bluuebunny/crossref_metadata_2025 huggingface dataset:
The Reproducibility of a Binary Tumor Grading System for Uterine Endometrial Endometrioid Carcinoma, Compared with FIGO System and Nuclear Grading
Authors: Sagae Satoru , Saito Tsuyoshi , Satoh Masaaki , Ikeda Tatsuru , Kimura Sachiko , Mori Mitsuru , Sato Noriyuki , Kudo Ryuichi
Published: February 2005

Objective: A binary grading system has been proposed to assess the amount of solid growth, the pattern of invasion, and the presence of necrosis, and thereby divide endometrial endometrioid carcinomas into low- and high-grade tumors. We analyzed this system for predicting the prognosis, with respect to inter- and intraobserver reproducibility and treatment modalities. Methods: A total of 200 endometrial carcinomas, based on hysterectomy specimens, were graded according to the binary grading system, for comparison against The International Federation of Gynecology and Obstetrics (FIGO) system and nuclear grading. Results: Both inter- and intraobserver agreement using the binary grading system (ĸ = 0.57; percent agreement: 82% and ĸ = 0.62; 84%) were superior compared with the FIGO system (0.50; 60% and 0.62; 73%) and the nuclear grading (0.23; 49% and 0.43; 65%). Patients with early-stage low-grade tumors had a 98% rate for 5-year survival (5YS). Patients with early-stage high-grade tumors, and those with advanced-stage low-grade tumors, had respectively 86% to 87% rates for 5YS. But patients with advanced-stage high-grade tumors had a 49% rate for 5YS. In binary low-grade early-stage tumors, the patient outcome was better with no adjuvant therapy and chemotherapy, compared with other therapies. Conclusion: A binary grading system was superior to others in permitting greater reproducibility and predicting the prognosis of endometrial cancer patients.
Higher Farnesyl Diphosphate Synthase Activity in Human Colorectal Cancer Inhibition of Cellular Apoptosis
Authors: Notarnicola Maria , Messa Caterina , Cavallini Aldo , Bifulco Maurizio , Tecce Mario Felice , Eletto Davide , Di Leo Alfredo , Montemurro Severino , Laezza Chiara , Caruso Maria Gabriella
Published: February 2005

Objective: Farnesyl diphosphate synthase (FPPs) produces FPP which is considered a branch-point intermediate in the synthesis of sterols and isoprenylated cellular metabolites. In this study we investigated whether detectable FPPs activity was present in human colorectal cancer (CRC), also evaluating in vitro the role of this enzyme in the growth and apoptosis of CRC cells by using Pamidronate (PAM), a FPPs activity inhibitor. Methods: The activity level of FPPs was determined in CRC and the normal surrounding mucosa of 50 patients by radiochemical assay. The FPPs mRNA expression was investigated in 15 of 50 patients by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). K-ras mutation was evaluated using PCR and restriction enzyme analysis. Cell growth and apoptosis, after PAM treatment, in human CRC cell line DLD-1 were measured by MTT test and DNA fragmentation, respectively. Results: FPPs activity was detectable in human CRC. FPPs activity and its mRNA were significantly more abundant in cancer samples than in normal mucosa. In vitro PAM resulted in a significant reduction of cell growth and also gave rise to a marked proapoptotic effect. Conclusions: This study provides the first evidence of the presence of FPPs activity in human CRC. Moreover, FPPs enzyme was found to play a significant role in colon cancer proliferation.
Dose Escalation of Busulfan with Pentoxifylline and Ciprofloxacin in Patients with Breast Cancer Undergoing Autologous Transplants
Authors: Bensinger William I. , Buckner C. Dean , Lilleby Kathy , Holmberg Leona , Storb Rainer , Slattery John T.
Published: February 2005

Objective: There is evidence that pentoxifylline (PTX) and ciprofloxacin (Cipro) may protect patients from the effects of chemotherapy and radiation, which could allow further drug dose escalation. This study was conducted to determine whether oral and intravenous (IV) PTX and Cipro permits increased dose levels of oral busulfan (BU) with a fixed dose of IV cyclophosphamide (CY) in patients with breast cancer receiving autologous or syngeneic hematopoetic cell transplantation. Methods: Sixty-seven patients received PTX and Cipro with CY of 150 mg/kg and escalating doses of BU. The BU dosing began at 15 mg/kg, escalating in 1 mg/kg increments in groups of 4 patients. If no grade 3 or 4 regimen- related toxicities (RRT) were observed, the next 4 patients were treated at a higher dose. Results: Excessive RRT was not observed until BU 21 mg/kg was reached. Two patients at this dose level had RRTs and their BU steady-state concentration (Css) were 1,414 and 1,545 ng/ml. At a BU dose of 20 mg/kg , average BU Css 1,280 ng/ml, 0/4 had RRT. Among 10 patients who had BU Css targeted to 1,350 ng/ml, RRTs occurred in 2 (20%). Conclusions: In this preliminary study with PTX and Cipro, the maximum tolerated dose of BU that can be given with CY (150 mg/kg) was 20 mg/kg, a BU Css of approximately 1,300 ng/ml. A randomized trial is necessary to determine whether PTX and Cipro reduce the toxicities of this regimen.
Clinicopathological Features of Extranodal Lymphomas: Kuwait Experience
Authors: Temmim L. , Baker H. , Amanguno H. , Madda J.P. , Sinowatz F.
Published: February 2005

