Search PubMed⌕ Search

Biomedical subjects

D Schoenfeld

Publications and source records attributed to D Schoenfeld.

At least 37 records · Page 2Linked to original sources
PubMed2000

Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and body composition in men with adult-onset GH deficiency.

Adults with acquired GH deficiency (GHD) have been shown to have osteopenia associated with a 3-fold increase in fracture risk and exhibit increased body fat and decreased lean mass. Replacement of GH results in decreased fat mass, increased lean mass, and increased bone mineral density (BMD). The possible differential effect of withdrawal of GH replacement on body composition compartments and regional bone mass is not known. We performed a randomized, single blind, placebo-controlled 36-month cross-over study of GH vs. placebo (PL) in adults with GHD and now report the effect of withdrawal of GH on percent body fat, lean mass, and bone density, as measured by dual energy x-ray absorptiometry. Forty men (median age, 51 yr; range, 24-64 yr) with pituitary disease and peak serum GH levels under 5 microg/L in response to two pharmacological stimuli were randomized to GH therapy (starting dose, 10 microg/kg x day, final dose 4 microg/kg x day) vs. PL for 18 months. Replacement was provided in a physiological range by adjusting GH doses according to serum insulin-like growth factor I levels. After discontinuation of GH, body fat increased significantly (mean +/- SEM, 3.18 +/- 0.44%; P = 0.0001) and returned to baseline. Lean mass decreased significantly (mean loss, 2133 +/- 539 g; P = 0.0016), but remained slightly higher (1276 +/- 502 g above baseline; P = 0.0258) than at study initiation. In contrast to the effect on body composition, BMD did not reverse toward pretreatment baseline after discontinuation of GH. Bone density at the hip continued to rise during PL administration, showing a significant increase (0.0014 +/- 0.00042, g/cm2 x month; P = 0.005) between months 18-36. Every bone site except two (radial BMD and total bone mineral content), including those without a significant increase in BMD during the 18 months of GH administration, showed a net increase over the entire 36 months. Therefore, there is a critical differential response of the duration of GH action on different body composition compartments. Physiological GH administration has a persistent effect on bone mass 18 months after discontinuation of GH.

Absorptiometry, Photon↗
PubMed2000

The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer's disease.

beta-Amyloid (Abeta) deposits in diffuse and compact senile plaques in the brain are one of the defining histopathological features of Alzheimer's disease (AD). Preventing Abeta deposition is a goal of drug therapy for AD, because excessive amounts of Abeta may be toxic to neurons. In preclinical studies, activation of the muscarinic M1 receptor subtype inhibited Abeta secretion from cultured cells. To determine whether a similar sequence occurs in human beings, we administered the selective M1 agonist AF102B to 19 AD patients and measured total Abeta (Abeta(total)) levels in cerebrospinal fluid (CSF) before and during treatment. Abeta(total) levels in CSF decreased in 14 patients by 22%, increased in 3 patients, and were unchanged in 2 patients; the overall decrease in the group as a whole was statistically significant. To test the specificity of the M1 effect, we also measured the relative changes in Abeta(total) levels in CSF during treatments in separate sets of AD patients with the acetylcholinesterase inhibitor physostigmine or the anti-inflammatory drug hydroxychloroquine. CSF Abeta(total) levels did not change significantly in the 9 AD patients in the physostigmine protocol or in the 10 AD patients in the hydroxychloroquine study. These data provide evidence that the activation of M1 receptors reduces Abeta levels in the CSF of AD patients. If this effect also occurs in brain, M1 agonists may have long-term therapeutic benefits by lowering amyloid in AD.

Aged↗
PubMed1999

Free alpha-subunit is superior to luteinizing hormone as a marker of gonadotropin-releasing hormone despite desensitization at fast pulse frequencies.

