acrylate monomer and/or sufficient protonation of the carboxylic acid groups were important parameters for efficient membrane destabilization. Excessive copolymer hydrophobicity was not associated with membrane destabilization, but resulted in high macrophage cytotoxicity. Overall, this study gave more insights into the structure-activity relationship of MAA copolymers with membrane bilayers. Gaining knowledge of modulation of the physicochemical properties of copolymers and the optimization of copolymer-lipid interactions may lead to the elaboration of much more efficient drug delivery systems.

Animals↗
PubMed2003

Diffusion in compartmental systems. I. A comparison of an analytical model with simulations.

This article examines the way in which microscopic tissue parameters affect the signal attenuation of diffusion-weighted MR experiments. The influence of transmembrane water flux on the signal decay is emphasized using the Kärger equations, which are modified with respect to the cellular boundary restrictions for intra- and extracellular diffusion. This analytical approach is extensively compared to Monte-Carlo simulations for a tissue model consisting of two compartments. It is shown that diffusion-weighted MR methods provide a unique tool for estimation of the intracellular exchange time. Restrictions of applicability to in vivo data are examined. It is shown that the intracellular exchange time strongly depends on the size of a cell, leading to an apparent diffusion time dependence for in vivo data. Hence, an analytical model of a two-compartment system with an averaged exchange time is inadequate for the interpretation of signal curves measured in vivo over large ranges of b-values. Furthermore, differences of multiexponential signal curves, as obtained by different methods of diffusion weighting, can be explained by the influence of transmembrane water flux.

Algorithms↗