A total of 935 patients with extranodal non-Hodgkin lymphoma (NHL) diagnosed in the period between January 1985 and December 2000 in Kuwait Cancer Center, serving the whole population of Kuwait, were used to describe the clinicopathological and epidemiological features of extranodal lymphomas in Kuwait. Extranodal lymphomas accounted for 45% of all NHL observed during this time. All NHL cases from Kuwait Cancer registry were analyzed and pathologically reclassified using the latest WHO (2000) classification. The most common lymphoma observed was diffuse large B-cell lymphoma (58.60%) followed by Burkitt´s lymphoma (BL) (3.80%). In the pediatric group, BL comprises more than two thirds of all patients (77.20%). The most common extranodal sites were stomach (19.70%) and skin (17.80%) in the adult group, large intestine (29.80%) and small intestine (19.30%) in the pediatric age group. The majority (73.40%) of adult extranodal lymphomas was in stage IE–IIE and had a very good prognosis. On the contrary, the majority of pediatric extranodal lymphomas were found to be in stage III and IV. Variations in treatment policies (single agent or combined chemotherapy, radiotherapy, combined modality treatment) adopted and changed during the time period of 16 years of this retrospective study were documented.
The Cost of Treatment of Skeletal-Related Events in Patients with Bone Metastases from Lung Cancer
Authors: Delea Thomas , Langer Corey , McKiernan James , Liss Martin , Edelsberg John , Brandman Jane , Sung Jennifer , Raut Monika , Oster Gerry
Published: February 2005

Purpose: Patients with bone metastases from lung cancer often experience skeletal-related events (SREs) including pathological fracture, spinal cord compression, hypercalcemia or pain requiring surgery, radiotherapy or opioid analgesics. These complications result in impaired mobility and reduced quality of life and have a significant negative impact on survival. The economic consequences of SREs in patients with lung cancer have not been examined. Methods: We conducted a retrospective analysis using a large US health insurance claims database to estimate the incidence and costs of treatment of SREs in patients with bone metastases of lung cancer treated in a naturalistic setting. Study subjects had ≧2 encounters with a diagnosis of primary lung cancer and ≧2 encounters with a diagnosis of metastases to bone. SREs were identified based on the occurrence on or after the date of first diagnosis of bone metastases, of (1) ≧1 encounter with a diagnosis of pathological fracture, spinal cord compression or hypercalcemia, (2) ≧1 bone surgery or radiotherapy procedure, or (3) the initiation of opioid analgesic therapy. Survival and costs of SRE-related care in patients with SREs were estimated using Kaplan-Meier methods. Results: We identified 534 patients with lung cancer and bone metastases, including 295 (55%) with ≧1 SRE. Radiotherapy (68%) and fracture (35%) were the most common SREs. Median survival after the first identified SRE was 4.1 months (95% confidence interval: 3.6–5.5 months). The estimated lifetime SRE-related cost per patient was USD 11,979 (95% confidence interval: USD 10,193–13,766). Radiotherapy accounted for the greatest proportion of cost (61%) by SRE type. Conclusion: The economic burden of SREs in patients with bone metastases of lung cancer is substantial. Intravenous bisphosphonates, such as zoledronic acid, which have been shown to prevent these events, may reduce these costs.
S100A4 Expression Is an Early Event of Papillary Carcinoma of the Thyroid
Authors: Ito Yasuhiro , Yoshida Hiroshi , Tomoda Chisato , Uruno Takashi , Miya Akihiro , Kobayashi Kaoru , Matsuzuka Fumio , Kakudo Kennichi , Kuma Kanji , Miyauchi Akira
Published: February 2005

Objectives: S100A4 is a calcium-binding protein related to the metastatic potential of carcinoma. In order to elucidate its contribution to the progression of thyroid carcinoma, we investigated S100A4 expression in various thyroid neoplasms. Methods: We immunohistochemically examined S100A4 expression in 195 cases of thyroid neoplasms. Results: Although S100A4 was absent in normal follicular cells and follicular adenoma, S100A4 was positive in all 115 cases of papillary carcinoma examined, including 58 microcarcinomas. However, a significant relationship could not be established between S100A4 expression and clinicopathological features of papillary carcinoma. In follicular carcinoma, the widely invasive type expressed S100A4 more frequently than the minimally invasive type (p = 0.0028). In anaplastic carcinoma, S100A4 was expressed in 61.9% of cases, but the incidence was significantly lower (p < 0.0001) than that in papillary carcinoma. Conclusions: These findings suggest that (1) S100A4 plays a constitutive role in papillary carcinoma and (2) S100A4 may be a useful marker for early the detection of this carcinoma.
The Effect of Edrecolomab (Mo17-1A) or Fluorouracil-Based Chemotherapy on Specific Immune Parameters in Patients with Colorectal Cancer
Authors: Tsavaris Nick B. , Katsoulas Haralabos L. , Kosmas Christos , Papalambros Efstathios , Gouveris Panayiotis , Papantoniou Nikitas , Rokana Sophia , Kosmas Nicolaos , Skopeliti Margarita , Tsitsilonis Ourania E.
Published: February 2005

Objectives: We investigated the immune profile of patients with resected Dukes’ stage C colorectal cancer (CRC), receiving adjuvant therapy with edrecolomab (Mo17-1A) or first-line 5-fluorouracil (5-FU)-based chemotherapy. Patients and Methods: Patients received either 5 doses of Mo17-1A over 13 weeks, or 5-FU/leucovorin, or 5-FU/levamisole over 6 and 12 months, respectively. Peripheral blood was collected postoperatively and 4 months after therapy initiation. Peripheral blood mononuclear cells were tested in the autologous mixed lymphocyte reaction (AMLR), for natural killer (NK) and lymphokine-activated killer (LAK) cell activity. Serum cytokines were quantified by ELISA. Results: Fifty-two patients entered the study. Postoperatively, they exhibited decreased levels of interleukin (IL)-2, interferon-γ, IL-12, granulocyte-macrophage colony-stimulating factor and IL-15, low cellular immune responses (AMLR, NK- and LAK-cytotoxicity) and increased levels of IL-1β, tumor necrosis factor-α, IL-6, IL-10 and prostaglandin E2. After four months of therapy, patients receiving edrecolomab demonstrated enhanced AMLR, NK, LAK activity, increased serum levels of cytokines regulating such responses and reduced levels of acute-phase cytokines and immune suppressors, compared to patients treated with conventional chemotherapy. Conclusions: Postoperative adjuvant therapy with edrecolomab restores the in vivo deficient immune responses of patients with resected Dukes’ C CRC despite its clinical ineffectiveness in recent randomized adjuvant trials. These results suggest that further immunological studies with the combination of edrecolomab and chemotherapy are required.
The Expression of a Type II Transmembrane Serine Protease (Seprase) in Human Gastric Carcinoma
Authors: Mori Yoshiyuki , Kono Koji , Matsumoto Yoshirou , Fujii Hideki , Yamane Tetsu , Mitsumata Masako , Chen Wen-Tien
Published: February 2005

