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A J Yates

Publications and source records attributed to A J Yates.

At least 37 records · Page 2Linked to original sources
PubMed1999

An open-label extension study of alendronate treatment in elderly women with osteoporosis.

We have recently reported the results of a 24-month, double-blind, placebo-controlled study in 359 elderly osteoporotic women who were treated with daily oral alendronate (ALN) 1, 2.5, or 5 mg or placebo (PBO). We report the results of a 12-month, open-label, extension study during which 246 patients from the original study were treated with ALN 10 mg/day. Significant increases in lumbar spine bone mineral density (BMD) were observed in patients who had previously received PBO or ALN 1 and 2.5 mg/day for 24 months. Significant gains in trochanter BMD were seen in all treatment groups. Small changes were observed in femoral neck, total body, and forearm BMD during the course of this extension study. In general, the greatest increases in BMD during the open-label extension year occurred in patients who received either PBO or the lower doses of ALN during the previous 2-year blinded study. The frequencies of all categories of upper gastrointestinal adverse experiences (AEs) were less during months 25-36 (open-label extension) than during months 0-24 (original study). In conclusion, treatment with ALN 10 mg/day for 12 months in elderly women with osteoporosis who were previously treated for 24 months with PBO or ALN 1, 2.5, or 5 mg/day increased or maintained BMD of the spine, trochanter, and forearm, and was generally safe and well tolerated, especially in the upper gastrointestinal tract.

Absorptiometry, Photon↗
PubMed1999

Sex- and age-related differences in ceramide dihexosides of primary human brain tumors.

Neutral glycolipids (NGL) are promising diagnostic markers of human gliomas, but differences in NGL with age and sex have not been examined. Previous work demonstrated that ceramide dihexosides (CDH) levels in mouse kidney are age- and sex-dependent, probably due to levels of sex hormones. We quantitated CDH in 181 human gliomas and found significant differences with sex and age, particularly menopause and male puberty. This emphasizes the importance of assessing results of studies on glycolipids in disease states with respect to age and sex in order to avoid erroneous conclusions concerning the relationship of glycolipid composition with diagnosis and pathogenesis.

Adolescent↗
PubMed1999

Mechanisms through which PDGF alters intracellular calcium levels in U-1242 MG human glioma cells.

PDGF-BB induces a rapid, sustained increase in intracellular calcium levels in U-1242 MG cells. We used several calcium channel blockers to identify the types of channels involved. L channel blockers (verapamil, nimodipine, nicardipine, nitrendipine and taicatoxin) had no effect on PDGF-BB induced alterations in intracellular calcium. Blockers of P, Q and N channels (omega-agatoxin-IVA, omega-conotoxin MVIIC and omega-conotoxin GVIA) also had no effect. This indicates that these channels play an insignificant role in supplying the Ca2+ necessary for PDGF stimulated events in U-1242 MG cells. However, a T channel blocker (NDGA) and the non-specific (NS) calcium channel blockers (FFA and SK&F 9365) abolished PDGF-induced increases in intracellular calcium. This indicates that PDGF causes calcium influx through both non-specific cationic channels and T channels. To study the participation of intracellular calcium stores in this process, we used thapsigargin, caffeine and ryanodine, all of which cause depletion of intracellular calcium stores. The PDGF effect was abolished using both thapsigargin and caffeine but not ryanodine. Collectively, these data indicate that in these human glioma cells PDGF-BB induces release of intracellular calcium from caffeine- and thapsigargin-sensitive calcium stores which in turn lead to further calcium influx through both NS and T channels.

Becaplermin↗
PubMed1999

Immunohistochemical staining for ganglioside GD1b as a diagnostic and prognostic marker for primary human brain tumors.

Immunohistochemical staining intensity for ganglioside GD1b was determined for 108 human neuroectodermal tumors. Most of the tissue elements that immunostained were tumor cells; only a few axons and occasional neurons reacted in some specimens. All pilocytic astrocytomas stained very positively, whereas none of the ependymomas and only 11% of primitive neuroectodermal tumors, 20% of glioblastomas, and 28% of anaplastic astrocytomas showed more than faint staining. A similar association between grade and immunostaining was seen in tumors containing an oligodendrogliomatous component, but reactivity was not as strong as in astrocytic tumors or primitive neuroectodermal tumors. Results of Cox regression showed significant associations between immunostaining intensity and survival for all cases taken together (P = 0.007); for the group consisting of astrocytomas, oligoastrocytomas, and oligodendrogliomas (P = 0.002); and for astrocytomas alone (P = 0.04). Results were also significant using a proportional hazards model controlling for patient age (all cases P = 0.005; astrocytomas only P = 0.02), but not when controlling for tumor grade. Our results indicate that immunohistochemical staining for GD1b is correlated with tumor grade and that it may be of prognostic utility in some primary human brain tumors, especially astrocytomas.