A pulsatile pattern of GnRH stimulation is essential for normal secretion of luteinizing hormone (LH), while both continuous and fast-frequency GnRH stimulation result in a paradoxical decrease in gonadotrope responsiveness known as desensitization. Under physiological conditions there is striking concordance between the pulsatile secretion of LH and the glycoprotein free alpha-subunit (FAS). The aims of this study were to determine whether the FAS response to GnRH is also decreased at fast frequencies of GnRH stimulation and whether FAS is superior to LH as a marker of GnRH secretory activity at fast-pulse frequencies. The model of GnRH-deficient men was chosen to permit precise control of the dose and frequency of GnRH stimulation of the gonadotrope. The frequency of i.v. administration of GnRH to 5 GnRH-deficient men was progressively increased from every 120 to every 60 min, from 60 to 30 min, and from 30 to 15 min during three 12-h admissions, 1 week apart. The bolus dose of GnRH remained constant and was set at that dose previously shown to produce physiological concentrations and amplitudes of LH secretion and normal testosterone levels. As the frequency of GnRH stimulation was increased, a progressive rise in mean FAS levels was noted (353 +/- 13, 448 +/- 42, 466 +/- 50, and 698 +/- 85 ng/L [mean +/- SEM] for 120, 60, 30, and 15 min intervals; P < 0.005). However, normalization of mean FAS levels to account for the increase in total GnRH delivered with increasing frequencies revealed a progressive decrease in pituitary responsiveness to each GnRH bolus with increasing frequency of stimulation (353 +/- 13, 224 +/- 21, 117 +/- 13, 87 +/- 11 ng/L; P < 0.001). The decrease in normalized mean levels was supported by a decrease in the FAS pulse amplitude with increasing frequency (517 +/- 53, 365 +/- 50, 176 +/- 29 ng/L for 120, 60, and 30 min intervals, respectively; P < 0.005). At interpulse intervals of 120 and 60 min, there was complete concordance of LH and FAS pulses in response to GnRH. However, at the 30-min frequency FAS proved to be a better marker of GnRH with a higher true positive rate and lower number of false positives than LH (P < 0.05). At all frequencies, the number of false positive pulses detected tended to be lower for FAS than for LH (P = 0.06). From these data we conclude that FAS is subject to desensitization in response to increasing frequencies of GnRH administration in GnRH-deficient men, but is superior to LH as a surrogate marker of GnRH pulse generator activity at fast pulse frequencies.

Adult↗
PubMed1998

Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Development of successful anabolic strategies to reverse the loss of lean body mass is of critical importance to increase survival in men with the AIDS wasting syndrome. Hypogonadism, an acquired endocrine deficiency state characterized by loss of testosterone, occurs in more than half of all men with advanced HIV disease. It is unknown whether testosterone deficiency contributes to the profound catabolic state and loss of lean body mass associated with the AIDS wasting syndrome. OBJECTIVE: To investigate the effects of physiologic testosterone administration on body composition, exercise functional capacity, and quality of life in androgen-deficient men with the AIDS wasting syndrome. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: University medical center. PATIENTS: 51 HIV-positive men (age 42 +/- 8 years) with wasting (body weight < 90% of ideal body weight or weight loss > 10% of baseline weight) and a free testosterone level less than 42 pmol/L (normal range for men 18 to 49 years of age, 42 to 121 pmol/L [12.0 to 35.0 pg/mL]). INTERVENTION: Patients were randomly assigned to receive testosterone enanthate, 300 mg, or placebo intramuscularly every 3 weeks for 6 months. MEASUREMENTS: Change in fat-free mass was the primary end point. Secondary clinical end points were weight, lean body mass, muscle mass, exercise functional capacity, and change in perceived quality of life. Virologic variables were assessed by CD4 count and viral load. RESULTS: Compared with patients who received placebo, testosterone-treated patients gained fat-free mass (-0.6 kg and 2.0 kg; P = 0.036), lean body mass (0.0 kg and 1.9 kg; P = 0.041), and muscle mass (-0.8 kg and 2.4 kg; P = 0.005). The changes in weight, fat mass, total-body water content, and exercise functional capacity did not significantly differ between the groups. Patients who received testosterone reported benefit from the treatment (P = 0.036), feeling better (P = 0.033), improved quality of life (P = 0.040), and improved appearance (P = 0.021). Testosterone was well tolerated in all patients. CONCLUSIONS: Physiologic testosterone administration increases lean body mass and improves quality of life among androgen-deficient men with the AIDS wasting syndrome.