Objective: The invasion and metastasis of carcinoma cells require the proteolytic degradation of the extracellular matrix by various cell surface proteases. Among these, seprase is a type II transmembrane serine protease absent in normal tissues and it has been implicated in the invasion of the extracellular matrix by both tumor and stromal cells in human breast carcinoma and melanoma. In the present study, the expression of seprase mRNA, protein and its gelatin-degrading activity in human gastric carcinoma were examined to substantiate the potential role of seprase in gastric carcinoma invasion. Methods: We have examined the seprase expression in human gastric carcinoma (n = 34) by RT-PCR, Western immunoblotting analysis, immunohistochemistry, and gelatin zymography. Results: Immunoblotting analysis using mAb D8 directed against seprase showed that the carcinoma tissues in 26 out of 34 cases of gastric cancer expressed a dimeric form of seprase but their normal counterparts did not. Gelatin zymography confirmed that the isolated seprase exhibited the gelatin-degrading activity and was active. Seprase-expressing carcinoma tissues were more often found in the scirrhous type than in other types of gastric carcinoma. RT-PCR analysis showed that seprase mRNA was present in carcinoma tissues but not in normal tissues. Immunohistochemically, seprase was mainly located in gastric carcinoma cells, weakly in stromal cells and microvessel endothelial cells in the tumor nest, and none in normal cells. Conclusions: Our studies showed the unique expression and localization of seprase in the tumor and stromal cells within human gastric carcinoma but not in normal tissues, suggesting a role of seprase in the invasive and metastatic progression of gastric carcinoma.
Reduction in p48-ISGFγ Levels Confers Resistance to Interferon-α2a in MHCC97 Cells
Authors: Wu Wei-Zhong , Sun Hui-Chuan , Gao Yan-Qin , Li Yan , Wang Lu , Zhou Kang , Liu Kang-Da , Iliakis George , Tang Zhao-You
Published: February 2005

Objectives: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in China and, due to the limited efficacy of currently available therapies, is responsible for a large number of deaths. IFN-α therapy has shown promise in the treatment of various forms of human cancer and is considered in the treatment of HCC. Previous results from our group showed that high doses of IFN-α exert a significant antiproliferative effect on MHCC97 human xenografts in nude mice, but not on MHCC97 cells when tested in vitro. Here we present experiments designed to characterize the molecular mechanism underlying the defective response of MHCC97 cells to IFN-α. Elucidation of the mechanism underlying the defective response of MHCC97 to IFN-α may help to explain and possibly to overcome clinical failures of this form of tumor therapy. Methods: IFN-α2a was administered between 3,000 and 10,000 IU/ml, a range strongly inhibiting proliferation in other cell lines. Gene expression profiles of MHCC97 cells were obtained before and after treatment with IFN-α2a using cDNA microarray analysis. The transcriptional activity of relevant genes responding to IFN-α2a in the cDNA microarray experiments was confirmed by RT-PCR and Northern blot analysis. Transient transfection with an expression vector was used to restore p48-ISGFγ (IRF9) protein levels. Cell proliferation was evaluated using the MTT assay. Results: Although IFN-α treatment caused the activation of several signal transduction pathways in MHCC97 cells, the lack of an antiproliferative effect was found to mainly derive from a defect in the activation of the transcription factor ISGF3 required for Jak/STATS signaling. We show that the defect in ISGF3 activation is mainly caused by the absence of one of its essential components, the protein p48-ISGFγ from MHCC97 cells. Indeed, transient expression of p48-ISGFγ restores sensitivity to IFN-α2a. Although the mRNA levels of p48-ISGFγ were normal in MHCC97 cells, mutations could be detected in the gene coding for the protein. We hypothesize, therefore, that these mutations alter the message or protein stability, leading to the reduced protein levels observed. Conclusion: Our results confirm the important role of Jak/STATS signaling in the antiproliferative effects of IFN-α in tumor cells and indicate that defects in ISGF3 can cause resistance to IFN-α2a treatment.
Cell Density Modulates the Metastatic Aggressiveness of a Mouse Colon Cancer Cell Line, Colon 26
Authors: Kuwano Hiroyuki , Miyazaki Tatsuya , Tsutsumi Soichi , Hirayama Isao , Shimura Tatsuo , Mochiki Erito , Nomoto Ken-ichi , Fukuchi Minoru , Kato Hiroyuki , Asao Takayuki
Published: February 2005

