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Humans↗
Biomedical subjects
N Santoro
Publications and source records attributed to N Santoro.
Effects of aging and gonadal failure on the hypothalamic-pituitary axis in women.
OBJECTIVE: Our aim was to determine the effect of aging on the hypothalamic-pituitary-gonadal axis function. STUDY DESIGN: We studied 9 women aged 25 to 40 years with well-defined idiopathic premature ovarian failure and compared them with 8 women aged 51 to 70 years who had age-appropriate menopause. All women underwent 24 hours of frequent blood sampling every 10 minutes before and after replacement with transdermal estradiol targeted to achieve serum concentrations of approximately 100 pg/ml. RESULTS: In the absence of estrogen exposure, women with premature ovarian failure demonstrated a greater 24-hour mean luteinizing hormone concentration compared with that in the older women with age-appropriate menopause (32.3+/-4.3 mlU/ml vs 19.2+/-2.4 mlU/ml, p=0.0001). Despite the lesser luteinizing hormone serum levels in the older group, the luteinizing hormone pulse frequency per 24 hours was similar (22.1+/-3.0 pulses per 24 hours in prematurely menopausal women vs 21.9+/-2.5 pulses per 24 hours in the older postmenopausal women, p=0.94). When exposed to estrogen, mean luteinizing hormone concentrations decreased to 11.6+/-2.7 mlU/ml in prematurely menopausal women versus 4.4+/-1.0 mlU/ml in older postmenopausal women, p=0.017. Both groups had suppressed mean luteinizing hormone secretion compared with their paired, non-estradiol-exposed studies, p=0.0001. Frequency of luteinizing hormone pulsations was reduced to 16.5+/-3.5 pulses per 24 hours in prematurely menopausal women exposed to estradiol (p < 0.0058, compared with non-estradiol-exposed women). Further reduction was observed in older postmenopausal women (11.5+/-1.1 pulses per 24 hours, p=0.0001, compared with nonestradiol exposure, and p=0.0125, vs prematurely menopausal, estradiol-exposed women). Pulse amplitude was suppressed in both prematurely menopausal women (5.6+/-0.5 mlU/ml to 2.3+/-0.5 mlU/ml, p=0.0001) and older postmenopausal women (3.6+/-0.4 mlU/ml to 2.3+/-0.6 mlU/ml p=0.04) in the presence of estradiol. Although luteinizing hormone pulse amplitudes were greater in the women with premature menopause in the absence of estradiol (p=0.0028) compared with those in older postmenopausal women, pulse amplitudes became similar in the presence of estradiol. Parallel changes in mean follicle-stimulating hormone were observed. Women with premature ovarian failure had a mean follicle-stimulating hormone level of 71.1+/-9.4 mlU/ml that was suppressed to 18.0+/-4.1 mlU/ml after estradiol exposure (p=0.0001); values in older postmenopausal women were 45.9+/-6.0 and 10.3+/-2.0, respectively (p=0.0001). Although the women with premature ovarian failure secreted more follicle-stimulating hormone in the absence and presence of estradiol, only the former situation was statistically significant (p=0.0008 and p=0.23, respectively). CONCLUSIONS: These data suggest that there is an age-related decrease in gonadotropin secretion that may be hypothalamic or pituitary in origin. There is less luteinizing hormone secreted in women older than age 50. There is greater suppression of luteinizing hormone and follicle-stimulating hormone secretion by estradiol in aged women. Thus these data indicate that postmenopausal hormone changes involve central hypothalamic-pituitary alterations, as well as ovarian changes.
Adult↗
"Coasting" does not adversely affect cycle outcome in a subset of highly responsive in vitro fertilization patients.
