bluuebunny/crossref_metadata_2025 huggingface dataset:
Homocysteine, Pharmacogenetics, and Neurotoxicity in Children With Leukemia
Authors: Kishi Shinji , Griener James , Cheng Cheng , Das Soma , Cook Edwin H. , Pei Deqing , Hudson Melissa , Rubnitz Jeffrey , Sandlund John T. , Pui Ching-Hon , Relling Mary V.
Published: August 2003

Purpose: Despite its clinical success, methotrexate (MTX) therapy is associated with toxicities such as seizures, the pathogenesis of which remains unclear. It has been suggested that hyperhomocysteinemia is caused by MTX and is responsible for its neurotoxic effects. The purposes of this study were to explore whether hyperhomocysteinemia was related to MTX administration and toxicity and whether homocysteine or MTX toxicity differed by methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier (RFC) genetic polymorphisms.

Patients and Methods: We studied 53 children with newly diagnosed acute lymphoblastic leukemia who were consecutively treated on a single clinical protocol that included two courses of high-dose MTX (high-dose methotrexate [HDMTX]; 2.5 or 5.0 g/m2 per day) as consolidation therapy.

Results: The study participants’ median plasma homocysteine concentrations at 23 and 44 hours after HDMTX (9.00 μmol/L and 10.12 μmol/L, respectively) were greater than the concentrations immediately before HDMTX (5.77 μmol/L, P < .0001 for both comparisons). Seven days after HDMTX treatment, their plasma concentration returned to baseline. Nine patients experienced seizures, and five patients experienced thrombosis during the first 15 months of therapy, with a tendency for there to be higher plasma homocysteine in patients with seizures across all time points (P = .063) but not in patients with thrombosis (P = .59). We observed no significant differences in plasma or cerebrospinal fluid homocysteine levels or in toxicity based on the MTHFR 677C/T or RFC 80G/A genotypes.

Conclusion: We conclude that homocysteine was transiently elevated after HDMTX and may be related to seizure risk in children with leukemia.
Importance of Predosing of Recombinant Human Thrombopoietin to Reduce Chemotherapy-Induced Early Thrombocytopenia
Authors: Vadhan-Raj Saroj , Patel Shreyaskumar , Bueso-Ramos Carlos , Folloder Jody , Papadopolous Nicholas , Burgess Andrew , Broemeling Lyle D. , Broxmeyer Hal E. , Benjamin Robert S.
Published: August 2003

Purpose: Recombinant human thrombopoietin (rhTPO) increases platelets, and the peak response of rhTPO is delayed and is, therefore, not uniformly effective when administered after chemotherapy. The purpose of this study was to identify an effective schedule of rhTPO to best attenuate early thrombocytopenia.

Patients and Methods: Cohorts of six patients with sarcoma (66 assessable patients) were treated sequentially with doxorubicin and ifosfamide (AI), with rhTPO by a fixed dose and varying schedules being administered before and/or after chemotherapy in cycle 2 and subsequent cycles. Cycle 1 without rhTPO served as an internal control.

Results: AI causes cumulative thrombocytopenia. The platelet nadir in cycle 2 was higher than in cycle 1 (mean nadir ± SEM, 119 ± 12 × 103/μL v 80 ± 7 × 103/μL, respectively; P < .001) in 24 (80%) of the 30 patients (P < .001) in whom rhTPO (1.2 μg/kg) was administered starting from 5 days before chemotherapy (pre/postdoses, three/one or one/one) compared with only four (17%) of 24 patients given rhTPO by other schedules (pre/postdoses, two/two, one/three, zero/four, or four/zero) and none of 15 historical control patients. The need for platelet transfusions in four cycles was significantly lower (13 [11%] of 114 cycles, P < .001) in patients who received rhTPO from day −5 (pre/post doses, three/one or one/one) compared with patients who received rhTPO at later time points (28 [47%] of 60 cycles). Bone marrow megakaryocytes increased markedly (four-fold) before chemotherapy with predosing rhTPO and remained elevated (two-fold) after chemotherapy, which may explain the possible mechanism for response. One patient developed subclavian vein thrombosis, and no patients developed neutralizing antibodies to rhTPO.

Conclusion: These results demonstrate the importance of timing of rhTPO in relation to chemotherapy and indicate that, by optimizing the timing, only two doses of rhTPO (one before and one after chemotherapy) were required to significantly reduce the severity of chemotherapy-related early thrombocytopenia.
Risk of Acute Leukemia Following Epirubicin-Based Adjuvant Chemotherapy: A Report From the National Cancer Institute of Canada Clinical Trials Group
Authors: Crump Michael , Tu Dongsheng , Shepherd Lois , Levine Mark , Bramwell Vivien , Pritchard Kathleen
Published: August 2003

Purpose: Cyclophosphamide, epirubicin, and fluorouracil (CEF), compared with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy. has lead to an improvement in relapse-free and overall survival in premenopausal women with node-positive breast cancer. We undertook this analysis to more accurately define the estimate of risk of secondary acute leukemia (sAL) following epirubicin-containing chemotherapy regimens.

Patients and Methods: We assessed the conditional probability of sAL among 1,545 women who received adjuvant (n = 1,477) or neoadjuvant (n = 68) chemotherapy in four National Cancer Institute of Canada Clinical Trials Group trials from 1990 to 1999. The risks associated with epirubicin-containing regimens (CEF or epirubicin and cyclophosphamide [EC]) and other regimens (doxorubicin and cyclophosphamide [AC] or CMF) were determined.