Objective: Although cell density in cultured cells has demonstrated several alterations in the nature of cell kinetics, the changes in the metastatic aggressiveness of cancer lines under different cell densities have not yet been studied. Methods: In the current study, we investigated the influence of changing the cell density of cultured cancer cells (colon 26 and B16-F10) injected into the tail vein in BALB/c mice on the metastatic activity by evaluating the number of lung metastases, and the possible mechanisms of this phenomenon were discussed based on the basis of the results of an invasion assay and a cell adhesion assay. Results: The number of metastatic nodules was significantly higher in the high-density group than in the low one in colon 26 (p < 0.005), however, this phenomenon was not seen in B16-F10. Next, we performed the same experiment by changing the environment to the opposite conditions for the cells in the low- and high-density groups, and the results showed the metastatic activities to be always higher in the high-density group. Moreover, although no difference was seen regarding the invasive activity between the high- and low-density groups, an adhesion assay showed the difference in the adhesion cell rate to be significantly higher in the high-density group especially in early period after coculture with human umbilical vein endothelial cells (HUVEC) (p < 0.05). Conclusion: In some cell types, the metastatic activity could be altered and reversed by changing the environment, such as the cell density, during a relatively short period. As a result, the epigenetic changes of cancer cells are thus suggested to play a certain role in the malignant potentiality.
ERK, PKC and PI3K/Akt Pathways Mediate Extracellular ATP and Adenosine-Induced Proliferation of U138-MG Human Glioma Cell Line
Authors: Jacques-Silva Maria C. , Bernardi Andressa , Rodnight Richard , Lenz Guido
Published: February 2005

Objective: Extracellular nucleotides and nucleosides induce proliferation in a set of human glioma cell lines. In this study we investigate the signal transduction pathways involved in ATP and adenosine-mediated proliferation in U138-MG human glioma cells. Methods: Cell proliferation was accessed through [3H]thymidine incorporation, cell counting and flow cytometry. Protein phosphorylation was detected through Western blotting. Results: ATP or adenosine (100 µM) induced extracellular signal-regulated protein kinase (ERK), Akt and GSK3β phosphorylation. The increase in [3H]thymidine incorporation induced by ATP or adenosine was decreased when cells were incubated with LY 294002 (by ±90%), GF 109203X (by ±76%) or PD 098059 (by ±63%). The increase in cell numbers with ATP or adenosine was less after a 48-hour treatment of cells with ATP or adenosine plus GF 109203X (by ±66%) or LY 294002 (by ±83%). Percentage of cells in S phase was decreased in cells treated with LY 294002 plus ATP when compared to ATP- treated cells. Conclusion: Stimulation of purinergic receptors in U138-MG cells leads to cell proliferation mediated by PI3K/Akt, ERK and PKC signaling. It may be clinically important for pharmacological intervention in gliomas to associate purinergic receptor antagonists and signal transduction pathways blockers.
Centrosome Hyperamplification and Chromosomal Damage after Exposure to Radiation
Authors: Kawamura K. , Fujikawa-Yamamoto K. , Ozaki M. , Iwabuchi K. , Nakashima H. , Domiki C. , Morita N. , Inoue M. , Tokunaga K. , Shiba N. , Ikeda R. , Suzuki K.
Published: February 2005

Objective: In order to elucidate the effects of radiation on centrosome hyperamplification (CH), we examined the centrosome duplication cycle in KK47 bladder cancer cells following irradiation. Methods: KK47 cells were irradiated with various doses of radiation and were examined for CH immunostaining for γ-tubulin. Results: Nearly all control cells contained one or two centrosomes, and mitotic cells displayed typical bipolar spindles. The centrosome replication cycle is well regulated in KK47. Twenty-four hours after 5-Gy irradiation, ∼80% of irradiated cells were arrested in G2 phase, and at 48 h after irradiation, 56.9% of cells contained more than two centrosomes. Laser scanning cytometry performed 48 h after irradiation showed the following two pathways: (1) unequal distribution of chromosomes to daughter cells, or (2) failure to undergo cytokinesis, resulting in polyploidy. With mitotic collection, M-phase cells with CH could be divided into G1 cells with micronuclei and polyploidal cells. Fluorescence in situ hybridization analysis showed clear signs of chromosomal instability (CIN) at 48 h after irradiation. The present study had two major findings: (1) continual duplication of centrosomes occurred in the cell cycle-arrested cells upon irradiation, leading to centrosome amplification; (2) cytokinesis failure was due to aberrant mitotic spindle formation caused by the presence of amplified centrosomes. Abnormal mitosis with amplified centrosomes was detected in the accumulating G2/M population after irradiation, showing that this amplification of centrosomes was not caused by failure to undergo cytokinesis, but rather that abnormal mitosis resulting from amplification of centrosomes leads to cytokinesis block. Conclusion: These results suggest that CH is a critical event leading to CIN following exposure to radiation.
Thalidomide Inhibits the Growth and Progression of Hepatic Epithelioid Hemangioendothelioma
Authors: Mascarenhas Ranjan C.V. , Sanghvi Amit N. , Friedlander Lois , Geyer Stanley J. , Beasley H. Scott , van Thiel David H.
Published: February 2005

Hepatic epithelioid hemangioendothelioma (HEH) is a rare vascular tumor of the liver with an unpredictable malignant potential. Its growth can lead to hepatic failure, extrahepatic metastasis and death. Surgical resection or liver transplantation is the treatment of choice if metastasis is not identified. Several antineoplastic agents have been proposed for cases of nonresectable HEH. We report the case of a 52-year-old patient with HEH metastatic to the lungs who was successfully treated with oral thalidomide therapy.
Germline Mutation of the LKB1/STK11 Gene with Loss of the Normal Allele in an Aggressive Breast Cancer of Peutz-Jeghers Syndrome
Authors: Nakanishi Chikashi , Yamaguchi Tatsuro , Iijima Takeru , Saji Shigehira , Toi Masakazu , Mori Takeo , Miyaki Michiko
Published: February 2005