Adolescent↗
PubMed1998

Determinants of increased energy expenditure in HIV-infected women.

BACKGROUND: Little is known about sex-specific effects of HIV infection on energy expenditure. OBJECTIVE: We investigated the determinants of energy expenditure in HIV-infected women. DESIGN: Resting energy expenditure (REE), body composition, and hormonal and nutritional indexes were compared in 33 ambulatory, premenopausal HIV-infected women and 26 weight-matched, healthy premenopausal control subjects. REE was determined by indirect calorimetry and body composition by dual-energy X-ray absorptiometry (DXA), bioelectrical impedance analysis, and skinfold-thickness analysis. Hormonal indexes included leptin, testosterone, estradiol, and insulin-like growth factor I. RESULTS: HIV-infected subjects had a higher REE than control subjects [6794 +/- 1374 compared with 6011 +/- 607 kJ/d (1624 +/- 329 compared with 1437 +/- 145 kcal/d), P = 0.0096]. On average, REE was 119 +/- 23% of Harris-Benedict predictions in HIV-infected subjects compared with 102 +/- 9% for control subjects (P = 0.0007). In HIV-infected subjects, REE was highly correlated with fat-free mass (FFM) by DXA (R = 0.641, P < 0.001), but not with weight or disease status. The slope of the regression equation for REE and FFM was significantly greater (P = 0.027, analysis of covariance) for HIV-infected subjects [REE (kJ/d) = 203.5 (kg FFM) - 1237] than for control subjects [REE (kJ/d) = 77.4 (kg FFM) + 2923]. In a stepwise regression analysis, FFM was the most significant variable (P = 0.005), followed by free testosterone (P = 0.029), which together explained 49% of the variation in REE. The final equation was REE (kJ/d) = 230.8 (kg FFM) + 395.9 (free testosterone, pmol/L) - 3304. CONCLUSIONS: Energy expenditure was higher in HIV-infected women than in control women. FFM is the primary determinant of REE in HIV-infected women, but energy expenditure is greater per kg FFM in HIV-infected subjects than in control subjects, which may contribute to the wasting syndrome.

Absorptiometry, Photon↗
PubMed1998

Polyamines in human and rat milk influence intestinal cell growth in vitro.

BACKGROUND: Polyamines are required for intestinal growth and development. In this study, we examined whether milk can supply the polyamines needed for growth of IEC-6 cells, a line on non-transformed rat intestinal crypt cells. METHODS: Human, bovine, and rat milk, and cow's milk-based infant formula were studied. Human, bovine, and rat milk were defatted and sterilized by filtration. IEC-6 cells were stabilized in Dulbecco's modified Eagle's medium (DMEM) containing 0.5% fetal bovine serum, 5 mM L-glutamine, 100 U/mL penicillin and 100 microg/mL streptomycin for 24 h at 37 degrees C. Thereafter, to initiate active growth, cells were placed in fresh DMEM containing 5% FBS (plus the other ingredients) supplemented with 5% (vol/vol) milk or infant formula. In some experiments, cells were also treated with difluoromethylornithine (2.5 mM) (DFMO), an inhibitor of polyamine synthesis, or dialyzed milk plus DFMO. After 44 hours of culture, cells were pulsed with 3H-thymidine (3H-TdR) for 4 hours, harvested and the radioactivity incorporated into DNA was measured. RESULTS: Human and rat milk stimulated proliferation of IEC-6 cells (p < 0.05 compared to controls); addition of DFMO did not reverse the stimulatory effect. Bovine milk and the infant formula did not stimulate proliferation or prevent the growth inhibition induced by DFMO. After dialysis, human milk had less ability to reverse the DFMO inhibition (p < 0.05). CONCLUSIONS: These experiments suggest that both human and rat milk, but neither bovine milk nor the infant formula, contain sufficient bioactive polyamines to sustain cell growth during inhibition of polyamine synthesis.