Astrocytoma↗
PubMed1999

Glycolipid markers of astrocytomas and oligodendrogliomas.

Neutral glycolipids and gangliosides were analyzed in 149 astrocytomas (A), 46 oligodendrogliomas (O), and 21 oligoastrocytomas (OA) to determine if specific glycolipids correlate with histologic diagnosis and grade. Positivity for asialoGM1 (GA1) and negativity for paragloboside by immuno-TLC correlated with histological diagnosis of O and OA, whereas the reverse pattern correlated with A. High levels (over 5 microg hexose per mg dry weight) of CMH generally correlated with an O component, but the association was not as strong as for either GA1 presence or paragloboside absence. Pilocytic astrocytomas and pleomorphic xanthoastrocytomas had high proportions (> 15%) of globoside, low ratios (< 0.5) of GD1a: GD1b, and identifiable ceramide trihexoside (CTH). Three gangliosides of the 1b pathway were progressively lost with increasing grade of A, but a similar correlation with grade was not seen in O or OA. A high proportion of cases expressing sialosylparagloboside (3'LM1; 6'LM1) were grade 4 A. Glycolipids are synthesized by glycosyltransferases that add specific sugars to the nascent oligosaccharide. Correlation of specific glycolipids with histological diagnoses and grades indicate that these tumor types express specific patterns of glycosyltransferases, several of which have been cloned. It is possible that critical genes coding for these enzymes are deleted, overexpressed, or mutated in certain tumor types and grades, thus leading to the patterns of glycolipids that we found to be associated with these tumors.

Adolescent↗
PubMed1999

Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study.

To establish whether biochemical markers could be used to monitor alendronate (ALN) treatment and predict long-term response in bone mass, we used results from an ongoing, randomized trial of ALN treatment for prevention of postmenopausal osteoporosis (n = 1202). In women treated with ALN (5 mg), change from baseline at month 6 in urine N-telopeptide cross-links of type I collagen (NTX) and osteocalcin (OC) correlated with change from baseline at month 24 in spine, hip, and total body bone mineral density (BMD) [r = -0.28 to -0.31 (NTX) and r = -0.16 to -0.25 (OC), P<0.001]. This corresponded to a 4- to 5-fold greater increase at month 24 in BMD in the tertiles, with the greatest decrease at month 6 in NTX or OC. In women treated with ALN (5 mg) who had a change at month 24 in spine BMD of at least 0%, 86% (NTX) and 79% (OC) had a decrease at month 6 of at least 40% (NTX) or 20% (OC) (sensitivity). The corresponding specificities were 48% (NTX) and 53% (OC). In conclusion, change at month 6 in NTX and OC, in groups of women treated with ALN, indicated the numeric long-term response in BMD within these groups. In individual women, a decrease at month 6, in NTX or OC below the cut-point, validly identified women who responded, on ALN treatment, with a stabilization or an increase in bone mass. However, lack of decrease below the cut-point in NTX or OC could not be used to identify women with a bone loss during ALN treatment.

Alendronate↗
PubMed1999

Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. Early Postmenopausal Intervention Cohort (EPIC) study group.

