Copyright (c) 2009 All rights reserved. http://works.bepress.com/stephen_baker Recent documents in Stephen Baker en-us Sun, 31 May 2009 12:16:37 PDT 3600 http://works.bepress.com/stephen_baker/29 http://works.bepress.com/stephen_baker/29 Mon, 07 Jul 2008 12:32:12 PDT PURPOSE: We performed a phase I trial of piroxantrone with and without granulocyte colony-stimulating factor (G-CSF) to determine whether the use of this cytokine would enable us to increase the dose-intensity of piroxantrone. PATIENTS AND METHODS: Thirty-eight patients received 121 courses of piroxantrone administered once every 21 days. Initial patient cohorts received piroxantrone alone starting at 150 mg/m2 and the dose was escalated in subsequent patients until dose-limiting toxicity (DLT) was reached. Patient cohorts then received escalating doses of piroxantrone starting at 185 mg/m2 administered with G-CSF beginning day 2. RESULTS: Dose-limiting neutropenia occurred in three of six patients treated with 185 mg/m2 piroxantrone; the maximum-tolerated dose (MTD) of piroxantrone alone was 150 mg/m2. Three of six patients treated with piroxantrone and G-CSF exhibited dose-limiting thrombocytopenia at 445 mg/m2; the MTD of piroxantrone with G-CSF was thus 355 mg/m2. Seven patients developed symptomatic congestive heart failure (CHF) at cumulative piroxantrone doses ranging from 855 to 2,475 mg/m2 and two have died of cardiotoxicity. Of these patients, six of seven had previously received doxorubicin. Other nonhematologic toxicity was mild. CONCLUSION: The use of G-CSF results in a more than twofold increase in the MTD of piroxantrone. However, symptomatic cardiotoxicity is prominent, especially in patients who have received prior treatment with anthracyclines. Diane M. F. Savarese Adult Aged Anthraquinones Antineoplastic Agents Bone Marrow Diseases Drug Administration Schedule Female Granulocyte Colony-Stimulating Factor Humans Logistic Models Male Middle Aged Multivariate Analysis Neoplasms Pyrazoles http://works.bepress.com/stephen_baker/28 http://works.bepress.com/stephen_baker/28 Mon, 07 Jul 2008 12:32:08 PDT Mullerian inhibiting substance (MIS) causes Mullerian duct regression during sexual differentiation and regulates postnatal Leydig cell development. MIS knockout (MIS-KO) mice with targeted deletions of MIS develop Leydig cell hyperplasia, but their circulating androgen concentrations are reportedly unaltered. We compared reproductive hormone profiles, androgen biosynthesis, and the expression of key steroidogenic and metabolic enzymes in MIS-KO and wild-type (WT) mice at puberty (36 d) and sexual maturity (60 d). In pubertal animals, basal testosterone and LH concentrations in plasma were lower in MIS-KO than WT mice, whereas human chorionic gonadotropin-stimulated testosterone concentrations were similar. In adults, basal LH, and both basal and human chorionic gonadotropin (hCG)-stimulated testosterone concentrations were similar. Purified Leydig cells from pubertal MIS-KO mice had lower testosterone but higher androstanediol and androstenedione production rates. In contrast, testosterone, androstanediol, and androstenedione production rates were all lower in adult MIS-KO Leydig cells. Steroidogenic acute regulatory protein expression was lower in pubertal MIS-KO mice compared with WT, whereas 17beta-hydroxy-steroid dehydrogenase and 5alpha-reductase were greater, and P450c17 and P450scc were similar. The expression of steroidogenic acute regulatory protein and 17beta-hydroxysteroid dehydrogenase was lower in adult MIS-KO mice, whereas that of 5alpha-reductase, P450c17, and P450scc was similar. Collectively, these results suggest that in the absence of MIS, Leydig cells remain less differentiated, causing an altered intratesticular androgen milieu that may contribute to the infertility of MIS-KO mice. In immature mice, this deficit in steroidogenic capacity appears to be mediated by a direct loss of MIS action in Leydig cells as well as by indirect effects via the hypothalamic-pituitary-gonadal axis. Xiufeng Wu Age Factors Animals Anti-Mullerian Hormone Body Weight Cells, Cultured Glycoproteins Leydig Cells Male Mice Mice, Inbred C57BL Mice, Knockout Organ Size Phosphoproteins RNA, Messenger Sexual Maturation Testicular Hormones Testis