Peutz-Jeghers syndrome (PJS) is an autosomal-dominant polyposis disorder with an increased risk of multiple cancer. The LKB1/STK11 gene, which acts as a tumor suppressor, is responsible for PJS and plays a role in suppressing breast cancer. The low expression of LKB1/STK11 in sporadic breast cancer is significantly associated with shorter survival. Here we describe a PJS patient with aggressive breast cancer that carried not only a germline mutation of LKB1/STK11 but also loss of the normal allele. The combination of these mutations may be associated with the poor prognosis of this patient. To our knowledge, we are the first to show that a germline mutation causing PJS is combined with the loss of the homologous normal allele of LKB1/STK11 in breast cancer.
Distribution of Rhesus Blood Group System in the French Basques: A Reappraisal Using the Allele-Specific Primers PCR Method
Authors: Touinssi Mhammed , Chiaroni Jacques , Degioanni Anna , De Micco Philippe , Dutour Olivier , Bauduer Frédéric
Published: February 2005

Objectives: To determine for the first time using PCR the distribution of Rhesus (Rh) blood group in French Basques and compare these results with those obtained by serology in the same sample and in the historical series from various Basque subgroups. Methods: Rh polymorphism was determined in a sample of 127 autochthonous French Basques using allele-specific primers (ASP) PCR and traditional serological technique. Statistical comparisons were performed between both techniques and with the data published from various Basque subpopulations. Results: No intra-sample discrepancies were detected between ASP-PCR and serology. A high frequency of RH Ddel exceeding 0.50, as typically described from several decades, was found here (0.511), as the peculiar frequency of cde (0.456) and cDE (0.073) haplotypes. This profile, obtained by molecular analysis, was within the range of previous historical studies in various Basque subpopulations using serological approach. The Rh polymorphism among the reviewed autochthonous Basque samples indicates a heterogeneous pattern of distribution, with individuals from the Alava province demonstrating the most atypical profile. Conclusions: Molecular biology approach using PCR confirms the peculiar pattern of Rh polymorphism which was previously defined by serology among Basques. Nevertheless, this distribution profile is not homogeneous within the Basque area.
MDR and PRP: A Comparison of Methods for High-Order Genotype-Phenotype Associations
Authors: Bastone L. , Reilly M. , Rader D.J. , Foulkes A.S.
Published: February 2005

Complex diseases such as cardiovascular disease are likely due to the effects of high-order interactions among multiple genes and demographic factors. Therefore, in order to understand their underlying biological mechanisms, we need to consider simultaneously the effects of genotypes across multiple loci. Statistical methods such as multifactor dimensionality reduction (MDR), the combinatorial partitioning method (CPM), recursive partitioning (RP), and patterning and recursive partitioning (PRP) are designed to uncover complex relationships without relying on a specific model for the interaction, and are therefore well-suited to this data setting. However, the theoretical overlap among these methods and their relative merits have not been well characterized. In this paper we demonstrate mathematically that MDR is a special case of RP in which (1) patterns are used as predictors (PRP), (2) tree growth is restricted to a single split, and (3) misclassification error is used as the measure of impurity. Both approaches are applied to a case-control study assessing the effect of eleven single nucleotide polymorphisms on coronary artery calcification in people at risk for cardiovascular disease.
Properties of Structured Association Approaches to Detecting Population Stratification
Authors: Purcell Shaun , Sham Pak
Published: February 2005

Objective: To examine the properties of the structured association approach for the detection and correction of population stratification. Method: A method is developed, within a latent class analysis framework, similar to the methods proposed by Satten et al. (2001) and Pritchard et al. (2000). A series of simulations illustrate the relative impact of number and type of loci, sample size and population structure. Results: The ability to detect stratification and assign individuals to population strata is determined for a number of different scenarios. Conclusion: The results underline the importance of careful marker selection.
The Pedigree Trimming Problem
Authors: Lange Kenneth , Sinsheimer Janet S.
Published: February 2005

This report mathematically validates a fast algorithm for trimming irrelevant members from a pedigree. These individuals are typically dead or otherwise unavailable for study. Left in the pedigree, they slow likelihood evaluation. Of course, each pedigree of interest will have some core people who must be retained. The described algorithm retains just enough of the pedigree to maintain the proper relationships among the core people.
Laryngeal Mask Airway Used as a Delivery Conduit for the Administration of Surfactant to Preterm Infants with Respiratory Distress Syndrome
Authors: Trevisanuto Daniele , Grazzina Nicoletta , Ferrarese Paola , Micaglio Massimo , Verghese Chandy , Zanardo Vincenzo
Published: February 2005

Background: The laryngeal mask airway (LMATM, Laryngeal Mask Co. Ltd, Jersey, UK) is a supraglottic device used to administer positive pressure ventilation (PPV) in adults, pediatric and neonatal patients. Objectives: To avoid endotracheal intubation, we evaluated the feasibility and practicality of administering surfactant via the LMATM in preterm infants with respiratory distress syndrome (RDS). Methods: Infants less than 72 h old with a gestational age of ≤35 weeks and a birth weight of >800 g, treated with nasal continuous positive airway pressure (CPAP, 5 cm H2O) for RDS were eligible for inclusion in the study if the arterial-to-alveolar oxygen tension ratio (a/APO2) was <0.20 over a period of >60 min. Results: Eight preterm infants, median gestational age 31 (range 28–35) weeks; birth weight 1,700 (880–2,520) g, treated with nasal CPAP for RDS were enrolled. Three hours after surfactant instillation, the mean a/APO2 was significantly increased (0.13 ± 0.04 to 0.34 ± 0.11; p < 0.01) without complications. Conclusions: The LMATM may be a useful and noninvasive conduit for the administration of surfactant therapy. A large randomized comparative clinical trial will be required to confirm the efficacy of this technique.
Intravenous Immunoglobulin G Attenuates Pulmonary Hypertension but Induces Local Neutrophil Influx in Meconium Aspiration in Piglets
Authors: Holopainen R. , Soukka H. , Halkola L. , Kääpä P.
Published: February 2005