Results: A total of 10 cases of sAL were observed (eight acute myelogeneous leukemia, two acute lymphoblastic leukemia): seven among women treated with CEF, two who had received AC, and one following CMF. Using competing risk statistics, the conditional probability of sAL was 1.7% (95% confidence interval [CI], 0.5 to 3.6) among 539 women treated with CEF chemotherapy at a follow-up of 8 years, 0.4% (95% CI, 0% to 1.3%) among the 678 who received CMF, and 1.3% (95% CI, 0% to 4.7%) among the 231 treated with AC. The conditional probability of death from breast cancer at 8 years for the entire group of women treated with epirubicin-containing regimens in all four trials was approximately 34.9%.

Conclusion: CEF chemotherapy for breast cancer carries a small increased risk of sAL compared with CMF. These estimates of acute leukemia risk are important in discussing treatment with women, especially patients with a lower risk of death from breast cancer, such as those with node-negative breast cancer.
Prognostic Value of the Human Kallikrein Gene 15 Expression in Ovarian Cancer
Authors: Yousef George M. , Scorilas Andreas , Katsaros Dionyssios , Fracchioli Stefano , Iskander Lisa , Borgono Carla , Rigault de la Longrais Irene A. , Puopolo Manuela , Massobrio Marco , Diamandis Eleftherios P.
Published: August 2003

Purpose: KLK15 is a newly cloned human kallikrein gene. Many kallikreins were found to be differentially expressed in ovarian cancer. Like other kallikreins, KLK15 is regulated by steroid hormones in cancer cell lines. KLK15 is upregulated mainly by androgens and to a lesser extent by progestins. The purpose of this study was to examine the prognostic value of KLK15 in ovarian cancer tissues.

Materials and Methods: We studied KLK15 expression by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in 168 consecutive patients with epithelial ovarian cancer. Ten patients with benign ovarian tumors were also included in the study. An optimal cutoff point equal to the 50th percentile was defined based on the ability of KLK15 to predict progression-free survival and overall survival of the study population.

Results: KLK15 expression levels were significantly higher in cancerous tissues compared with benign tumors. Kaplan-Meier survival curves showed that KLK15 overexpression is a significant predictor of reduced progression-free survival (PFS; P < .001) and overall survival (OS; P < .009). Univariate and multivariate analyses indicate that KLK15 is an independent prognostic factor for PFS and OS. A weak positive correlation was found between KLK15 expression and serum CA-125 levels.

Conclusion: KLK15 expression, as assessed by quantitative RT-PCR, is an independent marker of unfavorable prognosis for ovarian cancer.
Automated, Multiplex Assay for High-Frequency Microsatellite Instability in Colorectal Cancer
Authors: Nash G.M. , Gimbel M. , Shia J. , Culliford A.T. , Nathanson D.R. , Ndubuisi M. , Yamaguchi Y. , Zeng Z.S. , Barany F. , Paty P.B.
Published: August 2003

Purpose: In a series of hereditary nonpolyposis colorectal cancer (HNPCC) patients, we evaluated the sensitivities of the individual microsatellites recommended by the National Cancer Institute (NCI) consensus workshop for detection of high-frequency microsatellite instability (MSI-H). On the basis of this evaluation, we developed a three-marker assay that assigns microsatellite instability (MSI) in a multiplex polymerase chain reaction.

Methods: Individual marker sensitivity was assessed in 18 HNPCC tumors. Multiplex and NCI assays were then assessed in a series of 120 patients with early-onset colon cancer.

Results: The sensitivity of microsatellite markers BAT25, BAT26, D2S123, D5S346, and D17S250 for ASI in HNPCC cancers was 100%, 94%, 72%, 50%, and 50%, respectively. The three most accurate markers were combined and optimized in a multiplex assay that assigned MSI-H whenever at least two of three markers revealed ASI. In early-onset colon cancers, the prevalence of MSI-H determined by the multiplex assay and by the NCI assay was 16% and 23%, respectively. The additional MSI-H tumors and patients with MSI-H identified by the NCI assay lacked the traits characteristic of MSI-H seen in tumors and patients identified by the multiplex assay: retention of heterozygosity (NCI additional 22% v multiplex 84%; P = .003), characteristic tumor morphology (0% v 64%; P = .006), and 5-year cancer survival rate (44% v 100%; P = .0003).

Conclusion: The multiplex assay identifies colon cancers with MSI-H by assessing three highly accurate microsatellite markers. This assay identifies a smaller MSI-H cohort with more homogeneous clinical features and is superior as a marker of favorable prognosis. It merits prospective evaluation as a marker of prognosis and as a screening test for HNPCC.
Patterns of Failure Using a Conformal Radiation Therapy Tumor Bed Boost for Medulloblastoma
Authors: Wolden Suzanne L. , Dunkel Ira J. , Souweidane Mark M. , Happersett Laura , Khakoo Yasmin , Schupak Karen , Lyden David , Leibel Steven A.
Published: August 2003

Purpose: To assess the patterns of failure for patients with medulloblastoma receiving a conformal tumor bed boost rather than a boost to the entire posterior fossa.

Patients and Methods: From 1994 to 2002, 32 consecutive patients with newly diagnosed medulloblastoma treated at Memorial Sloan-Kettering Cancer Center (New York, NY) received a conformal boost to the tumor bed in conjunction with craniospinal radiation therapy. Twenty-eight patients also received chemotherapy. The median age was 9 years (range, 3 to 34 years), and the male to female ratio was 3:1. Twenty-seven patients had standard-risk disease, and five patients had high-risk disease. Craniospinal doses ranged from 23.4 to 39.6 Gy, and total tumor bed doses ranged from 54 to 59.4 Gy.