OBJECTIVE: To study the effect of postponing hCG administration while continuing daily GnRH agonist therapy ("coasting") on highly responsive patients undergoing IVF-ET. DESIGN: Retrospective analysis. SETTING: University-affiliated Center for Fertility and Reproductive Medicine. PATIENT(S): Patients undergoing IVF-ET from March 1995 to March 1997. INTERVENTION(S): Three groups of IVF-ET patients were compared to explore the effect of coasting on cycle outcome: a group of highly responsive coasted patients, a group of equally responsive noncoasted patients, and an age-matched normally responsive control group. Two groups of coasted patients were also compared to assess the effect of E2 levels at the time that they met the follicular criteria for hCG administration. Last, the effect of varying coast duration was examined by regression analysis. MAIN OUTCOME MEASURE(S): Patient characteristics, outcome parameters, and incidence of ovarian hyperstimulation syndrome (OHSS). RESULT(S): Coasting had no detrimental effect on cycle outcome in the subset studied. Regression analysis, however, suggests an inverse relationship between coast duration and the number of mature oocytes retrieved as well as the clinical pregnancy rate. CONCLUSION(S): Coasting in the studied subset of IVF patients did not adversely affect cycle outcome parameters or the incidence of OHSS, but prolonged coasting intervals may impair IVF cycle outcome.
Chorionic Gonadotropin↗
Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial.
OBJECTIVE: To determine the effect of administering 6 months of oral postmenopausal DHEA therapy on serum DHEA, DHEAS, and T levels and on physiologic endpoints including lipoproteins and insulin-like growth factor-I (IGF-I). DESIGN: Randomized, double-blind, parallel trial. SETTING: Academic referral practice. PATIENT(S): Thirteen normal-weight or overweight, healthy, nonsmoking, postmenopausal women. INTERVENTION(S): Administration of oral micronized DHEA (25 mg/d). MAIN OUTCOME MEASURE(S): Monthly fasting 23 hours postdose levels of serum DHEA, DHEAS, T, lipoproteins, IGF-I, IGF binding protein-3 (IGFBP-3), and liver function tests. Morphometric indices by dual-energy x-ray absorptiometry scan (percent body fat; lean body mass), immune indices, and insulin sensitivity. RESULT(S): Levels of DHEA, DHEAS, and T all rose into premenopausal ranges, but after 6 months, levels of DHEA and T did not differ from baseline or placebo. At 3 months, the ratio of IGF-I to IGFBP-3 rose by 36.1% +/- 12.7%, but it fell to placebo values by 6 months. High-density lipoprotein and apolipoprotein A1 levels declined. CONCLUSION(S): Patients appeared to tolerate 6 months of DHEA therapy well. Given the small study size, no statistically significant differences in morphometric indices, immune indices, or insulin-sensitizing properties were observed, but significant attenuation of bioavailability occurred. Supplementation with DHEA increased IGF-I/IGFBP-3 levels at 3 months and decreased high-density lipoprotein and apolipoprotein A1 levels at 6 months.
Androgens↗
Gynecologic health and disease.
Traditionally the obstetrician/gynecologist has been the sole provider of health care for women. As the United States moves toward a system of greater managed care, however, family practitioners, internists, and other physician extenders (physician assistants, nurse-practitioners, and nurse-midwives) are the first-line providers for many women. These practitioners have the opportunity to influence behavioral changes and promote healthy habits by identifying risk factors and their potential consequences.
Adolescent↗
Elevated maternal serum relaxin concentrations throughout pregnancy in singleton gestations after superovulation.
OBJECTIVE: To test the hypothesis that superovulation results in elevated maternal circulating relaxin concentrations throughout the second and third trimesters of pregnancy, independent of the pattern of hCG secretion. METHODS: Two groups of women with singleton gestations were studied: a group of nine women who achieved pregnancy after stimulation with human menopausal gonadotropin and a group of six women who achieved pregnancy without prior stimulation. Peripheral blood samples were drawn approximately every 5 weeks throughout the second and third trimesters. Serum relaxin concentrations were measured using a human relaxin-specific enzyme-linked immunosorbent assay; hCG was measured by an immunofluorometric assay. RESULTS: The stimulated group had significantly higher relaxin levels throughout pregnancy (P=.007, multivariate analysis of variance) than did nonstimulated controls. The mean relaxin level in stimulated patients was 1.78 ng/mL (95% confidence interval [CI] 1.5, 2.17) and in nonstimulated subjects the level was 0.73 ng/mL (95% CI 0.59, 1.25). Spline fits demonstrated that stimulated patients had higher relaxin levels throughout the second and third trimesters. There was no significant difference in hCG concentrations between the two groups (P=.61). CONCLUSION: In singleton gestations after superovulation, maternal serum relaxin concentrations are significantly higher throughout the second and third trimesters of pregnancy. These differences are independent of the pattern of hCG secretion. It appears that luteal relaxin secretion is controlled by factors in addition to hCG.