Testosterone http://works.bepress.com/stephen_baker/27 http://works.bepress.com/stephen_baker/27 Mon, 07 Jul 2008 12:32:04 PDT Laminin, a glycoprotein component of basement membrane, and cathepsin B, a lysosome-derived proteinase, are thought to play a role in the complex process of tumor invasion and metastasis. This study evaluates the possible prognostic significance of laminin degradation and cathepsin B expression in Stage I (T1NO, T2NO) human non-small cell lung cancer. Archival, formalin-fixed, paraffin-embedded lung tissue from patients with documented Stage I non-small cell cancer was studied in a series of 31 patients (14 men, 17 women; ages 40-82 yr; mean age, 67 yr) by using polyclonal antibodies against laminin and cathepsin B. The immunoexpression of laminin was assessed with respect to a continuous versus discontinuous pattern, whereas that of cathepsin B was semiquantitated according to a four-tiered grading scale: 0, 0% positive cells; 1, 1 to 9%; 2, 10 to 49%; and 3, more than 50% positive cells. Cox proportional hazards models and Kaplan-Meler survival analysis were used to evaluate the association of possible risk factors, including laminin and cathepsin B, with survival. Univariate analysis looking at possible associations of survival with age, sex, histologic type, degree of tumor differentiation, and tumoral stage (T1NO, T2NO) did not show significant association. Likewise, degradation of laminin and immunoexpression of cathepsin B did not show significant association with survival. Although previous studies suggested improved survival with increased laminin expression and decreased survival with high expression of cathepsin B, the results applying to intrastage (Stage I) non-small cell cancer suggest that the expression of laminin and cathepsin B has little prognostic significance. Masuko Mori Adult Aged Aged, 80 and over Carcinoma, Non-Small-Cell Lung Cathepsin B Female Humans Immunohistochemistry Laminin Lung Neoplasms Male Middle Aged Neoplasm Proteins Neoplasm Staging Prognosis Retrospective Studies Survival Rate http://works.bepress.com/stephen_baker/26 http://works.bepress.com/stephen_baker/26 Mon, 07 Jul 2008 12:31:46 PDT PURPOSE: To compare the contrast-detail (CD) characteristics of screen-film (SF) and postprocessed digital images by using a phantom-based method. MATERIALS AND METHODS: Images of a CD phantom with polymerized methyl methacrylate were acquired with SF and full-field digital mammography systems at matched exposure conditions. A four-alternative forced-choice experiment was conducted with seven observers participating in the study. Each observer was required to identify randomly located disks in phantom images from which detection curves were computed. The CD diagrams for the SF and digital systems were estimated from the detection curves and compared at 50% and 62.5% threshold levels. Furthermore, a theoretic model was used to estimate the CD performance of the SF and digital systems. RESULTS: Analysis of covariance for mixed models was used with the natural logarithm of disk thickness as the dependent variable, the natural logarithm of disk diameter as the covariate, and the observer as a random factor. The results of statistical analysis indicated significant differences between the CD characteristics of SF and digital mammographic images at both 50% (P <.001) and 62.5% (P <.001) detection thresholds. CONCLUSION: The authors conclude that digital CD curves, on average, exhibit threshold contrast characteristics that are lower (better) than those of SF mammography. Sankararaman Suryanarayanan Algorithms Female Humans Mammography Phantoms, Imaging Radiographic Image Enhancement X-Ray Intensifying Screens http://works.bepress.com/stephen_baker/25 http://works.bepress.com/stephen_baker/25 Mon, 07 Jul 2008 12:31:34 PDT Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters (GAD2, NPY, SST) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5' end of GAD1. Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, Gad1 H3K4 (tri)methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D2 and D3 receptors, suggesting that blockade of D2-like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia. Hsien-Sung Huang Adult Animals Cells, Cultured Child *DNA Methylation Female Glutamate Decarboxylase Histones Humans Male Mice Mice, Inbred C57BL Mice, Mutant Strains Myeloid-Lymphoid Leukemia Protein Prefrontal Cortex Promoter Regions (Genetics) Rats Schizophrenia gamma-Aminobutyric Acid http://works.bepress.com/stephen_baker/24 http://works.bepress.com/stephen_baker/24 Mon, 07 Jul 2008 12:31:11 PDT BACKGROUND: Schizophrenia is frequently accompanied by hypometabolism and altered gene expression in the prefrontal cortex. Cellular metabolism regulates chromatin structure, including covalent histone modifications, which are epigenetic regulators of gene expression. OBJECTIVE: To test the hypothesis that down-regulated metabolic gene expression is associated with histone modification changes in the prefrontal cortex of subjects with schizophrenia. DESIGN AND SUBJECTS: Histones and gene transcripts were profiled in the postmortem prefrontal cortex of 41 subjects with schizophrenia and 41 matched controls. The phosphorylation, acetylation, and methylation of 6 lysine, serine, and arginine residues of histones H3 and H4 were examined together with 16 metabolic gene transcripts using serial immunoblotting, immunohistochemical analysis, custom-made complementary DNA arrays, and quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: Subjects with schizophrenia, as a group, showed no significant alterations in histone profiles or gene expression. In a subgroup of 8 patients with schizophrenia, levels of H3-(methyl)arginine 17, H3meR17, exceeded control values by 30%, and this was associated with the decreased expression of 4 metabolic transcripts. CONCLUSIONS: High levels of H3-(methyl)arginine 17 are associated with down-regulated metabolic gene expression in the prefrontal cortex of a subset of subjects with schizophrenia. Histone modifications may contribute to the pathogenesis of prefrontal dysfunction in schizophrenia. Schahram Akbarian Chromatin Down Syndrome Epigenesis, Genetic Gene Expression Gene Expression Profiling Gene Expression Regulation Histones Humans Immunoblotting Immunohistochemistry Oligonucleotide Array Sequence Analysis Prefrontal Cortex Reverse Transcriptase Polymerase Chain Reaction Schizophrenia http://works.bepress.com/stephen_baker/23 http://works.bepress.com/stephen_baker/23 Mon, 07 Jul 2008 12:31:02 PDT Catherine Yu Adolescent Adult Caliciviridae Infections *Disease Outbreaks Female Gastroenteritis Humans Male Norovirus Reverse Transcriptase Polymerase Chain Reaction http://works.bepress.com/stephen_baker/22 http://works.bepress.com/stephen_baker/22 Mon, 07 Jul 2008 12:30:42 PDT HYPOTHESIS: An analysis of patients undergoing laparoscopic Roux-en-Y gastric bypass (RYGB) may identify factors predictive of complication and of suboptimal weight loss. DESIGN: Inception cohort. SETTING: Metropolitan university hospital. PATIENTS: One hundred eighty-eight consecutive patients with severe obesity who met National Institutes of Health consensus guidelines for bariatric surgery. INTERVENTIONS: Laparoscopic RYGB. MAIN OUTCOME MEASURES: Complications requiring therapeutic intervention and percentage of excess body weight lost at 1 year after surgery. RESULTS: Of the 188 patients who underwent laparoscopic RYGB, 50 (26.6%) developed complications that required an invasive therapeutic intervention, including 2 deaths. The average follow-up was 351 days (range, 89-1019 days). Multivariate analysis by stepwise logistic regression identified surgeon experience, sleep apnea (P =.003; odds ratio, 3.0; 95% confidence interval, 1.3-7.1), and hypertension (P =.07; odds ratio, 2.0; 95% confidence interval, 1.0-4.0) as predictors of complications. The most common complication requiring therapeutic intervention was stricture at the gastrojejunal anastomosis, occurring in 27 patients (14.4%). Of the 115 patients who underwent surgery more than 1 year previously, 1-year follow-up data were available for 93 (81%). The body mass index (weight in kilograms divided by the square of height in meters) decreased from 53 +/- 8 preoperatively to 35 +/- 6 at 1 year. The mean +/- SD percentage of excess body weight lost at 1 year was 61% +/- 14%. Diabetes mellitus was negatively correlated with percentage of excess body weight lost at 1 year (P =.06). CONCLUSIONS: Surgeon experience, sleep apnea, and