Thinness (low percentage of body fat, low body mass index [BMI], or low body weight) was evaluated as a risk factor for low bone mineral density (BMD) or increased bone loss in a randomized trial of alendronate for prevention of osteoporosis in recently postmenopausal women with normal bone mass (n = 1609). The 2-year data from the placebo group were used (n = 417). Percentage of body fat, BMI, and body weight were correlated with baseline BMD (r = -0. 13 to -0.43, p < 0.01) and 2-year bone loss (r = -0.14 to -0.19, p < 0.01). Women in the lowest tertiles of percentage of body fat or BMI had up to 12% lower BMD at baseline and a more than 2-fold higher 2-year bone loss as compared with women in the highest tertiles (p </= 0.004). Women with a lower percentage of body fat or BMI had higher baseline levels of urine N-telopeptide cross-links (r = -0.24 to -0.31, p < 0.0001) and serum osteocalcin (r = -0.12 to -0.15, p < 0.01). To determine if the magnitude of treatment effect of alendronate was dependent on these risk factors, the group treated with 5 mg of alendronate was included (n = 403). There were no associations between fat mass parameters and response to alendronate treatment, which indicated that risk of low bone mass and increased bone loss caused by thinness could be compensated by alendronate treatment. In conclusion, thinness is an important risk factor for low bone mass and increased bone loss in postmenopausal women. Because the response to alendronate treatment is independent of fat mass parameters, prevention of postmenopausal osteoporosis can be equally achieved in thinner and heavier women.

Alendronate↗
PubMed1999

The effects of alendronate on bone turnover and bone quality.

During Phase III clinical trials with alendronate, biochemical and histological studies assessed bone turnover and bone quality in patients treated for 3 years. Patients were randomised in double-blind fashion to receive placebo, alendronate 5 or 10 mg/day for 3 years or 20 mg/day for 2 years followed by 5 mg/day for 1 year. All patients also received 500 mg/day of calcium carbonate. Decreases in bone resorption with alendronate preceded decreases in bone formation. After approximately 6 months of continuous treatment, a new steady state of bone turnover was attained, leading to the increase in bone density. No subsequent decrease in the rate of bone turnover or of frozen bone was noted. Alendronate treatment did not impair bone mineralisation, induce the formation of woven bone or have any other adverse effects on bone quality.

Alendronate↗
PubMed1999

Alendronate in the treatment of postmenopausal osteoporosis.

The following article reviews the results of 2 investigational Phase III trials of alendronate. Alendronate has been found to induce clinically significant increases in bone mineral density at the spine, hip and other cortical and trabecular sites while maintaining bone quality thereby reducing the rate of vertebral fracture. Alendronate was revealed to be well tolerated, with a good safety profile; a dose of 10 mg daily offers the best risk:benefit ratio and appears to be the optimal dosage for the treatment of established postmenopausal osteoporosis. The persistence of bone gain with extended treatment offers a considerable advantage over currently available forms of therapy.

Aged↗
PubMed1998

Sphingolipids as receptor modulators. An overview.

Glycosphingolipids are amphipathic compounds that exist mainly in the plasmalemma with their oligosaccharide portion protruding into the extracellular environment. In this position they are admirably situated for interacting with both ligands and receptors. Binding studies have demonstrated that specific glycolipids function as receptors for some microorganisms and bacterial toxins. Specific oligosaccharides on both glycolipids and glycoproteins bind members of the selection families, and some gangliosides facilitate integrins binding to their ligands. Gangliosides modulate the trophic factor-stimulated dimerization, tyrosine phosphorylation, and subsequent signal transduction events of several tyrosine kinase receptors. GM3 inhibits both the epidermal growth factor receptor and basic fibroblast factor receptor; several gangliosides except GM3 inhibit the platelet-derived growth-factor receptor; GM1 enhances nerve growth-factor-stimulated activation of TrkA; insulin receptor is inhibited to varying degrees by several gangliosides, but 2-->3 sialosylparagloboside is most effective. Activities of the beta(1)-adrenergic and delta-opioid receptors are modulated by GM1. Available information suggests that glycolipids serve as coordinators of multiple receptor functions.

Animals↗
PubMed1998

Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group.

BACKGROUND: Estrogen-replacement therapy prevents osteoporosis in postmenopausal women by inhibiting bone resorption, but the balance between its long-term risks and benefits remains unclear. Whether other antiresorptive therapies can prevent osteoporosis in these women is also not clear. METHODS: We studied the effect of 2.5 mg or 5 mg of alendronate per day or placebo on bone mineral density in 1174 postmenopausal women under 60 years of age. An additional 435 women who were prepared to receive a combination of estrogen and progestin were randomly assigned to one of the above treatments or open-label estrogen-progestin. The main outcome measure was the change in bone mineral density of the lumbar spine, hip, distal forearm, and total body measured annually for two years by dual-energy x-ray absorptiometry. RESULTS: The women who received placebo lost bone mineral density at all measured sites, whereas the women treated with 5 mg of alendronate daily had a mean (+/-SE) increase in bone mineral density of 3.5+/-0.2 percent at the lumbar spine, 1.9+/-0.1 percent at the hip, and 0.7+/-0.1 percent for the total body (all P<0.001). Women treated with 2.5 mg of alendronate daily had smaller increases in bone mineral density. Alendronate did not increase bone mineral density of the forearm, but it slowed the loss. The responses to estrogen-progestin were 1 to 2 percentage points greater than those to the 5-mg dose of alendronate. Alendronate was well tolerated, with a safety profile similar to that of placebo or estrogen-progestin. CONCLUSIONS: Alendronate prevents bone loss in postmenopausal women under 60 years of age to nearly the same extent as estrogen-progestin.