Results: With a median follow-up of 56 months, six patients have relapsed; five relapsed outside of the posterior fossa, and one failed within the posterior fossa, outside of the high-dose boost volume. Five-year actuarial disease-free and overall survival rates were 84% and 85%, respectively. Freedom from posterior fossa failure was 100% and 86% at 5 and 10 years, respectively. Freedom from distant failure was 84% at 5 years, with a trend for improvement when full-dose craniospinal radiation (36 to 39.6 Gy) was used compared with a reduced dose (23.4 Gy) of radiation (100% v 63%, respectively; P = .06). No other predictive variables were identified.

Conclusion: Conformal treatment to the tumor bed allows for significant sparing of critical structures. The posterior fossa failure rate in this series is similar to that reported when the entire posterior fossa is treated. This approach should be investigated further in a phase III trial.
High-Dose Therapy for Patients With Primary Multifocal and Early Relapsed Ewing’s Tumors: Results of Two Consecutive Regimens Assessing the Role of Total-Body Irradiation
Authors: Burdach S. , Meyer-Bahlburg A. , Laws H.J. , Haase R. , van Kaik B. , Metzner B. , Wawer A. , Finke R. , Göbel U. , Haerting J. , Pape H. , Gadner H. , Dunst J. , Juergens H.
Published: August 2003

Purpose: Risk stratification of metastatic and relapsed Ewing’s tumors (ETs) has been a matter of debate during the last decade. Patients with bone or bone marrow metastases or early or multiple relapses constitute the worst risk group in ET and have a poorer prognosis than patients with primary lung metastases or late relapses. In this article, the results of the present Meta European Intergroup Cooperative Ewing Sarcoma Study (MetaEICESS) (tandem melphalan/etoposide [TandemME]) were compared with the result of the previous study (hyper melphalan/etoposide [HyperME]), both at 5 years, in a patient population within the same high-risk stratum to determine toxicity.

Patients and Methods: Among 54 eligible patients, 26 were treated according to the HyperME protocol, and 28 were treated according to TandemME protocol. Patients received six cycles of the Cooperative Ewing Sarcoma Study treatment in HyperME and six cycles of the EICESS treatment in TandemME as induction chemotherapy. Patients also received involved-compartment irradiation for local intensification and myeloablative systemic intensification consolidation with hyperfractionated total-body irradiation (TBI) combined with melphalan/etoposide in HyperME or two times the melphalan/etoposide in TandemME followed by autologous stem-cell transplantation.

Results: The event-free survival (EFS) rate ± SD in HyperME and TandemME was 22% ± 8% and 29% ± 9%, respectively. The dead of complication rate was 23% in HyperME and 4% in TandemME.

Conclusion: TandemME offers a decent, albeit still not satisfactory, rate of long-term remissions in most advanced ETs (AETs), with short-term treatment and acceptable toxicity. TBI was not required to maintain EFS level in this setting but was associated with a high rate of toxic death. Future prospective studies in unselected patients are warranted to evaluate high-dose therapy in an unselected group of patients with AET.
Pheochromocytoma: State-of-the-Art and Future Prospects
Authors: Bravo Emmanuel L. , Tagle Rodrigo
Published: August 2003

This review provides current understanding of the pathophysiology of pheochromocytoma and the wide range of associated clinical manifestations that have led to earlier recognition of the disease. In addition, it reviews optimal screening methods and localization techniques that have enhanced the clinician’s ability to make the diagnosis with greater certainty. This article will also discuss alternative antihypertensive regimens and innovative anesthetic and surgical procedures that have made successful management more promising than ever before.

Areas requiring further development include additional clinical experience with the measurement of plasma metanephrines that have been shown to have high sensitivity and specificity in the diagnosis of sporadic and familial pheochromocytoma, optimizing cost effectiveness of diagnostic imaging, improving the ability to predict and treat malignant pheochromocytoma, and elucidating not only the surgical approach but, perhaps with rapid advances in molecular genetics, ways of preventing familial pheochromocytoma.
Dietary Carbohydrate Deprivation Increases 24-Hour Nitrogen Excretion without Affecting Postabsorptive Hepatic or Whole Body Protein Metabolism in Healthy Men
Authors: Bisschop P. H. , de Sain-van der Velden M. G. M. , Stellaard F. , Kuipers F. , Meijer A. J. , Sauerwein H. P. , Romijn J. A.
Published: August 2003

Because insulin is an important regulator of protein metabolism, we hypothesized that physiological modulation of insulin secretion, by means of extreme variations in dietary carbohydrate content, affects postabsorptive protein metabolism. Therefore, we studied the effects of three isocaloric diets with identical protein content and low-carbohydrate/high-fat (2% and 83% of total energy, respectively), intermediate-carbohydrate/intermediate-fat (44% and 41% of total energy, respectively), and high-carbohydrate/low-fat (85% and 0% of total energy, respectively) content in six healthy men. Whole body protein metabolism was assessed by 24-h urinary nitrogen excretion, postabsorptive leucine kinetics, and fibrinogen and albumin synthesis by infusion of [1-13C]leucine and [1-13C]valine.

The low-carbohydrate/high-fat diet resulted in lower absorptive and postabsorptive plasma insulin concentrations, and higher rates of nitrogen excretion compared with the other two diets: 15.3 ± 0.9 vs. 12.1 ± 1.1 (P = 0.03) and 10.8 ± 0.5 g/24 h (P = 0.005), respectively. Postabsorptive rates of appearance of leucine and of leucine oxidation were not different among the three diets. In addition, dietary carbohydrate content did not affect the synthesis rates of fibrinogen and albumin.