Adult↗
Autologous bone marrow transplantation for treatment of isolated central nervous system relapse of childhood acute lymphoblastic leukemia. AIEOP/FONOP-TMO group. Associzione Italiana Emato-Oncologia Pediatrica.
The purpose of this study was to assess the role of ABMT in children with ALL who are in 2nd CR after an early isolated CNS relapse. All children experiencing an isolated CNS relapse at 10 AIEOP centers (Associazione Italiana Emato-Oncologia Pediatrica) from 1986 to 1992 were eligible for this study. The series included 69 patients who relapsed within 3 years from diagnosis: 19 underwent ABMT, nine patients underwent ALLO-BMT from an HLA-identical sibling, and 41 received conventional chemotherapy (CHEMO). Statistical analysis was performed using a Cox's regression model, adjusting for the waiting time before transplantation and prognostic factors. The 5 years DFS was 56.3% (s.e. 12.3) for patients in the ABMT group. This compared favorably with the poor result (12.6% (s.e. 5.9)) seen in the CHEMO group. The risk of failures was reduced by one-third in the ABMT group as compared to the CHEMO group in the multivariate analysis (P < 0.01). In the ALLO group four out of nine patients were in CCR 4-5 years post-transplant. This study suggests that ABMT may also represent a valuable therapeutic choice for patients lacking a matched familiar donor in 2nd CR after an early isolated CNS relapse.
Adolescent↗
Critical ovarian hyperstimulation syndrome in a coasted in-vitro fertilization patient.
We report an instance of critical ovarian hyperstimulation syndrome in a highly responsive in-vitro fertilization patient despite the preventive measure of a 4 day 'coast' interval during which no gonadotrophins were administered while gonadotrophin-releasing hormone agonist therapy continued until serum oestradiol concentrations fell below 3000 pg/ml.
Adult↗
Persistent pregnanediol glucuronide secretion after gonadotrophin suppression indicates adrenal source of progesterone in premature ovarian failure.
A 2-3 fold higher urinary pregnanediol glucuronide excretion has been observed in women with premature ovarian failure, compared with age-appropriate menopausal women. Progesterone, the precursor of urinary pregnanediol glucuronide, is a secretory product of either adrenal or ovarian origin. We postulated that suppression of pituitary gonadotrophin secretion by down-regulation with a long-acting gonadotrophin-releasing hormone agonist, leuprolide acetate, would decrease ovarian but not adrenal pregnanediol glucuronide. This would demonstrate a major difference in the ovarian hormonal milieu of these two groups of women. Four volunteers with premature ovarian failure collected daily first morning voided urine samples for 1 month prior to leuprolide acetate administration. Leuprolide acetate was then administered monthly for 3 months while continuing daily urinary collection. Luteinizing hormone (LH), follicle stimulating hormone (FSH), and pregnanediol glucuronide were measured in all samples and normalized for creatinine. Comparisons of pre- and post-median values for luteinizing hormone (LH), FSH, and pregnanediol glucuronide were made using the Wilcoxon rank sum test. This demonstrated significant suppression of both LH and FSH. Pregnanediol glucuronide, however, did not demonstrate a significant decline, strongly implying an adrenal source of the enhanced excretion. The decreased pregnanediol glucuronide noted in age-appropriate menopausal women compared with premature ovarian failure is likely to be a reflection of adrenal ageing.
Adrenal Glands↗
Heat shock element architecture is an important determinant in the temperature and transactivation domain requirements for heat shock transcription factor.