Alendronate↗
PubMed1998

Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double-blind, randomized, controlled trial. Alendronate Osteoporosis Prevention Study Group.

BACKGROUND: Preventing bone loss associated with menopause and aging and maintaining the normal micro-architecture of bone provide important opportunities for the prevention of osteoporosis and fractures. OBJECTIVE: To determine the safety and efficacy of alendronate, an aminobisphosphonate, for preventing postmenopausal bone loss. DESIGN: 3-year double-blind, randomized, placebo-controlled trial. SETTING: 15 osteoporosis centers throughout the world. PARTICIPANTS: 447 women who had recently experienced menopause (6 to 36 months before study entry). INTERVENTION: Participants were randomly assigned to one of five regimens: oral placebo; oral alendronate, 1, 5, or 10 mg/d; or oral alendronate, 20 mg/d for 2 years followed by placebo during the third year (20/0 mg/d). MEASUREMENTS: Bone mineral density was measured by dual-energy x-ray absorptiometry. Bone turnover and bone quality were assessed with biochemical markers and bone histomorphometry. RESULTS: Alendronate at 5, 10, and 20/0 mg/d increased bone mineral density from baseline at the lumbar spine, femoral neck, and trochanter by 1% to 4% and in the total body by 0.3% to 1.0%; placebo led to losses of 2% to 4% at these sites. Alendronate, 1 mg/d, attenuated losses relative to those seen with placebo. Alendronate decreased markers of bone resorption to a new steady state by 3 months and decreased markers of bone formation by 6 to 12 months. Bone quality remained normal. At all dosages studied, alendronate had a safety and tolerability profile similar to that of placebo. CONCLUSIONS: In early postmenopausal women, alendronate given for 3 years at dosages of 5 mg/d or greater prevented the loss of bone mineral density at the spine and hip and in the total body. Alendronate seems to be a safe and effective nonhormonal option for prevention of postmenopausal bone loss.

Adult↗
PubMed1998

Prediction of fracture risk by radiographic absorptiometry and quantitative ultrasound: a prospective study.

Recent developments in computer-assisted radiographic absorptiometry (RA) and quantitative ultrasound techniques (QUS) provide readily accessible and relatively inexpensive methods for assessing bone mineral status. However, few population-based studies have investigated the ability of RA and ultrasound to predict fracture risk prospectively. We explored the ability of RA and QUS to predict fracture risk among 560 postmenopausal women from the Hawaii Osteoporosis Study; average follow-up was 2.7 years. An incident vertebral fracture was defined as a decrease of more than 15% in vertebral heights on subsequent films. Self-reported nonspine fractures were verified by medical records. The prospective associations of vertebral fractures, nonspine fractures, and any (spine or nonspine) fractures with bone measurements were examined using logistic regression, adjusting for age. Both phalangeal bone mineral density (BMD) and metacarpal BMD, measured using RA, predicted future fracture risk. The age-adjusted odds ratios (corresponding to 1 SD decrease in BMD) for vertebral fractures, nonspine fractures, and any fractures were 3.41, 1.50, and 1.91, respectively, for phalangeal BMD, and 1.71, 1.49, 1.55, respectively for metacarpal BMD. Calcaneal broadband ultrasound attenuation (BUA) also showed significant association with fracture risk, with age-adjusted odds ratios of 1.50, 1.89, and 1.72 for vertebral fractures, nonspine fractures, and any fractures, respectively. We conclude that hand RA and calcaneal BUA are significant predictors of nonspine fracture, vertebral fracture, and overall fracture risk. The attractive features of these techniques, such as portability, relatively low cost, and ease of use, make them promising alternatives to conventional bone measurement techniques used for the assessment of fracture risk.

Absorptiometry, Photon↗