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Biomedical subjects

M Haber

Publications and source records attributed to M Haber.

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

MYCN expression is not prognostic of adverse outcome in advanced-stage neuroblastoma with nonamplified MYCN.

PURPOSE: The clinical significance of MYCN expression in children with neuroblastoma (NB) remains controversial. To determine the prognostic significance of MYCN expression in the absence of MYCN amplification, we analyzed MYCN mRNA and protein expression in tumors from 69 patients. PATIENTS AND METHODS: Sixty-nine NB tumor samples with nonamplified MYCN from patients with stage C or D disease were obtained from the Pediatric Oncology Group Neuroblastoma Tumor Bank. MYCN mRNA was analyzed using a real-time reverse transcriptase polymerase chain reaction assay, and MYCN protein was examined by Western blot analyses. RESULTS: The estimated 5-year event-free survival (EFS) and survival (S) rates plus SE for the cohort were 57% +/- 17% and 60% +/- 16%, respectively. Infants younger than 1 year had significantly higher rates of EFS and S than children >/= 1 year of age (P =.003 and P <.001, respectively); patients with stage C disease had better outcome than those with stage D NB (P <.001); and patients with hyperdiploid tumors had better outcome than those with diploid NB (P <.001). Surprisingly, outcome was slightly better for patients with high versus low levels of MYCN mRNA expression (4-year S, 70% +/- 13% v 50% +/- 16%; P =.290), and for patients with tumors that expressed MYCN protein (4-year S, 73% +/- 19% v 53% +/- 15%, respectively; P =.171). CONCLUSION: High levels of MYCN expression are not prognostic of adverse outcome in patients with advanced-stage NB with nonamplified MYCN. A trend associating high levels of MYCN expression with improved outcome was observed.

Blotting, Western↗
PubMed2000

Synergy between 5' and 3' flanking regions of the human tyrosine hydroxylase gene ensures specific, high-level expression in neuroblastoma cells.

Factors regulating tyrosine hydroxylase (TH) gene transcription are of major importance in the studies of malignant and degenerative diseases of catecholamine-synthesizing tissues. In this study, we used transient transfection of a reporter gene to show that high-level, tissue-specific TH expression was only achieved when the reporter gene was cloned between a 5' TH promoter sequence (-513-+1), and, a 3' TH gene flanking sequence (end of exon 14-+976). We also show that TH mRNA expression level is closely linked to the expression level of the proto-oncogene, MYCN in neuroblastoma tumor cell lines. Taken together our data indicate that MYCN may regulate TH expression in neuroblastoma cells, but not through binding to the 5' or 3' TH gene flanking sequences used in our experiments.

3' Untranslated Regions↗
PubMed2000

Effectiveness of influenza vaccination of day care children in reducing influenza-related morbidity among household contacts.

CONTEXT: A growing proportion of young children in the United States participate in day care, and these children are considered to be at high risk for influenza infection. Whether vaccinating day care children reduces household transmission of influenza is not known. OBJECTIVE: To evaluate the effect of vaccinating day care children on reducing influenza-related morbidity among their household contacts. DESIGN: Single-blind, randomized controlled trial conducted during the 1996-1997 influenza season. SETTING: Ten day care centers for children of US Navy personnel in San Diego, Calif. PARTICIPANTS: A total of 149 day care attendees (aged 24-60 months) and their families were randomized; 127 children and their 328 household contacts received 2 vaccine doses and were included in the analysis. INTERVENTIONS: Inactivated influenza vaccine was administered to 60 children with 162 household contacts, and hepatitis A vaccine as a control was administered to 67 age-matched children with 166 household contacts. MAIN OUTCOME MEASURES: Information regarding febrile respiratory illnesses and related morbidity for household contacts of influenza-vaccinated vs control children (subgrouped by influenza-vaccinated and unvaccinated contacts), obtained by telephone interviews with parents every 2 weeks from November 1996 through April 1997. RESULTS: Influenza-unvaccinated household contacts (n = 120) of influenza-vaccinated day care children had 42% fewer febrile respiratory illnesses (P =.04) compared with unvaccinated household contacts of control children. Among school-aged household contacts (aged 5-17 years), there was an 80% reduction among contacts of vaccinated children (n = 28) vs contacts of unvaccinated children (n = 31) in febrile respiratory illnesses (P =.01), as well as reductions of more than 70% in school days missed (P =.02), reported earaches (P =.02), physician visits (P =.007), physician-prescribed antibiotics (P =.02), and adults who missed work to take care of ill children (P =.04). CONCLUSIONS: These results indicate that vaccinating day care children against influenza helps reduce influenza-related morbidity among their household contacts, particularly among school-aged contacts. Future studies should be conducted in civilian populations to assess the full effect of vaccinating day care children against influenza. JAMA. 2000;284:1677-1682.