The baker's yeast Saccharomyces cerevisiae possesses a single gene encoding heat shock transcription factor (HSF), which is required for the activation of genes that participate in stress protection as well as normal growth and viability. Yeast HSF (yHSF) contains two distinct transcriptional activation regions located at the amino and carboxyl termini. Activation of the yeast metallothionein gene, CUP1, depends on a nonconsensus heat shock element (HSE), occurs at higher temperatures than other heat shock-responsive genes, and is highly dependent on the carboxyl-terminal transactivation domain (CTA) of yHSF. The results described here show that the noncanonical (or gapped) spacing of GAA units in the CUP1 HSE (HSE1) functions to limit the magnitude of CUP1 transcriptional activation in response to heat and oxidative stress. The spacing in HSE1 modulates the dependence for transcriptional activation by both stresses on the yHSF CTA. Furthermore, a previously uncharacterized HSE in the CUP1 promoter, HSE2, modulates the magnitude of the transcriptional activation of CUP1, via HSE1, in response to stress. In vitro DNase I footprinting experiments suggest that the occupation of HSE2 by yHSF strongly influences the manner in which yHSF occupies HSE1. Limited proteolysis assays show that HSF adopts a distinct protease-sensitive conformation when bound to the CUP1 HSE1, providing evidence that the HSE influences DNA-bound HSF conformation. Together, these results suggest that CUP1 regulation is distinct from that of other classic heat shock genes through the interaction of yHSF with two nonconsensus HSEs. Consistent with this view, we have identified other gene targets of yHSF containing HSEs with sequence and spacing features similar to those of CUP1 HSE1 and show a correlation between the spacing of the GAA units and the relative dependence on the yHSF CTA.
Base Sequence↗
Intensive BFM chemotherapy for childhood ALL: interim analysis of the AIEOP-ALL 91 study. Associazione Italiana Ematologia Oncologia Pediatrica.
BACKGROUND AND OBJECTIVE: Since 1988 the AIEOP has used BFM-based chemotherapy for childhood ALL. Current organization and results and role of cranial irradiation in the AIEOP-ALL 91 study are reported. DESIGN AND METHODS: From 1991 to 1995, 1194 children (< 15 years) with non-B ALL, were enrolled and assigned to the standard risk [SR: age > 1 year, non-T-ALL, BFM risk factor (RF) < 0.8], intermediate risk (IR: RF > or = 0.8 but < 1.7, or with RF < 0.8 and age < 1 year, or T-ALL), or high risk [HR: RF > or = 1.7, or t(9;22), or t(4;11) or prednisone poor response or late response or CNS involvement] groups. All patients received initially protocol Ia. Thereafter SR patients received HD-MTX 2 g/m2, a modified protocol II, and continuation therapy with triple intrathecal chemotherapy (TIT); IR patients received protocol Ib, HD-MTX 5 g/m2, protocol II and continuation therapy with TIT; HR patients received 9 polychemotherapy blocks, cranial irradiation and continuation therapy. Duration of treatment was 24 months. A randomized study was conducted to evaluate the impact of high-dose asparaginase in non high risk patients: the results of this study cannot be disclosed yet. RESULTS: One thousand one hundred and fifty-two (96.5%) patients achieved CR. Overall EFS (SE) at 5-years was 71.0% (1.4), with a survival of 80.3% (1.3). Relapse occurred in 262 children (21.9%), either in the marrow (n = 192 isolated and 32 with other sites, 18.7%), in the CNS (n = 18, 1.5%), or elsewhere (n = 20, 1.7%). 5-year EFS (SE) was 83.3% (2.4) in SR, 74.7% (1.8) in IR, and 39.7% (3.5) in HR groups, respectively. INTERPRETATION AND CONCLUSIONS: Overall cure rate was higher than in the previous AIEOP-ALL 88 study. Treatment intensification with polychemotherapy blocks did not improve results in HR. Cranial irradiation can be safely omitted in over 80% of children treated with BFM based chemotherapy.
Adolescent↗
Conservation of a stress response: human heat shock transcription factors functionally substitute for yeast HSF.