In conclusion, eucaloric carbohydrate deprivation increases 24-h nitrogen loss but does not affect postabsorptive protein metabolism at the hepatic and whole body level. By deduction, dietary carbohydrate is required for an optimal regulation of absorptive, rather than postabsorptive, protein metabolism.
Efficacy of Glyburide/Metformin Tablets Compared with Initial Monotherapy in Type 2 Diabetes
Authors: Garber Alan J. , Donovan Daniel S. , Dandona Paresh , Bruce Simon , Park Jong-Soon
Published: August 2003

Many patients with type 2 diabetes fail to achieve or maintain the American Diabetes Association’s recommended treatment goal of glycosylated hemoglobin levels. This multicenter, double-blind trial enrolled patients with type 2 diabetes who had inadequate glycemic control [glycosylated hemoglobin A1C (A1C), >7% and <12%) with diet and exercise alone to compare the benefits of initial therapy with glyburide/metformin tablets vs. metformin or glyburide monotherapy. Patients (n = 486) were randomized to receive glyburide/metformin tablets (1.25/250 mg), metformin (500 mg), or glyburide (2.5 mg). Changes in A1C, fasting plasma glucose, fructosamine, serum lipids, body weight, and 2-h postprandial glucose after a standardized meal were assessed after 16 wk of treatment. Glyburide/metformin tablets caused a superior mean reduction in A1C from baseline (−2.27%) vs. metformin (−1.53%) and glyburide (−1.90%) monotherapy (P = 0.0003). Glyburide/metformin also significantly reduced fasting plasma glucose and 2-h postprandial glucose values compared with either monotherapy. The final mean doses of glyburide/metformin (3.7/735 mg) were lower than those of metformin (1796 mg) and glyburide (7.6 mg). First-line treatment with glyburide/metformin tablets provided superior glycemic control over component monotherapy, allowing more patients to achieve American Diabetes Association treatment goals with lower component doses in drug-naive patients with type 2 diabetes.
Bone Histomorphometry in Children and Adolescents with β-Thalassemia Disease: Iron-Associated Focal Osteomalacia
Authors: Mahachoklertwattana Pat , Sirikulchayanonta Vorachai , Chuansumrit Ampaiwan , Karnsombat Patcharee , Choubtum Lulin , Sriphrapradang Arporn , Domrongkitchaiporn Somnuek , Sirisriro Rojana , Rajatanavin Rajata
Published: August 2003

Thalassemia/hemoglobinopathy is a hereditary disease that causes chronic anemia and increased erythropoiesis. Consequently, an expansion of bone marrow spaces may contribute to osteopenia/osteoporosis. However, the pathogenesis of bone changes is not yet known. We, therefore, carried out the study on bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated β-thalassemia disease with the hope of gaining some new insight into the cellular and structural alterations of thalassemic bone. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Bone mineral density (BMD) measurements were performed by dual energy x-ray absorptiometry. Most patients had growth retardation and delayed bone age. BMD was low especially at the lumbar spine. Serum IGF-I levels were almost always low. Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. Moreover, focal thickened osteoid seams were found together with focal iron deposits. Dynamic bone formation study revealed reduced bone formation rate. These findings indicate that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. Iron deposits in bone and low circulating IGF-I levels may partly contribute to the above findings.
CYP21 Gene Mutation Analysis in 198 Patients with 21-Hydroxylase Deficiency in The Netherlands: Six Novel Mutations and a Specific Cluster of Four Mutations
Authors: Stikkelbroeck Nike M. M. L. , Hoefsloot Lies H. , de Wijs Ilse J. , Otten Barto J. , Hermus Ad R. M. M. , Sistermans Erik A.
Published: August 2003

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. The aim of this study was to assess the frequencies of CYP21 mutations and to study genotype-phenotype correlation in a large population of Dutch 21-hydroxylase deficient patients. From 198 patients with 21-hydroxylase deficiency, 370 unrelated alleles were studied. Gene deletion/conversion was present in 118 of the 370 alleles (31.9%). The most frequent point mutations were I2G (28.1%) and I172N (12.4%). Clustering of pseudogene-derived mutations in exons 7 and 8 (V281L-F306 + 1nt-Q318X-R356W) on a single allele was found in seven unrelated alleles (1.9%). This cluster had been reported before in two other Dutch patients and in two patients in a study from New York, but not in other series worldwide. Six novel mutations were found: 995–996insA, 1123delC, G291R, S301Y, Y376X, and R483Q. Genotype-phenotype correlation (in 87 well documented patients) showed that 28 of 29 (97%) patients with two null mutations and 23 of 24 (96%) patients with mutation I2G (homozygous or heterozygous with a null mutation) had classic salt wasting. Patients with mutation I172N (homozygous or heterozygous with a null or I2G mutation) had salt wasting (2 of 17, 12%), simple virilizing (10 of 17, 59%), or nonclassic CAH (5 of 17, 29%). All six patients with mutation P30L, V281L, or P453S (homozygous or compound heterozygous) had nonclassic CAH. The frequency of CYP21 mutations and the genotype-phenotype correlation in 21-hydroxylase deficient patients in The Netherlands show in general high concordance with previous reports from other Western European countries. However, a cluster of four pseudogene-derived point mutations on exons 7 and 8 on a single allele, observed in almost 2% of the unrelated alleles, seems to be particular for the Dutch population and six novel CYP21 gene mutations were found.
Interaction between Vitamin D Receptor Genotype and Estrogen Receptor α Genotype Influences Vertebral Fracture Risk
Authors: Colin E. M. , Uitterlinden A. G. , Meurs J. B. J. , Bergink A. P. , Van De Klift M. , Fang Y. , Arp P. P. , Hofman A. , van Leeuwen J. P. T. M. , Pols H. A. P.
Published: August 2003