Adolescent↗
PubMed2000

Studies of the 1996-1997 inactivated influenza vaccine among children attending day care: immunologic response, protection against infection, and clinical effectiveness.

A randomized, blinded, pilot study of influenza vaccine administered to children attending day care centers was conducted during the 1996-1997 winter. Vaccine efficacy in preventing serologically proven influenza virus infection was 0.45 (95% confidence limit [CL]: -0.02, 0.69) for influenza B and 0.31 (95% CL: -0.95, 0.73) for influenza A(H3N2). For both influenza A(H3N2) and B, children without preexisting hemagglutination inhibition (HI) antibody to these antigens had lower antibody responses to vaccine, were less likely to develop a serological response, and were more likely to develop serological evidence of influenza infection. Although there were no reductions in respiratory or febrile respiratory illnesses among all vaccinated children, there was a trend for reductions in such illnesses among vaccinated children with preexisting HI antibodies to influenza A(H3N2) and B. Therefore, immunologic priming in young children may be important for vaccine response and for protection against infection. Larger studies are needed in other influenza seasons to assess vaccine efficacy and clinical effectiveness.

Antibodies, Viral↗
PubMed2000

Expression of N-myc and MRP genes and their relationship to N-myc gene dosage and tumor formation in a murine neuroblastoma model.

BACKGROUND: Although the association between N-myc gene amplification and poor clinical outcome in neuroblastoma is well established, the mechanism by which amplification influences prognosis is not well defined. PROCEDURE: We used a human N-myc transgenic mouse model to investigate the role of N-myc in neuroblastoma, including its relationship to the multidrug-resistance-associated protein (MRP) gene. We developed a rapid real-time PCR method to distinguish homozygous and hemizygous N-myc mice that is comparable to Southern analysis. RESULTS: A highly significant correlation (P < 0.0001) between N-myc and MRP expression was demonstrated in murine tumors. Amplification of the transgene was observed in the majority of tumors, highlighting the clinical relevance of this model. However, no correlation between N-myc expression and transgene dosage or tumor latency was observed. CONCLUSIONS: The data suggest that increased N-myc dosage contributes to increased tumor incidence and decreased latency by mechanisms independent of N-myc expression.

ATP-Binding Cassette Transporters↗
PubMed2000

Intraoperative scrape cytology: comparison with frozen sections, using receiver operating characteristic (ROC) curve.

The diagnostic role of intraoperative cytology (IC) has been demonstrated by many comparative studies. These studies have used sensitivity and specificity as statistical tools, based on binary principles. Statistical methods based on binary principles appear to be inappropriate for comparing anatomic pathology studies which involve significant human judgment with a range of subjective nonbinary result patterns. In this study, we applied the receiver operating characteristic (ROC) curve, which is based on probabilistic principles for the comparison of diagnostic accuracy with IC and frozen sections (FS). Seven observers studied a variable number of IC alone, FS alone, and IC/FS together from a pool of 446 specimens. The results were analyzed by ROC curve, using the MEDCALC software program (MedCalc Software, Mariakerke, Belgium). The accuracy with IC alone and FS alone was comparable. IC alone was diagnostic for many lesions, offering the choice of not freezing the tissue, and thus avoiding the introduction of artifacts. This strongly favors the routine practice of preparing IC during intraoperative consultation.