Background: Pulmonary hypertension and inflammation are well-identified pathogenetic features in meconium aspiration syndrome of newborns, but current approaches to their treatment or prevention are still often unsatisfactory. Objectives: To investigate the possible protective effects of human intravenous immunoglobulin G (IVIG) on the hypertensive and inflammatory lung injury in severe neonatal meconium aspiration. Methods: Eleven newborn (10–12 days old) ventilated and catheterized piglets that received an intratracheal bolus (3 ml/kg) of a 65-mg/ml mixture of human meconium were studied for 6 h. IVIG was infused in 5 piglets 30 min before meconium administration, and 6 piglets served as controls and received the vehicle only. Results: Meconium instillation induced a biphasic pulmonary hypertensive response, which was significantly diminished by IVIG pretreatment. Similarly, IVIG improved the oxygenation of the piglets, but the intrapulmonary shunt fraction or systemic hemodynamic parameters did not differ between the study groups, except of a minor decrease in the mean arterial blood pressure caused by IVIG. The blood leukocyte count was comparable in the 2 groups. The lung tissue ultrastructural and histological changes, number of apoptotic cells and phospholipase A2 activity were similar in the 2 groups. The amount of neutrophil accumulation, assessed by myeloperoxidase activity, was however significantly increased in macroscopically damaged lung tissue after IVIG administration. Conclusions: Our results thus indicate that IVIG treatment of newborns with severe meconium aspiration significantly diminishes the pulmonary hypertensive response and improves oxygenation, but the effects do not extend to protection of lung cellular injury.
Different Doses of Dopamine Have Heterogeneous Effects on Cerebral Hemodynamics and Dopamine Receptors in Young Rabbits as Measured with Near Infrared Spectroscopy
Authors: Baserga Mariana C. , Bertolotto Cristina , Sola Augusto
Published: February 2005

Background: Fluctuations in cerebral blood volume and cerebral oxygenation may be important in the pathogenesis of intraventricular hemorrhage and hypoxic-ischemic brain injury in the neonate. The cerebral hemodynamic response to dopamine infusion in premature infants is not well established. The newborn rabbit, a rather immature species at birth, is a suitable model for monitoring the physiological changes of the cerebral circulation. Methods: The effect of dopamine upon cerebral hemodynamics and basal ganglia dopaminergic receptors were studied using four different dopamine doses. Results: No significant changes in near infrared spectroscopy (NIRS) parameters were observed in the animals that received 0.5 (n = 5) and 1 µg/kg/min (n = 4) of dopamine intravenously. In contrast, in those animals that received dopamine at 5 µg/kg/min (n = 7) and 50 µg/kg/min (n = 7), there was a significant decrease in oxygenated hemoglobin. Moreover, this was accompanied by a significant increase in deoxygenated hemoglobin soon after drug infusion. Cerebral blood volume was increased in the group that received 5 µg/kg/min, but significantly decreased in the group that received 50 µg/kg/min. In both groups NIRS parameters returned to baseline values soon after stopping dopamine infusion. Conclusion: Despite evidence of a physiological response, we found no difference in the distribution of dopamine receptors between experimental and control animals. We therefore speculate that dopamine has an effect on the cerebrovasculature that could be mediated by factors other than changes in the basal ganglia dopamine receptors.
Effect of Two Amino Acid Solutions on Leucine Turnover in Preterm Infants
Authors: Sáenz de Pipaón Miguel , Quero José , Wattimena Darcos J.L. , Sauer Pieter J.J.
Published: February 2005

Objective: To assess the effect of two different parenteral amino acid mixtures, Trophamine® and Primene®, on leucine turnover in preterm infants. Method: Leucine kinetics were measured with [5,5,5 D3]leucine tracer in 15 infants receiving Trophamine (group ‘T’) (mean birth weight 1,263 g) and 22 who received Primene (group ‘P’) (mean birth weight 1,336 g) during two study periods, within a few hours after birth but before introduction of parenteral amino acid solution, and again at postnatal day 7. The rate of appearance of leucine was calculated from the enrichment of α-ketoisocaproic acid in plasma. Results: There were no significant differences in leucine turnover within a few hours after birth in the two groups. In the infants who received Primene leucine turnover on day 7 was significantly lower than in those who received Trophamine (269 ± 43 vs. 335 ± 27, p < 0.05). Despite a higher intake of leucine in the Trophamine group (108 ± 10 vs. 77 ± 8 µmol·kg–1·h–1), leucine released from proteins at day 7 was higher in this group compared to Primene (227 ± 27 vs. 192 ± 42 µmol·kg–1·h–1). Conclusions: Primene administration results in lower leucine released from proteins, an estimate of protein breakdown, than Trophamine in preterm infants. Increases in whole body leucine turnover in response to administration of i.v. amino acids is influenced by the composition of the amino acid mixture. The factors responsible for this difference remain to be elucidated.
Normative Data of Penile Length for Term Chinese Newborns
Authors: Fok T.F. , Hon K.L. , So H.K. , Wong E. , Ng P.C. , Chang A. , Lau J. , Chow C.B. , Lee W.H.
Published: February 2005