In view of the interactions of vitamin D and the estrogen endocrine system, we studied the combined influence of polymorphisms in the estrogen receptor (ER) α gene and the vitamin D receptor (VDR) gene on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and three ERα haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. We captured 131 nonvertebral and 85 vertebral fracture cases during a mean follow-up period of 7 yr. ERα haplotype 1 was dose-dependently associated with increased vertebral fracture risk (P < 0.001) corresponding to an odds ratio of 1.9 [95% confidence interval (CI), 0.9–4.1] per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (P = 0.01) between ERα haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ERα haplotype 1 with vertebral fracture risk was only present in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6–9.9) for heterozygous and 10.3 (95% CI, 2.7–40) for homozygous carriers of ERα haplotype 1. These associations were independent of bone mineral density. In conclusion, interaction between ERα and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density.
Sexual Dimorphism in the Growth Hormone and Insulin-Like Growth Factor Axis at Birth
Authors: Geary Michael P. P. , Pringle P. Jane , Rodeck Charles H. , Kingdom John C. P. , Hindmarsh Peter C.
Published: August 2003

In rodents and humans there is a sexually dimorphic pattern of GH secretion that influences the serum concentration of IGF-I. Pattern differences can be identified in children, but it is not known how early this difference is established. We studied the plasma concentrations of IGF-I, IGF-II, IGF-binding protein-3 (BP-3), and GH in cord blood taken from the offspring of 1650 singleton Caucasian pregnancies born at term and related these values to birth weight, length, and head circumference. Pregnancies complicated by preterm delivery, antepartum hemorrhage, pregnancy-induced hypertension, preeclampsia, or gestational diabetes and where cigarette smoking continued were excluded, resulting in a cohort of 987. Cord plasma concentrations of IGF-I, IGF-II, and IGFBP-3 were influenced by factors influencing birth size: gestational age at delivery, mode of delivery, maternal height, and parity of the mother. Plasma GH concentrations were inversely related to the plasma concentrations of IGF-I and IGFBP-3; 10.2% of the variability in cord plasma IGF-I concentration and 2.7% for IGFBP-3 was explained by sex of the offspring and parity. None of the factors, apart from maternal height, influenced cord serum IGF-II concentrations (adjusted r2 = 1%). Sex of the baby, mode of delivery, and parity influenced cord serum GH concentrations (adjusted r2 = 2.6%). Birth weight, length, and head circumference measurements were greater in males than females (P < 0.001). Mean cord plasma concentrations of IGF-I (males, 66.4 ± 1.2 μg/liter; females, 74.5 ± 1.3 μg/liter; P < 0.001) and IGFBP-3 (males, 910 ± 13 μg/liter; females 978 ± 13 μg/liter; P < 0.001) were significantly lower in males than females. Cord plasma GH concentrations were higher in males than females (males, 30.0 ± 1.2 mU/liter; females, 26.9 ± 1.1 mU/liter; P = 0.05), but no difference was noted between the sexes for IGF-II (males, 508 ± 6 μg/liter; females, 519 ± 6 μg/liter; P = NS). After adjustment for gestational age, parity, and maternal height, cord plasma concentrations of IGF-I and IGFBP-3 along with sex explained 38.0% of the variability in birth weight, 25.0% in birth length, and 22.7% in head circumference. These data demonstrate that in a group of singleton Caucasian babies born at term, cord plasma IGF-I, IGFBP-3, and GH concentrations relate to birth size, with evidence for sexual dimorphism in the GH-IGF axis.
Early Treatment Improves Growth and Biochemical and Radiographic Outcome in X-Linked Hypophosphatemic Rickets
Authors: Mäkitie O. , Doria A. , Kooh S. W. , Cole W. G. , Daneman A. , Sochett E.
Published: August 2003

X-Linked hypophosphatemic rickets (XLH) is characterized by hypophosphatemia, rickets, and impaired growth. Despite oral phosphate and 1,25-dihydroxyvitamin D3 treatment, many patients have suboptimal growth and bone healing. The aim of this study was to assess whether age at treatment onset impacts the outcome. Growth data, biochemistry, and radiographs of 19 well-controlled patients with XLH were analyzed retrospectively. Patients were divided into two groups based on the age at treatment onset (group 1, <1.0 yr; group 2, ≥1.0 yr). The median height z-score was higher in group 1 (n = 8) than in group 2 (n = 11) at treatment onset [−0.4 sd score (SDS) vs. −1.7 SDS; P = 0.001], at the end of the first treatment year (−0.7 SDS vs. −1.8 SDS; P = 0.009), throughout childhood (P > 0.05) and until predicted adult height (−0.2 SDS vs. −1.2 SDS; P = 0.06). The degree of hypophosphatemia was similar in both groups, but serum alkaline phosphatase remained higher in group 2 throughout childhood. Radiographic signs of rickets were more marked in group 2, but even patients with early treatment developed significant skeletal changes of rickets. These data suggest that treatment commenced in early infancy results in improved outcome in patients with XLH, but does not completely normalize skeletal development.
Impaired Endothelium-Dependent Vasodilatation in Subclinical Hypothyroidism: Beneficial Effect of Levothyroxine Therapy
Authors: Taddei Stefano , Caraccio Nadia , Virdis Agostino , Dardano Angela , Versari Daniele , Ghiadoni Lorenzo , Salvetti Antonio , Ferrannini Ele , Monzani Fabio
Published: August 2003