Area Under Curve↗
PubMed2000

Functional decline among older adults: comparing a chronic disease cohort and controls when mortality rates are markedly different.

In studies of functional status decline in older persons, the strategy for handling deaths during follow-up may influence policy implications. We compared 301 older ESRD dialysis patients with 322 controls to determine whether functional decline over 3 years among dialysis patients exceeded that of "normal aging." We used two different statistical methods and, for each, compared results when deaths were excluded and then included in the analysis. Dialysis patients incurred a larger follow-up mortality rate and were more impaired at baseline. Findings based on functional transition over time, assessed by a nominal variable, were sensitive to whether or not deaths were included in the analysis. However, findings based on nonparametric methods for an ordinal scale (functional impairment) were not sensitive to whether or not deaths were included in the analysis. Analyzing data with and without deceased subjects may be the most comprehensive approach to comparing two cohorts over time.

Aged↗
PubMed2000

Simultaneous detection and quantification of minimal residual disease in childhood acute lymphoblastic leukaemia using real-time polymerase chain reaction.

A number of prospective studies have indicated the clinical utility of measuring minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia (ALL) and have highlighted the need for improved methodology for quantification of residual disease. We describe a novel real-time polymerase chain reaction (PCR) strategy for MRD analysis based on the exonuclease activity of Taq polymerase to cleave a fluorescently labelled probe. Using a consensus probe designed to the framework 2 region of the IgH gene, together with leukaemia-specific primers, the utility of this technique for simultaneous detection and quantification of MRD was demonstrated in samples from six ALL patients. This technique provides a rapid quantitative assay for determining MRD levels which lends itself to the routine monitoring of minimal residual leukaemia.

Bone Marrow Cells↗
PubMed2000

Postinjection vastus lateralis atrophy: 2 case reports.

We report two cases of postsurgical intramuscular meperidine injection with injury to the femoral nerve and subsequent vastus lateralis atrophy. The first case is a patient who had arthroscopic anterior cruciate ligament reconstruction; the second, a patient with a C6-C7 anterior fusion. Photographs, radiography, and electrodiagnostic studies clearly depict the nature of the injuries, and their etiology is discussed. These case reports describe a unique neuropathic injection injury that, to our knowledge, has never before been described in the literature.

Adult↗
PubMed2000

Functional impairment, depression, and life satisfaction among older hemodialysis patients and age-matched controls: a prospective study.

OBJECTIVE: To compare change over time in functional impairment, depression, and life satisfaction among older dialysis patients and age-matched controls. DESIGN: Prospective cohort study over 3 years. SETTING: Urban and rural communities throughout Georgia. SUBJECTS: One hundred thirteen prevalent renal failure patients on in-center hemodialysis and 286 controls. MAIN OUTCOME MEASURES: Ordinal functional impairment index and life satisfaction rating, and Center for Epidemiologic Studies Depression Scale. RESULTS: Dialysis patients, compared with controls, reported significantly more functional impairment at baseline, and also at follow-up after adjusting for baseline impairment and covariates. Dialysis patients had higher depression scores at baseline, and also at follow-up after adjusting for baseline depression and covariates. In contrast, dialysis patients reported lower life satisfaction at baseline than did controls, but the two cohorts were not significantly different on reported life satisfaction at follow-up, after adjusting for baseline life satisfaction and race. In both cohorts, functional impairment and depression were significantly related. CONCLUSION: Older dialysis patients' life satisfaction at a 3-year follow-up, which was similar to life satisfaction among age-matched controls, indicates the value of delivered dialysis care; the value of this care would be increased by reducing excess functional impairment in these patients.

Aged↗
PubMed1999

Estimation of the direct and indirect effects of vaccination.