Animals↗
PubMed1998

Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study.

Although human immunodeficiency virus (HIV) disease is increasing rapidly among women, no prior studies have investigated gender-based therapeutic strategies for the treatment of acquired immunodeficiency syndrome (AIDS) and its complications in this population. Markedly decreased serum androgen levels have been demonstrated in women with AIDS and may be a contributing factor to the wasting syndrome in this population. To assess the effects of androgen replacement therapy in women with AIDS wasting, we conducted a randomized, placebo-controlled, pilot study of transdermal testosterone administration. The primary aim of the study was to determine efficacy in terms of the change in serum testosterone levels, safety parameters and tolerability. A secondary aim of the study was to investigate testosterone effects on weight, body composition, quality of life, and functional indexes. Fifty-three ambulatory women with the AIDS wasting syndrome defined as weight less than 90% of ideal body weight or weight loss of more than 10% of the preillness maximum, free of new opportunistic infection within 6 weeks of study initiation, and with screening serum levels of free testosterone less than the mean of the normal reference range (< 3 pg/mL) were enrolled in the study. Subjects were age 37 +/- 1 yr old (mean +/- SEM), weighed 92 +/- 2% of ideal body weight, and had lost 17 +/- 1% of their maximum weight. CD4 count was 324 +/- 36 cells/mm3, and viral burden was 102,382 +/- 28,580 copies. Subjects were randomized into three treatment groups, in which two placebo patches (PP), one active/one placebo patch (AP group), or two active patches (AA group) were applied twice weekly to the abdomen for 12 weeks. The expected nominal delivery rates of testosterone were 150 and 300 microg/day, respectively, for the AP and AA groups. Forty-five subjects completed the study (PP group, n = 13; AP group, n = 14; AA group, n = 18). Two additional subjects from the PP group and two from the AP group were included in the intent to treat analysis. Serum free testosterone levels increased significantly from 1.2 +/- 0.2 to 5.9 +/- 0.8 pg/mL (AP) and from 1.9 +/- 0.4 to 12.4 +/- 1.6 pg/mL (AA) in response to testosterone administration (P < 0.0001 for comparison of AA vs. PP and AP vs. PP; normal range, 1.3-6.8 pg/mL). Testosterone administration was generally well tolerated locally and systemically, with no adverse trends in hirsutism scores, lipid profiles, or liver function tests. Weight increased significantly in the AP group (1.9 +/- 0.7 kg) vs. the PP group (0.6 +/- 0.8 kg; P = 0.043), but did not increase significantly in the AA group (0.9 +/- 0.4 kg; P = 0.263 vs. PP, by mixed effects model assessing the interaction of time and treatment on all available data, one-tailed test). Improved social functioning (P = 0.024, by one-tailed test) and a trend toward improved pain score (P = 0.059) were observed in the AP vs. the PP-treated patients (RAND 36-Item Health Survey questionnaire). Five of six previously amenorrheic patients in the AP group had spontaneous resumption of menses compared to only one of four amenorrheic patients in the AA group (P = 0.045 for comparison of actual number of periods during the study). This study is the first investigation of testosterone administration in women with AIDS wasting. We demonstrate a novel method to augment testosterone levels in such patients that is safe and well tolerated during short term administration. At the lower of the two doses administered in this study, testosterone therapy was associated with positive trends in weight gain and quality of life. Higher, more supraphysiological, dosing was not associated with positive trends in weight or overall well-being. These data suggest that testosterone administration may improve the status of women with AIDS wasting. Further studies are needed to assess the effects of testosterone on weight in HIV-infected women and to define the optimal therapeutic window for test

Administration, Cutaneous↗
PubMed1997

Evaluation of TAP1 polymorphisms with insulin dependent diabetes mellitus in Finnish diabetic patients. The Childhood Diabetes in Finland (DiMe) Study Group.

Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease with a strong association between disease and the HLA class II region. Because abnormal antigen processing, in part characterized by altered class I processing, has been identified in patients with IDDM, the TAP (transporter associated with antigen processing) genes located in the HLA class II region make attractive candidate genes for IDDM. Five coding region variants of TAP1 were typed in a cohort of well characterized Finnish patients with diabetes (n = 119) and compared to racially marched control subjects (n = 92). We found that although no single TAP1 polymorphism was associated with IDDM, a genotypic combination of Ile/Val at codon 333 with Asp/Asp at codon 637 was found more frequently in subjects with IDDM (9.4%) compared to controls (1.2%; p = 0.025). This could not be accounted for by an association with any particular haplotype defined by class I or class II serology.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Pupil dilation to tropicamide is not specific for Alzheimer disease.

BACKGROUND: The extent of pupil dilation after instillation of a dilute tropicamide solution was proposed as a noninvasive neurobiological diagnostic test for Alzheimer disease (AD). Pupils in patients with AD dilated 23% vs only 5% in control subjects. OBJECTIVE: To determine whether pupil dilation in response to tropicamide distinguishes patients with AD from control subjects without dementia. METHODS: There were 50 patients with AD and 51 control subjects; no participant had primarily ocular pathological conditions or took drugs that affected cholinergic tone. All participants received 1 drop of 0.01% tropicamide in 1 eye and 1 drop of 0.9% saline solution in the other eye in random order. Pupil measurements were obtained using a pupil and corneal reflection tracking system (RK-426 PC system, ISCAN Inc, Burlington, Mass) that illuminated the eye with a low-level infrared source and measured pupil diameters, fixation, and light level every 16.7 milliseconds during each 30-second-measurement. Pupil measurements were obtained from each eye at baseline and 5, 10, 15, and 30 minutes after drop instillation. RESULTS: The increase in pupil size after tropicamide instillation was equal between patients with AD and control subjects. The mean (+/- SD) pupil diameter increased from 4.5 +/- 1.1 to 5.5 +/- 1.1 mm after 30 minutes in patients with AD and from 4.7 +/- 0.9 to 5.8 +/- 0.9 mm in control subjects. Anisocoria and the mean rate of dilation did not differ between patients with AD and control subjects. Eye color and corneal moisture did not affect these results. The extent of pupil dilation in patients with AD was not related to clinical estimates of dementia severity. CONCLUSION: Pupil dilation in response to instillation of 0.01% tropicamide is not useful as an antemortem diagnostic test for AD.

Aged↗
PubMed1997

Evaluation of pharmacokinetics, safety, tolerance, and activity of combination of zalcitabine and zidovudine in stable, zidovudine-treated pediatric patients with human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 190 Team.

A double-blind phase II trial compared zalcitabine (0.03 mg/kg/day) in combination with zidovudine (720 mg/m2/day) and zidovudine monotherapy in 250 clinically stable, previously zidovudine-treated, human immunodeficiency virus-infected children. The combination was well-tolerated except for an increased incidence of neutropenia (14%) compared with that in children receiving monotherapy (5%). No differences were noted for time to first AIDS-defining illness or death, neuropsychologic status, or weight Z scores. In patients in the combination arm, the CD4 cell count decline was slower (13% per year) than in patients receiving monotherapy (25% per year) (P = .03), and quantitative peripheral blood mononuclear cell virus load remained lower at all time points (P = .08). Deaths were fewer in patients receiving combination therapy (4) compared with those in patients receiving monotherapy (10) (P = .083). Thus, administration of zidovudine with zalcitabine to children with prior zidovudine treatment did not result in a significant increase in toxicity compared with that resulting from zidovudine monotherapy and demonstrated improvement in immunologic and virologic surrogate markers.

AIDS-Related Opportunistic Infections↗
PubMed1997

Screening of the TAP1 gene by denaturing gradient gel electrophoresis in insulin-dependent diabetes mellitus: detection and comparison of new polymorphisms between patients and controls.