Subclinical hypothyroidism (sHT) is associated with enhanced cardiovascular risk. To test the hypothesis that patients with sHT are characterized by endothelial dysfunction and impaired nitric oxide (NO) availability, in 14 patients [serum cholesterol, 218 ± 41 mg/dl (5.6 ± 0.9 mm)] and 28 euthyroid subjects, subdivided into groups A and B [serum cholesterol, 170 ± 19 mg/dl (4.4 ± 0.5 mm) and 217 ± 21 mg/dl (5.6 ± 0.5 mm), respectively], we studied the forearm blood flow (strain-gauge plethysmography) response to intrabrachial acetylcholine, an endothelium-dependent vasodilator, at baseline and during infusion of NG-monomethyl-l-arginine (L-NMMA), a NO synthase inhibitor. Response to sodium nitroprusside and minimal forearm vascular resistances were also evaluated. In sHT patients, vasodilation to acetylcholine was reduced, compared with group B (+358 ± 29% vs. +503 ± 19%, P = 0.0003) and group A (663 ± 65%, P = 0.02 vs. group B and P = 0.0002 vs. sHT). L-NMMA blunted the vasodilation to acetylcholine in groups A and B (49.1 ± 6.3% and 42.7 ± 5.5% maximal forearm blood flow reduction, respectively, P < 0.0001 vs. acetylcholine), whereas it was ineffective in sHT patients (12.8 ± 2.5%). Response to sodium nitroprusside and minimal vascular resistances were similar. In sHT (n = 9) patients, 6 months of euthyroidism by levothyroxine replacement increased acetylcholine-vasodilation and restored L-NMMA inhibition. Patients with sHT are characterized by endothelial dysfunction resulting from a reduction in NO availability, an alteration partially independent of dyslipidemia and reversed by levothyroxine supplementation.
Pseudo-Cushing Syndrome Caused by Fenofibrate Interference with Urinary Cortisol Assayed by High-Performance Liquid Chromatography
Authors: Meikle A. Wayne , Findling James , Kushnir Mark M. , Rockwood Alan L. , Nelson Gordon J. , Terry Alan H.
Published: August 2003

Urinary free cortisol (UFC) excretion over 24 h reflects the production rate of cortisol and is used commonly in the diagnosis of Cushing syndrome. We report on two patients evaluated for Cushing syndrome who had elevated UFC when analyzed by HPLC but normal values for the analysis performed by RIA and HPLC-mass spectrometry/mass spectrometry (HPLC-MS/MS). Other laboratory testing was inconsistent with the diagnosis of Cushing syndrome and raised doubts about the diagnosis. We identified a probable cause of analytical interference as coming from fenofibrate (Tricor), medication taken by the patients. Fenofibrate peak overlapped with the HPLC peak of cortisol and produced an MS/MS transition overlapping the major transition of cortisol. A second MS/MS transition was free from interference. In summary, fenofibrate administration may cause false elevation of UFC values determined by HPLC or HPLC-MS/MS in patients evaluated for Cushing syndrome. An HPLC-MS/MS method using multiple mass transitions, rather than a single transition, allows accurate quantitation of urinary cortisol in patients taking fenofibrate.
Local and Systemic Impact of Transcriptional Up-Regulation of 11β-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity
Authors: Wake Deborah J. , Rask Eva , Livingstone Dawn E. W. , Söderberg Stefan , Olsson Tommy , Walker Brian R.
Published: August 2003

In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11β-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized β coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-α and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 ± 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.
Pins and Plaster Aren’t Enough: A Call for the Evaluation and Treatment of Patients with Osteoporotic Fractures
Authors: Siris Ethel S. , Bilezikian John P. , Rubin Mishaela R. , Black Dennis M. , Bockman Richard S. , Bone Henry G. , Hochberg Marc C. , McClung Michael R. , Schnitzer Thomas J.
Published: August 2003

A history of an osteoporotic fracture is a powerful predictor of future fractures. Older patients who sustain low trauma fractures are candidates for interventions that should include confirmation of the diagnosis of osteoporosis, adequate calcium and vitamin D administration, and use of an osteoporosis therapy that is proven to lower fracture risk. Recently, however, several reports in the literature have indicated that, in general, those physicians who diagnose and treat fractures, i.e. radiologists, orthopedic surgeons, physiatrists, and those who provide general medical care to these fracture patients, the primary care physicians, are not evaluating patients with acute fractures for the presence of osteoporosis and are not prescribing calcium, vitamin D, or specific pharmacological therapy to reduce future fracture risk. These reports suggest that implementation of a standard of care for the subsequent medical management of the older patient with an acute fracture is needed urgently. Diagnostic tools and several effective therapies exist, but these are underused by the physicians who interface with these patients. A call to action is necessary to reduce the human and economic costs associated with this serious and treatable disease.
The mediator coactivator complex: functional and physical roles in transcriptional regulation
Authors: Lewis Brian A. , Reinberg Danny
Published: August 2003

In vivo, the DNA is packed into chromatin and transcription is dependent upon activators that recruit other factors to reverse the repressive effects of chromatin. The response to activators requires additional factors referred to as coactivators. One such coactivator, mediator, is a multi-subunit complex capable of responding to different activators. It plays an key role in activation, bridging DNA-bound activators, the general transcriptional machinery, especially RNA polymerase II, and the core promoter. Its subunits are necessary for a variety of positive and negative regulatory processes and serve as the direct targets of activators themselves. In vivo and in vitro studies support various roles for mediator in transcription initiation, while structural studies demonstrate that it engages in multiple interactions with RNA polymerase II, and adopts conformations that are activator specific.
Phosphorylation of serine 10 in histone H3, what for?
Authors: Prigent Claude , Dimitrov Stefan
Published: August 2003