Heat shock factors (HSF) are important eukaryotic stress responsive transcription factors which are highly structurally conserved from yeast to mammals. HSFs bind as homotrimers to conserved promoter DNA recognition sites called HSEs. The baker's yeast Saccharomyces cerevisiae possesses a single essential HSF gene, while distinct HSF isoforms have been identified in humans. To ascertain the degree of functional similarity between the yeast and human HSF proteins, human HSF1 and HSF2 were expressed in yeast cells lacking the endogenous HSF gene. We demonstrate that human HSF2, but not HSF1, homotrimerizes and functionally complements the viability defect associated with a deletion of the yeast HSF gene. However, derivatives of hHSF1 that give rise to a trimerized protein, through disruption of a carboxyl- or aminoterminal coiled-coil domain thought to engage in intramolecular interactions that maintain the protein in a monomeric state, functionally substitute for yeast HSF. Surprisingly, hHSF2 expressed in yeast activates target gene transcription in response to thermal stress. Moreover, hHSF1 and hHSF2 exhibit selectivity for transcriptional activation of two distinct yeast heat shock responsive genes, which correlate with previously established mammalian HSF DNA binding preferences in vitro. These results provide new insight into the function of human HSF isoforms, and demonstrate the remarkable functional conservation between yeast and human HSFs, critical transcription factors required for responses to physiological, pharmacological and environmental stresses.
Animals↗
Effect of extremely low frequency (ELF) magnetic field exposure on morphological and biophysical properties of human lymphoid cell line (Raji).
Human B lymphoid cells (Raji) were exposed for 72 h to a 50 Hz sinusoidal magnetic field at a density of 2 milliTesla (rms). The results of exposure showed a decrease in membrane fluidity as detected by Laurdan emission spectroscopy and DPH fluorescence polarization. Field exposure also resulted in a reorganization of cytoskeletal components. Scanning electron microscopy (SEM) revealed a loss of microvilli in the exposed cells. This change in plasma membrane morphology was accompanied by a different actin distribution, as detected by phalloidin fluorescence. We also present evidence that EMF exposure of Raji cells can interfere with protein phosphorylation. Our observations confirm the hypothesis that electric and magnetic fields may modify the plasma membrane structure and interfere with the initiation of the signal cascade pathways.
Actins↗
Roles of aspartic acid-181 and serine-222 in intermediate formation and hydrolysis of the mammalian protein-tyrosine-phosphatase PTP1.
Protein tyrosine phosphatases (PTPases) share a number of conserved amino acid residues, including the active site sequence HCXXGXXRS(T), which are strongly implicated in catalysis. The roles of two conserved active site residues, Asp-181 and Ser-222, were investigated using a combination of site-directed mutagenesis and kinetic analysis in the mammalian PTPase PTP1. The pH profiles for k(cat)/K(m) and k(cat) of the wild-type enzyme indicate that two ionizable groups, of pK(a) values 5.1 and 5.44, must be deprotonated and one group with a pK(a) value of 4.93 must be protonated for maximal activity. The group of pK(a) value 5.1 is the second ionization of the substrate phosphate moiety. Selective thiolate anion inactivation indicates the residue with pK(a) value of 5.44 is C215. The pH-dependent profiles of the D181N mutant during establish the residue with pK(a) value of 4.93 to be Asp-181 and suggest that it functions as a general acid phosphoryl transfer to the enzyme. Rapid reaction kinetics of wild-type and D181N mutant enzymes indicate that the formation of the phospho-enzyme intermediate is rate-limiting at pH 7.0 and 30 degrees C. Enzymes containing the S222A mutation exhibited rapid reaction burst kinetics, strongly suggesting that phospho-enzyme intermediate hydrolysis is fully rate-limiting. The role of the active site S222 is to accelerate the rate of phospho-enzyme intermediate hydrolysis. The kinetic analysis of a third mutant, containing both the D181N and S222A mutations, suggests that D181 also serves as a general base in the breakdown of the phospho-enzyme intermediate.
Amino Acid Sequence↗
Relationships between insulin-like growth hormone factor-I and estradiol in reproductive aging.