New protective or disease-associated polymorphisms in the TAP1 gene were sought in insulin-dependent diabetes mellitus (IDDM) patients with the use of denaturing gradient gel electrophoresis (DGGE) screening of genomic DNA. The TAP1 gene is located in the human leukocyte antigen (HLA) class II region of the genome and encodes components of a peptide transporter essential for antigen presentation by HLA class I molecules. Fragments of TAP1 corresponding to the 5' promoter, each of the 11 exons (with portions of adjacent intronic regions) and the 3' flanking region were amplified by the polymerase chain reaction and then subjected to DGGE. DNA fragments of TAP1 yielded DGGE bands with patterns whose frequencies differed between IDDM patients and controls. Specific DGGE band patterns with fragments corresponding to the promoter, exons or introns 3, 6, 7, 8, 9 or 10 of TAP1 were detected exclusively in either patients or controls. Sequencing of TAP1 fragments encompassing exon 7 gave rise to a DGGE band pattern exclusively observed in an IDDM patient and sequencing revealed a previously unidentified polymorphisms at codon 518 (GTC-->ATC, Val-->Ile). Another unique polymorphism uncovered by DGGE revealed by sequencing a polymorphism in intron 2 in a diabetic patient. The genotypes of additional HLA class II matched patients and controls were determined with regard to five exonic and one intronic TAP1 polymorphism. A 10 base pair intronic insertion in intron 9 was exclusively identified in controls and missing from patients (P = 0.017). Further large population-based studies may reveal whether these newly identified at risk or protective TAP1 variants confer markers of statistical risk in diverse population groups.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome.

UNLABELLED: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of reproductive age women characterized in its broadest definition by the presence of oligoamenorrhea and hyperandrogenism and the absence of other disorders. Defects of gonadotropin secretion, including an elevated LH level, elevated LH to FSH ratio, and an increased frequency and amplitude of LH pulsations have been described, but the prevalence of these defects in a large, unbiased population of PCOS patients has not been determined. Sixty-one women with PCOS defined by oligomenorrhea and hyperandrogenism and 24 normal women in the early follicular phase had LH samples obtained every 10 min for 8-12 h. Pool LH levels from the frequent sampling studies were within the normal range in the 9 PCOS patients (14.8%) who were studied within 21 days after a documented spontaneous ovulation. Excluding these post-ovulatory patients, 75.0% of the PCOS patients had an elevated pool LH level (above the 95th percentile of the normal controls), and 94% had an elevated LH to FSH ratio. In the anovulatory PCOS patients, pool LH correlated positively with 17-OH progesterone (R = 0.30, P = 0.03), but not with estradiol, estrone, testosterone, androstenedione, or DHEA-S. Pool LH and LH to FSH ratio correlated positively with LH pulse frequency (R = 0.40, P = 0.004 for pool LH, and R = 0.39; P = 0.005 for LH/FSH). There was also a strong negative correlation between pool LH and body mass index (BMI) (R = -0.59, P < 10(-5)). The relationship between BMI and LH secretion in the PCOS patients appeared to be strongest with body fatness, as pool LH was correlated inversely with percent body fat, whether measured by skinfolds (R = -0.61, P < 10(-5)), bioimpedance (R = -0.55, P < 10(-4)), or dual energy x-ray absorptiometry (DEXA) (R = -0.70, P = 0.001; n = 18 for DEXA only). By DEXA, the only body region that was highly correlated with pool LH was the trunk (R = -0.71, P = 0.001). The relationship between body fatness and LH secretion occurred via a decrease in LH pulse amplitude (R = -0.63, P < 10(-5) for BMI; R = -0.58, P < 10(-4) for bioimpedance; and R = -0.64, P = 0.004 for whole body DEXA), with no significant change in pulse frequency with increasing obesity (R = -0.17, P = 0.23 for BMI). IN CONCLUSION: 1) the prevalence of gonadotropin abnormalities is very high in women with PCOS selected on purely clinical grounds, but is modified by recent spontaneous ovulation; 2) the positive relationship between LH pulse frequency and both pool LH and LH to FSH ratio supports the hypothesis that a rapid frequency of GnRH secretion may play a key etiologic role in the gonadotropin defect in PCOS patients; 3) pool LH and LH pulse amplitude are inversely related to body mass index and percent body fat in a continuous fashion; and 4) the occurrence of a continuous spectrum of gonadotropin abnormalities varying with body fat suggests that nonobese and obese patients with PCOS do not represent distinct pathophysiologic subsets of this disorder.