Eukaryotic cells must possess mechanisms for condensing and decondensing chromatin. Chromatin condensation is particularly evident during mitosis and cell death induced by apoptosis, whereas chromatin decondensation is necessary for replication, repair, recombination and transcription. Histones are among the numerous DNA-binding proteins that control the level of DNA condensation, and post-translational modification of histone tails plays a critical role in the dynamic condensation/decondensation that occurs during the cell cycle. Phosphorylation of Ser10 in the tails of histone H3 has been extensively studied in many organisms. Interestingly, this modification is involved in both transcription and cell division, two events requiring opposite alterations in the degree of chromatin compaction. How does one and the same modification of histone H3 fulfil such roles? For instance, in interphase, phosphorylation of H3 correlates with chromatin relaxation and gene expression, whereas in mitosis it correlates with chromosome condensation. What is the kinase and under what circumstances does Ser10 becomes phosphorylated? Most importantly, what are the consequences of phosphorylation of this residue?
Carbohydrates to Heterocycles: A New Strategy for the Synthesis of Enantiomerically Pure Pyridazines and Oxazines Derived from Epoxypyranoside Scaffolds
Authors: Al-Qawasmeh Raed A , Al-Tel Taleb H , Abdel-Jalil Raid J , Voelter Wolfgang
Published: August 2003

An easy and high yield access to enantiomerically pure pyridazines and oxazines from epoxy pyranosides via β-keto ester functionalization is described.
Anionic Polymerization of Tetraphenylgermole-spiro-cyclogermatetrasilane. A Striking Contrast in the Mechanism to the Corresponding Silole Case
Authors: Sanji Takanobu , Funaya Munehito , Sakurai Hideki
Published: August 2003

Germole-incorporated polygermatetrasilanes are prepared by ring-opening anionic polymerization of tetraphenylgermole-spiro-cyclogermatetrasilane. Interesting contrasts in the polymerization mechanism between silole- and germole-incorporated polymers are discussed. Properties of novel polymers are described.
Synthesis of Poly(3-hexylthiophene) by Using the VO(acac)2-FeCl3-O2 Catalytic System
Authors: Yu Shuyan , Hayakawa Teruaki , Ueda Mitsuru
Published: August 2003

Poly(3-hexylthiophene) (P3HT) was prepared by the oxidation coupling polymerization of 3-hexylthiophene (3HT) with molecular oxygen as an oxidant in the presence of vanadyl acetylacetonate (IV) (VO(acac)2) and ferric chloride (FeCl3). The polymerization at a molar ratio of VO(acac)2 / FeCl3 / 3HT = 1 / 2 / 5 in 1,2-dichloroethane at 0 °C for 164 h under oxygen gave P3HT in 61% yield. The resulting polymer gave a number average molecular weight (Mn) of 2.1 × 104 (Mw / Mn = 3.0; Mw: weight average molecular weight) and a head-to-tail content of 65%. The VO(acac)2-FeCl3 complex is supposed to work as a catalyst.
Dehydrogenation of Ethane into Ethylene by Carbon Dioxide over Chromium Supported on Sulfated Silica
Authors: Wang Shaobin , Murata Kazuhisa , Hayakawa Takashi , Hamakawa Satoshi , Suzuki Kunio
Published: August 2003

Cr2O3 supported on sulfated silica catalysts exhibit excellent performance for the oxidative dehydrogenation of ethane into ethylene by carbon dioxide, giving 90% selectivity towards ethylene at 60% ethane conversion at 650 °C.
Syntheses of New {Tetrakis(1-pyrazolyl)borato}samarium(III) Complexes and Their Temperature-Dependent Exchange Motions of All Pyrazolyl Groups
Authors: Onishi Masayoshi , Yamaguchi Hitoshi , Shimotsuma Hirokazu , Hiraki Katsuma , Nagaoka Junko , Kawano Hiroyuki
Published: August 2003

As the first unambiguous syntheses and characterization of the {tetrakis(1-pyrazolyl)borato}lanthanide(III) complexes, stable eight-coordinate (β-ketoenolato)samariums [Sm{η3-B(pz)4}2(β-ketoenolato)] (pz = 1-pyrazolyl group) were prepared, and novel stereochemically non-rigid temperature-dependent motions of the B(pz)4 ligands were observed on their solution-state 1H-NMR spectra, showing the spectroscopic equivalence of coordinated and uncoordinated pyrazolyl groups at high temperatures.
Biocatalytic One-step Synthesis of n-Octyl β-d-Xylotrioside and Xylobioside from Xylan and n-Octanol in Supercritical Carbon Dioxide
Authors: Matsumura Shuichi , Nakamura Takehiro , Yao Eiya , Toshima Kazunobu
Published: August 2003

n-Octyl β-d-xylotrioside and xylobioside, which are effective next generation surfactants, can be prepared by the one-step reaction of xylan and n-octanol using acetone powder (acetone-dried cells) of Aureobasidium pullulans KK415 (ATCC 201145) as the enzyme source of xylanase in supercritical carbon dioxide (scCO2). Yields of the octyl glycosides were significantly increased using scCO2. Furthermore, without scCO2, n-octyl xylotrioside was hardly produced.
Linked Cluster Complex: Crystal Structure of [RuCo2(CO)9](μ3-η2HC2CH2OC6H4OCH2C2Hη2-μ3)[RuCo2(CO)9]
Authors: Chen Xue-Nian , Zhang Jie , Yin Yuan-Qi , Wang Wen-Ling
Published: August 2003

Two configurations of RuCo2(CO)9(HC2R) unit confirmed by the crystal structure of the linked cluster complex [RuCo2(CO)9](μ3-η2HC2CH2OC6H4OCH2C2Hη2-μ3)[RuCo2(CO)9] are reported.
Spin-Glass Behavior of Hydrogen Molybdenum Bronze, HxMoO3
Authors: Sotani Noriyuki , Fukumoto Takuya , Eda Kazuo , Kunitomo Masakazu , Nakagawa Masahito
Published: August 2003