hypertension are associated with complications after laparoscopic RYGB. Diabetes mellitus may be associated with poorer postoperative weight loss. Richard A. Perugini Adult Aged Anastomosis, Roux-en-Y Clinical Competence Constriction, Pathologic Female *Gastric Bypass Humans Laparoscopy Male Middle Aged Postoperative Period *Weight Loss http://works.bepress.com/stephen_baker/21 http://works.bepress.com/stephen_baker/21 Mon, 07 Jul 2008 12:30:16 PDT A retrospective review is presented of 20 patients with traumatic brain injury who were treated during the course of their illness by lobectomies either after a herniation or other significant deterioration or to reduce elevated intracranial pressure. All the patients suffered from blunt head trauma. Patient ages ranged from 19 to 59 years (average, 34 yr). The initial Glasgow Coma Scale score ranged from 3 to 15 (average, 8.2). There were 14 frontal lobectomies, 2 temporal, 3 frontal and temporal, and 1 occipital. Surgery was performed between 0 and 8 days after injury (average, 2.8). Outcome was favorable (good or moderately disabled) in 11 patients and unfavorable (severely disabled, persistently vegetative, or dead) in 9. No patients survived in a persistently vegetative state. A higher initial Glasgow Coma Scale score was positively correlated with a more favorable outcome (P < 0.03). Younger patients also showed a significant positive relationship to outcome (P < 0.0005). Better pupillary reactivity showed a significant trend toward a more favorable outcome (P < 0.04). The type of lesions identified on computed tomographic scans had no association with outcome. A lobectomy can be a useful adjuvant in the management of severe brain injury, especially in younger patients with relatively higher initial Glasgow Coma Scale scores who subsequently deteriorate or develop elevated intracranial pressure. N. Scott Litofsky Adult Cerebral Cortex Encephalocele Female Follow-Up Studies Glasgow Coma Scale Head Injuries, Closed Humans Male Middle Aged Neurologic Examination Postoperative Complications Pseudotumor Cerebri *Psychosurgery Retrospective Studies Survival Rate http://works.bepress.com/stephen_baker/20 http://works.bepress.com/stephen_baker/20 Mon, 07 Jul 2008 12:29:56 PDT OBJECTIVE: The clinical characteristics and outcomes of endometrial cancer patients 45 years of age and younger were compared with those of patients older than 45 years of age. METHODS: We performed a cross-sectional study of 301 consecutive endometrial cancer patients referred to our center from 1989 to 1994. Of the 289 patients eligible for study, 40 were 45 years of age or younger (group A) and 249 were older than 45 years of age (group B). RESULTS: The majority of patients in both groups presented with stage I disease. Of the women with stage I disease, patients in group A were more likely than those in group B to have low-grade disease localized to the endometrium (P < .001; relative prevalence 3.39; confidence interval [CI] 1.88, 6.12). However, the distribution of stages I to IV overall was the same for the two groups (P = .269). Although univariate analysis revealed that 11% of the patients in group A and 2% in group B had synchronous ovarian malignancies (P = .007; relative prevalence 5.42; CI 1.39, 21.14), multivariate logistic regression found that nulliparity, not age, was an independent risk factor for synchronous ovarian malignancy (P = .017; relative prevalence 6.15; CI 1.52, 25.61). There were no statistically significant differences by age in the prevalence of high-risk endometrial histology (serous and clear cell carcinoma) or in survival. CONCLUSION: The overall distribution of tumor stage and survival were the same for the younger and older women; this finding contradicts previous reports that suggest that young women with endometrial cancer are at lower risk. Additionally, nulliparity, which occurs with a higher prevalence in younger women who develop endometrial cancer, is associated statistically with the development of synchronous ovarian malignancies. Elaine R. Evans-Metcalf Adult Age Distribution Age Factors Aged Cross-Sectional Studies *Endometrial Neoplasms Female Humans Middle Aged Multivariate Analysis Neoplasm Staging Neoplasms, Multiple Primary Ovarian Neoplasms Parity