Adolescent↗
PubMed1996

Sequential effects of chronic human PTH (1-84) treatment of estrogen-deficiency osteopenia in the rat.

Although daily injections of parathyroid hormone (PTH) can rapidly reverse estrogen-deficiency bone loss in rats, PTH treatment of osteoporotic humans has to date produced more modest increases in bone mass. To explore the reasons for this important difference, we evaluated the dose- and time-dependence of human PTH 1-84 treatment effects on bone mass and biochemical markers of bone metabolism in rats with estrogen-deficiency bone loss. The highest doses of PTH increased spinal, femoral, and total skeletal mass to supra-normal levels and stimulated cortical endosteal bone formation. Spine and whole skeleton mass and density increased rapidly at first, but then increased more slowly; the rate of change decreased significantly (p < 0.01) during continued treatment with the highest doses of PTH. The effects of PTH treatment on biochemical markers also were both dose-dependent and time-dependent. Serum osteocalcin, a marker of osteoblast function, increased with the highest doses of PTH (p < 0.001), but reached an early plateau and later returned toward baseline. Urinary excretion of pyridinolines, a marker of osteoclast function, increased in a time-dependent fashion throughout treatment (p < 0.001). Serum 1,25(OH)2 vitamin D levels increased in a dose-related fashion, but then decreased toward control levels despite continued treatment. We demonstrate that both osteoblast and osteoclast function are increased during daily PTH therapy in the rat. The pattern of response depends on both the dose of PTH and the duration of therapy. These dose- and time-related effects should be taken into account when designing experimental PTH treatments for osteoporosis, and they deserve intensive study.

Absorptiometry, Photon↗
PubMed1996

Global self-ratings of health and mortality: hazard in the North Carolina Piedmont.

We analyzed the first 5 years of surveillance data from the Established Population for the Epidemiologic Studies of the Elderly (EPESE) in the Piedmont of North Carolina (n = 4162) to estimate the effect of a global self-rating of health on survival. Covariates used in Cox proportional hazard models included sociodemographic factors, chronic medical conditions, activities of daily living, use of health services, health risk behaviors, cognitive function, affective mood, and negative life events. Adjusted risk of mortality associated with poor (compared to excellent) self-ratings of health was significantly elevated among urban men only. Confounders of the association between survival and overall health assessment varied widely by subgroup. Pooled estimates from heterogeneous populations may mask significant subgroup differences both in the pattern of variables that mediate crude risk and also in the magnitude of residual risk of global self-ratings of health.

Activities of Daily Living↗
PubMed1996

Increased clearance of IgG in mice that lack beta 2-microglobulin: possible protective role of FcRn.

The mechanisms that regulate immunoglobulin G (IgG) catabolism are little understood. We have previously found unusually low IgG concentrations in sera of mice homozygous for a targeted disruption of the beta 2-microglobulin gene. We therefore investigated whether this might result, at least in part, from increased clearance of IgG from the systemic circulation in mice lacking beta 2-microglobulin. We compared the half-lives of radiolabelled mouse IgG1 injected intravenously into beta 2-microglobulin-/- mice and wild-type or heterozygous siblings. The clearance of 125I-labelled IgG1 was strikingly more rapid in the mice lacking beta 2-microglobulin. beta 2-microglobulin-/- mice lack functional molecules of the MHC class I-related Fc receptor, FcRn. Some mutations in mouse IgG1 that increase its clearance have recently been shown to prevent binding to FcRn in the gut. To determine whether the slower degradation of immunoglobulin in mice with beta 2-microglobulin correlated with the ability of the antibody to bind FcRn, we measured the clearance of chicken IgY, which does not bind this receptor. The 125I-labelled IgY was catabolized equally rapidly in beta 2-microglobulin-deficient and wild-type mice. We compared the half-lives of the four subclasses of mouse IgG in beta 2-microglobulin-/-, +/-, and +/+ mice to determine whether the difference we had noted for IgG1 was peculiar to this subclass. The 125I-labelled IgG of all subclasses, with the possible exception of IgG2b. was degraded more rapidly in the beta 2-microglobulin-deficient mice than in heterozygous or wild-type siblings. These data suggest that FcRn can protect IgG from degradation, and is therefore important in maintaining IgG levels in the circulation.