According to magnetic studies, hydrogen molybdenum bronzes showed different magnetic behaviors. The magnetic susceptibility showed a cusp at around 60 K and the history dependence between the zero field cooled (ZFC) and the field cooled (FC) susceptibility. This is typical for the spin-glass behavior. This behavior was firstly found for hydrogen molybdenum bronzes.
Stereoselective Synthesis of the Chiral Tetrahydropyrane Core of Swinholides and Misakinolides
Authors: Hayakawa Hiroyuki , Iida Kouki , Miyazawa Masahiro , Miyashita Masaaki
Published: August 2003

Stereoselective synthesis of the optically pure tetrahydropyrane core of swinholides and misakinolide A starting from (S)-methyl lactate is described in which the highly stereoselective intramolecular iodoetherification for construction of the tetrahydropyrane ring and the regioselective ring-opening reaction of an epoxide are involved as key steps.
Rate Constants for Hydrogen Atom Abstraction by α-Tocopheroxyl Radical from Lipid, Hydroperoxide and Ascorbic Acid
Authors: Watanabe Akira , Noguchi Noriko , Takahashi Mareyuki , Niki Etsuo
Published: August 2003

The rate constants for each reaction of α-tocopheroxyl radical with methyl linoleate, t-butyl hydroperoxide and ascorbic acid, and also the bimolecular reaction of α-tocopheroxyl radicals were measured by a stopped-flow ESR technique in order to understand the antioxidant action of α-tocopherol. It was suggested that α-tocopheroxyl radical is primarily reduced by ascorbic acid in vivo.
Novel Channel Structure Formed with Methyl 3-(9-Anthrylcarbonyloxy)cholate Using Orthogonally Stacked Building Blocks
Authors: Kohmoto Shigeo , Sakayori Katsuya , Noguchi Yasuhiro , Yamaguchi Kentaro , Kishikawa Keiki , Yamamoto Makoto
Published: August 2003

The new type channel structure in the chemistry of cholic acid was created by the protection of both end (the hydroxy group at the 3-position and the carboxy group at the 23-position) of cholic acid. The inhibition of the intermolecular hydrogen bonding existing in cholic acid at these positions altered the crystal structure completely.
Sulfur-Bridged Cubane-Type Molybdenum-Cadmium Clusters with Diethyldithiophosphato or Nitrilotriacetato Ligands
Authors: Sakane Genta , Kawasaki Hideki , Yamasaki Mikio , Adachi Hirohiko , Shibahara Takashi
Published: August 2003

The metal incorporation reactions of the sulfur-bridged incomplete cubane-type molybdenum clusters in nonaqueous solvent or pure water are reported for the first time. The reaction of the clusters [Mo3S4(dtp)4(CH3CN)] (1) in acetonitrile and [Mo3S4(Hnta)3]2− in pure water with cadmium metal result in the formation of two novel molybdenum-cadmium mixed-metal clusters [(CH3CN)(dtp)4Mo3S4CdS4Mo3(dtp)4(CH3CN)] (3) and [(Hnta)3Mo3S4CdS4Mo3(Hnta)3]4− (4), respectively. Although the clusters 3 and 4 have sandwich cubane-type Mo3S4CdS4Mo38+ cores of the same type, the peak positions of electronic spectra of 3 (856 nm) and 4 (1235 nm) at the longest wavelength are distinctly different from each other.
A Cyclic Hexacopper(II) Complex with 1,2,4-Triazole and Hydroxo as Bridging Ligands
Authors: Liu Jia-Cheng , Zhuang Jin-Zhong , You Xiao-Zeng , Huang Xiao-Ying
Published: August 2003

A cyclic hexanuclear copper(II) complex, [Cu6(OH)6(admtrz)6(H2O)5(C2H5OH)2](ClO4)6·4H2O 1, (admtrz = 4-amino-3,5-dimethyl-1,2,4-triazole), has been isolated and structurally characterized by X-ray crystallography, which exhibited a strong antiferromagentic exchange in the range of 4-300 K.
Preparation of Monodisperse ZnS Nanoparticles by Size Selective Photocorrosion
Authors: Ohko Yoshihisa , Setani Masanobu , Sakata Takao , Mori Hirotaro , Yoneyama Hiroshi
Published: August 2003

The size-distribution of ZnS nanoparticles (Q-ZnS) of 4.2 ± 0.6 nm was narrowed to 2.6 ± 0.2 nm by sequential irradiation with monochromatic light of 313 nm, 303 nm, and 297 nm to an air-saturated ZnS colloidal solution in the presence of sodium hexametaphosphate as a stabilizer and methylviologen as an electron acceptor.
Micropolarity around a Zwitterionic Solvatochrome Covalently Fixed in the Cavity of Bowl-Shaped Cyclophanes
Authors: Akine Shigehisa , Goto Kei , Okazaki Renji
Published: August 2003

Bowl-shaped bimacrocyclic cyclophanes with a zwitterionic solvatochrome embedded in the cavity were synthesized and the micropolarity around their intracavity functionality in various solvents was estimated by using the absorption wavelengths of the chromophore, the solvent effects on which were found to be dependent on the properties of the cyclophane framework.
Enantioselective Synthesis of Pyrrolydinonyl Thymine Nucleoside Analogues
Authors: Jin Liren , Wu Hong , Wu Huailing , Huang Peiqiang , Jung Kyeongeun , Lim Hong
Published: August 2003

Enantioselective synthesis of a novel kind of optically active nucleoside analogues from natural malic acid is described. In the given nucleoside analogues the tetrahydrofuran ring is replaced by a pyrrolidinonyl ring bearing both a primary and a secondary hydroxy groups which could be useful for the preparation of novel oligonucleotides. Assay of the prepared nucleoside analogues showed non-activity against virus.