OBJECTIVE: To evaluate gonadotropins, estrogen, and insulin-like growth hormone factor (IGF)-I and its binding proteins throughout the normal menstrual cycle and during aging within the reproductive life span. DESIGN: Daily blood samples were obtained from 17 normally cycling women. SETTING: Center for Fertility and Reproductive Medicine, Newark, New Jersey. PARTICIPANTS: Ten women aged 19 to 34 years old and seven women aged 42 to 47 years old. MAIN OUTCOME MEASURES: Luteinizing hormone (LH), FSH, E2, and P were assayed in daily blood samples. Early follicular, late follicular, midluteal phase, and samples taken at ovulation were also assayed for IGF-I and IGFBP-I and IGFBP-III. RESULTS: Follicle-stimulating hormone (FSH) increased significantly with reproductive aging. IGF-I and its binding proteins did not fluctuate through the menstrual cycle. IGF-I and its binding proteins did not change over the 28-year time span studied, in the face of significantly increased circulating estradiol associated with reproductive aging. CONCLUSION: Rising E2 may be a subtle harbinger of the perimenopause. IGF-I and its binding proteins did not decrease with cycle stage or with aging during the reproductive years, perhaps because of increased estradiol stimulation of the somatotrophic axis.
Adult↗
Red blood cells mediated delivery of 9-(2-phosphonylmethoxyethyl)adenine to primary macrophages: efficiency metabolism and activity against human immunodeficiency virus or herpes simplex virus.
Red blood cells (RBC) may act as selective carriers of drugs to macrophages, an important reservoir of viruses such as human immunodeficiency virus (HIV) and herpes simplex virus type 1 (HSV-1). We therefore assessed the incorporation of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of HIV and HSV-1) into RBC, its delivery to macrophages and its activity against HIV or HSV-1. Loading of PMEA in artificially aged opsonized RBC affords significant levels of intracellular PMEA. RBC metabolize PMEA to its active congener PMEA-diphosphate, although with low efficiency. Exposure of macrophages to RBC-encapsulated PMEA inhibits the replication of both HIV and HSV-1 (about 90% inhibition at the highest RBC:macrophages ratios) even if RBC were removed before virus challenge. By contrast, the antiviral activity of free PMEA removed before virus challenge was irrelevant at concentrations up to 150-fold higher than the 50% effective concentration (EC50). Finally, the antiviral effect of RBC-encapsulated PMEA correlates with PMEA levels in macrophages about 500-fold higher than those achieved by free PMEA (at concentrations 10-fold higher than the EC50). The efficacy of RBC-mediated delivery to macrophages of PMEA (and perhaps of compounds with shorter intracellular half-lives) warrants further studies in infectious diseases involving phagocytizing cells as main targets of the pathogen.
Adenine↗
Exposure to a 50 Hz electromagnetic field induces activation of the Epstein-Barr virus genome in latently infected human lymphoid cells.
The EBV genome in latently infected lymphoid cells offers an opportunity to follow effects on the transcriptional and translational product clearly distinguishable from those of the host cell genome. Exposure of Akata cells, a human lymphoid cell line latently infected by the EBV genome, to a 50 Hz EMF resulted in an increased number of cells expressing the virus early antigens. This finding provides additional evidence that DNA can be modulated by a magnetic field.
Antigens, Viral↗
Hypercoagulability and hyperfibrinolysis in patients with melanoma.
The purpose of this study was to evaluate whether or not, using sensitive analytical methods for the measurement of coagulation and fibrinolysis enzyme activity, there was a hypercoagulable state in patients with melanoma, and whether differences existed between those with or without metastases. Seventy-one patients were studied, 45 with localized tumors (stages Ia and Ib) and 26 with metastases (stages II-IV). Plasma level of activated factor VII, prothrombin fragment 1 + 2, thrombin-antithrombin complex, fibrinopeptide A, plasmin-antiplasmin complex and D-dimer were much higher in the whole group of 71 patients than in 45 controls with benign nevi. However, when melanoma patients with or without metastases were compared, there were smaller differences, with only thrombin-antithrombin complex, plasmin-antiplasmin and D-dimer significantly higher in metastatic melanoma. These results indicate that in patients carrying a tumor endowed with high procoagulant activity in vitro, there is a laboratory picture of hypercoagulability with secondary hyperfibrinolysis in vivo. However, differences between patients with localized and metastatic tumors for markers of hypercoagulability are not striking, in spite of the fact that metastatic cells support greater coagulant activity than primary cells in vitro.
Adolescent↗