Animals↗
PubMed1996

Contour of the GnRH pulse independently modulates gonadotropin secretion in the human male.

GnRH pulse frequency, amplitude, and interpulse interval have all been demonstrated to regulate gonadotropin secretion individually. We tested the hypothesis that the contour of the GnRH pulse also modulates gonadotropin output in 10 men with isolated GnRH deficiency in whom a fixed GnRH dose was administered at a constant physiologic frequency by either instantaneous bolus or by 1-, 5-, or 30-min infusions. LH, FSH and free alpha subunit (FAS) responses were also compared to spontaneous gonadotropin secretion in normal adult men. While the LH and FAS pulses following the instantaneous bolus and 1-min infusion of GnRH were indistinguishable, further increases in the duration of gonadotrope stimulation by GnRH were associated with progressive decreases in all parameters of gonadotropin secretion (mean levels, amplitude, peak levels, AUC). FSH secretion was also decreased following variations in the contour of the GnRH pulse, although overall changes were less dramatic than for LH and FAS. The LH pulses following the bolus GnRH stimulation were indistinguishable from spontaneous LH pulses occurring in normal men whereas those stimulated by the 1-, 5-, and 30-min infusions of GnRH became progressively blunted with the lowest levels of secretion occurring after the longest infusion. In sharp contrast, FAS pulse parameters in the GnRH-deficient subjects greatly exceeded those of normal men regardless of the contour of the GnRH stimulus, whereas mean FSH levels were all modestly (although significantly) higher than those of normal adult men. These results demonstrate that the pituitary is sensitive to subtle changes in the contour of the GnRH stimulus, with a more prolonged duration of GnRH stimulation resulting in a diminished pituitary response. Alterations of the contour of endogenous GnRH secretion may represent an additional mechanism for altering gonadotrope function and provide additional evidence for the differential regulation of LH, FAS, and FSH by GnRH. However, the previously reported elevated levels of FAS secretion in GnRH-deficient men undergoing long-term GnRH replacement are not explained by abnormalities of GnRH contour.

Adult↗
PubMed1996

Mullerian inhibiting substance in humans: normal levels from infancy to adulthood.

Mullerian-inhibiting substance (MIS) is a gonadal hormone synthesized by Sertoli cells of the testis and granulosa cells of the ovary. To facilitate the use of MIS for the evaluation of intersex disorders and as a tumor marker in women with MIS-expressing ovarian tumors, we measured MIS in 600 serum samples from males and females. These data show that mean MIS values for males rise rapidly during the first year of life and are highest during late infancy, then gradually decline until puberty. In contrast, MIS values in females are lowest at birth and exhibit a minimal increase throughout the prepubertal years. Whereas MIS is uniformly measurable in all prepubertal boys studied, it is undetectable in most prepubertal female subjects. These data reveal an easily discernible sexually dimorphic pattern of expression and confirm that MIS can be used as a testis-specific marker during infancy and early childhood. MIS values that are above the upper limits for females are discriminatory for the presence of testicular tissue or ovarian tumor, and those below the lower limits for males are consistent with dysgenetic or absent testes or the presence of ovarian tissue. These data will enable normal and abnormal levels of MIS to be differentiated with higher precision and will facilitate the use of MIS in the management of gonadal disorders.

Adolescent↗