Careful examination and assessment of penile length in the newborn is important because micropenis is associated with hypothalamic disorders. This prospective cross-sectional study was designed to establish the norm of penile length for term Hong Kong Chinese newborns. 4,628 full-term healthy male newborns were enrolled in the study. Penile length was measured from pubic ramus to the tip of the glans penis by placing the end of a straight edge ruler against the pubic ramus. A gestation-associated graph of 3rd, 10th, 25th, 50th, 75th, 90th and 97th centiles for the penile length was created. The penile length was significantly correlated with gestational age, birth weight and body length. When compared with published data for other populations, Hong Kong newborns have significantly shorter penile length. The norm of the penile length is useful in diagnostic and therapeutics for the ethnic Chinese male newborns.
Effect of Maternal Administration of Selective Cyclooxygenase (COX)-2 Inhibitors on Renal Size, Growth Factors, Proteinases, and COX-2 Secretion in the Fetal Rabbit
Authors: Hartleroad Jeffrey Y. , Beharry Kay D. , Hausman Nicole , Stavitsky Yuri , Asrat Tamerou , Modanlou Houchang D.
Published: February 2005

Background: Selective cyclooxygenase (COX)-2 inhibitors are currently being considered for management of preterm labor. COX-2 is an important regulator of fetal renal growth and function. Its inhibition may lead to congenital oligonephropathy. Objectives: We investigated whether maternal administration of a selective COX-2 inhibitor would adversely affect fetal renal growth. Methods: Three groups of timed pregnant rabbits at 13 days gestation were examined. Group 1 received oral celecoxib (30 mg/kg/day) from 13 to 20 days gestation (Cel-A); group 2 received celecoxib from 13 to 28 days gestation (Cel-B), and group 3 received equivalent volumes of the vehicle from 13 to 28 days gestation. The fetuses were delivered by cesarean section at 29 days gestation. The kidneys were weighed and analyzed for vascular endothelial growth factor (VEGF) and its soluble receptors, matrix metalloproteinase (MMP)-2 and -9, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, COX-2, and total cellular protein levels. Sections from the cortex and medulla were assessed histologically. Results: Fetal kidney size was unaffected. VEGF levels were elevated in the Cel-B group. Soluble VEGF receptors, MMP-2, TIMP-1 and COX-2 levels remained unchanged. MMP-9 levels were suppressed in both treated groups, which resulted in significantly lower MMP-9/TIMP-1 ratios. Although TIMP-2 secretion was enhanced in the Cel-B group, MMP-2/TIMP-2 ratios were unaffected. No significant histological changes were detected. Conclusions: We conclude that maternal administration of therapeutic doses of celecoxib does not adversely affect fetal renal growth. MMP-9 is increased in various nephropathies, but may also have protective effects therefore its suppression by COX-2 inhibitors needs further study.
Antenatal Glucocorticoids Increase Early Total Thyroxine Levels in Premature Infants
Authors: Martin Camilia R. , van Marter Linda J. , Allred Elizabeth N. , Leviton Alan
Published: February 2005

Background: Hypothyroxinemia is associated with adverse neonatal outcomes including white matter damage, cerebral palsy, poor neurodevelopment and death. It has become increasingly important to understand the natural history and modifiers of thyroid function in the premature infant. It is standard obstetrical practice to offer antenatal glucocorticoids to pregnant women with threatened preterm delivery. Few studies have investigated the effect of antenatal glucocorticoids on neonatal thyroid function. Objective: To examine the association between antenatal exposure to glucocorticoids and early total thyroxine (T4) levels among extremely premature infants. Methods: We studied 521 infants born at 4 medical centers. Entry criteria included a gestational age of 23–28 weeks and a serum thyroxine level obtained in the first postnatal week. Receipt of antenatal glucocorticoids was recorded as none, partial, or complete. A complete course consisted of two doses of betamethasone or four doses of dexamethasone within a 48-hour period between 2 and 7 days of delivery. Early total T4 levels were obtained from state-mandated newborn screening programs. Results: Controlling for potential maternal, perinatal and neonatal confounding variables, infants exposed to a complete course of antenatal glucocorticoids had total T4 levels 0.8 µg/dl higher than their peers who were not exposed to a complete course of antenatal glucocorticoids (p = 0.03). Conclusions: Extremely premature infants who received a complete course of antenatal glucocorticoids had significantly higher total thyroxine levels in the first postnatal week. Maternal, perinatal, and early neonatal variables did not completely explain this association. We speculate that antenatal glucocorticoids influence early neonatal thyroid function.
Leber Hereditary Optic Neuropathy in 2 of 4 Siblings with 11778 mtDNA Mutation: Clinical Variability or Effect of Toxic Environmental Exposure?
Authors: Rufa Alessandra , Dotti Maria Teresa , Cardaioli Elena , Da Pozzo Paola , Federico Antonio
Published: February 2005

Although mitochondrial (mt) DNA mutation at nucleotide position 11778 accounts for most cases of Leber’s hereditary optic neuropathy (LHON), the phenotypic expression may vary greatly even in different members of the same family. The possible influence of exogenous toxicity on phenotypic expression is still debated in LHON. Here we describe 4 siblings carrying the 11778 mtDNA mutation with a different phenotype. The index case developed an atypical optic neuropathy at the age of 60 years after a long history of occupational exposure to polycyclic aromatic hydrocarbons (PAHs). This report underlines a number of unanswered questions about phenotypic variability of LHON including the possible influence of PAH toxicity.
mRNA Study on Cu/Zn Superoxide Dismutase Induction by Hemodialysis Treatment
Authors: Akiyama Shinichiro , Inagaki Masahiro , Tsuji Mayumi , Gotoh Hiromichi , Gotoh Tomomi , Gotoh Yoshikazu , Oguchi Katsuji
Published: February 2005

Background/Aims: There is little or no controversy about the increased oxidative stress of hemodialysis (HD) patients. Several reports show that the activity of superoxide dismutase (SOD), one of the major endogenous antioxidant enzymes, in plasma is elevated among HD patients. It is still unclear, however, whether this elevation is due to the promotion of SOD production or a decrease in renal excretion of SOD. This study was designed to investigate the cause of the SOD activation in HD patients, and we examined the expression of SOD mRNA levels in leukocytes of patients with chronic renal failure. Methods: The total plasma SOD activity was determined by the nitroblue tetrazolium method, plasma SOD contents by ELISA, and SOD mRNA levels in leukocytes by RT-PCR. Results: Our results demonstrated that contents and mRNA levels of Cu/Zn SOD in HD patients are 4.4 times and 2.0 times, respectively, as large as those in healthy controls. Furthermore, in contrast to nondialyzed chronic renal failure patients, we observed higher concentrations of Cu/Zn SOD in plasma and a more enhanced mRNA expression of Cu/Zn SOD in leukocytes of HD patients. Conclusion: Increased Cu/Zn SOD mRNA reflects enhanced antioxidant capacity of leukocytes and can be a promising oxidative stress marker in HD patients.
Accumulation of Transforming Growth Factor-β2 and Nitrated Chondroitin Sulfate Proteoglycans in Cerebrospinal Fluid Correlates with Poor Neurologic Outcome in Preterm Hydrocephalus
Authors: Chow Lily C. , Soliman Antoine , Zandian Mandana , Danielpour Moise , Krueger Jr. Richard C.
Published: February 2005

Background: Progressive post-hemorrhagic hydrocephalus in preterm infants strongly predicts abnormal neurologic development, and often accompanies cystic periventricular leukomalacia (cPVL). Transforming growth factor-β1 (TGF-β1), associated with hydrocephalus, can upregulate the chondroitin sulfate proteoglycan (CSPG) synthesis. To date, CSPG and their nitrated metabolites (NT-CSPG) have not been evaluated in hydrocephalus. Objectives: We hypothesized that TGF-β1, TGF-β2, CSPG, and NT-CSPG would accumulate in cerebrospinal fluid (CSF) in preterm hydrocephalus, and their concentrations would correlate with poor long-term outcomes. Methods: TGF-β1, TGF-β2, CSPG, and NT-CSPG concentrations in CSF were measured prospectively by ELISA in 29 preterm newborns with (n = 22) or without (n = 34) progressive post-hemorrhagic hydrocephalus, and correlated with progressive neonatal hydrocephalus and neurologic outcome. Only concentrations from each patient’s initial CSF sample were used for statistical analysis. Results: Compared to neonates without hydrocephalus, CSF [TGF-β1], [TGF-β2], [CSPG] and [NT-CSPG] were significantly greater by >3-, >35-, >8-, and >3-fold, respectively. Unlike CSF [TGF-β2] and [CSPG], [TGF-β1] correlated with CSF [total protein]. Only CSF [NT-CSPG] correlated with cPVL. Unlike [TGF-β2] or [CSPG], [NT-CSPG] correlation with preterm progressive post-hemorrhagic hydrocephalus (PPHH) was explained entirely by the presence of cPVL among these patients. [TGF-β2] was >20-fold greater in preterm survivors who required a ventriculoperitoneal shunt for PPHH (n = 9), as compared to survivors who did not require a shunt (n = 2), or those without hydrocephalus (n = 12). [TGF-β2] and [NT-CSPG] correlated inversely with Bayley Index Scores (15.0 months median adjusted age). Conclusions: This is the first report that [TGF-β2], [CSPG], and [NT-CSPG], measured well before term, accumulate abnormally in preterm progressive post-hemorrhagic hydrocephalus CSF, and correlate with adverse neurologic outcome.
Potential Substitution of Cord Blood for Infant Blood in the Neonatal Sepsis Evaluation
Authors: Hansen Anne , Forbes Peter , Buck Rosanne
Published: February 2005

Background: Evaluation of sepsis accounts for one third of all nursery triage admissions. If umbilical cord blood could be accurately substituted for infant blood, it would spare infants the discomfort of an invasive procedure and save both time and resources. While awaiting 48-hour blood culture results, we decide on clinical management based on whether the white blood cell (WBC) immature to total (I:T) granulocyte ratio is ≧0.2. Objectives: Our goal was to assess the correlation of complete blood count (CBC), I:T ratio and blood culture results between umbilical cord and infant blood. Methods: We conducted a prospective cohort study comparing CBC/differential and blood culture results of paired samples of umbilical cord and infant blood from term newborns. Results: We sent 113 paired samples of cord and infant venous blood for CBC/differential and blood culture. All 113 umbilical cord and infant blood cultures were negative, yielding a false-positive blood culture rate of zero. For 92% of babies, both the cord and infant blood I:T ratio were <0.2 or both were ≧0.2. Cord and infant WBC, hematocrit and platelet counts were moderately to highly correlated. Conclusion: We conclude that cord blood can be safely substituted for infant blood in routine sepsis evaluations of asymptomatic, term infants based on both the low false-positive cord blood culture rate and the significant association between high I:T ratios in cord and infant blood.
Does Gastroesophageal Reflux Cause Apnea in Preterm Infants?
Authors: Molloy Eleanor J. , Di Fiore Juliann M. , Martin Richard J.
Published: February 2005

Gastroesophageal reflux (GER) and apnea are both common occurrences in premature infants but their relationship is controversial. We present the evidence for and against an association between GER and apnea and discuss the merits and limitations of the various methodologies employed in characterizing such a relationship. Overall, GER and apnea do not appear temporally related in preterm infants, despite strong physiologic evidence that stimulation of laryngeal afferents elicits central apnea and laryngeal adduction. In a subpopulation of infants with neurodevelopmental compromise, there may be an increased incidence of both apnea and GER, although the direct association between GER and apnea in this population is unclear. Therefore, we believe there is no evidence to support widespread use of anti-reflux medications in the treatment of apnea in preterm infants. Further studies are needed to clarify the existence of a small subpopulation of infants who may have GER-induced apnea, to identify potential triggering mechanisms, and to document benefit from newer pharmacological approaches.