Indirect effects play a major role in the protection afforded by a vaccination programme. In this work we define new measures of direct, indirect and total (direct + indirect) effects of a vaccination programme in terms of the protection they provide to unvaccinated and vaccinated individuals, and to the entire population. We show how these measures can be estimated using data from a vaccine trial or an observational study. The bias and standard errors of these estimates can be evaluated via stochastic simulations. Examples from a mumps outbreak and a (hypothetical) HIV vaccine trial are used to illustrate the estimation of these new measures of vaccination effectiveness.

AIDS Vaccines↗
PubMed1999

Health consequences of religious and philosophical exemptions from immunization laws: individual and societal risk of measles.

CONTEXT: All US states require proof of immunization for school entry. Exemptions are generally offered for medical, religious, or philosophical reasons, but the health consequences of claiming such exemptions are poorly documented. OBJECTIVES: To quantify the risk of contracting measles among individuals claiming religious and/or philosophical exemptions from immunization (exemptors) compared with vaccinated persons, and to examine the risk that exemptors pose to the nonexempt population. DESIGN, SETTING, AND PARTICIPANTS: Population-based, retrospective cohort study of data from 1985 through 1992, collected by the Measles Surveillance System of the Centers for Disease Control and Prevention, as well as from annual state immunization program reports on prevalence of exemptors and vaccination coverage. The study group was restricted to individuals aged 5 to 19 years. To empirically determine and quantify community risk, a mathematical model was developed that examines the spread of measles through communities with varying proportions of exemptors and vaccinated children. MAIN OUTCOME MEASURES: Relative risk of contracting measles for exemptors vs vaccinated individuals based on cohort study data. Community risk of contracting measles derived from a mathematical model. RESULTS: On average, exemptors were 35 times more likely to contract measles than were vaccinated persons (95% confidence interval, 34-37). Relative risk varied by age and year. Comparing the incidence among exemptors with that among vaccinated children and adolescents during the years 1985-1992 indicated that the 1989-1991 measles resurgence may have occurred 1 year earlier among exemptors. Mapping of exemptors by county in California indicated that exempt populations tended to be clustered in certain geographic regions. Depending on assumptions of the model about the degree of mixing between exemptors and nonexemptors, an increase or decrease in the number of exemptors would affect the incidence of measles in nonexempt populations. If the number of exemptors doubled, the incidence of measles infection in nonexempt individuals would increase by 5.5%, 18.6%, and 30.8%, respectively, for intergroup mixing ratios of 20%, 40%, and 60%. CONCLUSIONS: These data suggest the need for systematic review of vaccine-preventable incidents to examine the effect of exemptors, increased surveillance of the number of exemptors and cases among them, and research to determine the reasons why individuals claim exemptions.

Adolescent↗
PubMed1999

Altered expression of the MYCN oncogene modulates MRP gene expression and response to cytotoxic drugs in neuroblastoma cells.

We have recently shown a close correlation between expression of the Multidrug Resistance-associated Protein (MRP) gene and the MYCN oncogene and provided evidence that high MRP expression is a powerful independent predictor of poor outcome in neuroblastoma (Norris et al., New Engl. J. Med., 334, 231-238, 1996). The effect of MYCN down-regulation on MRP expression and response to cytotoxic drugs was investigated in NBL-S neuroblastoma cells transfected with MYCN antisense RNA constructs. Concomitant with MYCN down-regulation, the level of MRP expression was decreased in the NBAS-4 and NBAS-5 antisense transfectants. These cells demonstrated significantly increased sensitivity to the high affinity MRP substrates vincristine, doxorubicin, sodium arsenate and potassium antimony tartrate, but not to the poor MRP substrates, taxol or cisplatin. Similarly, transfection of full-length MYCN cDNA into SH-EP neuroblastoma cells resulted in increased MRP expression and significantly increased resistance specifically to MRP substrates. The results provide evidence for the MYCN oncogene influencing cytotoxic drug response via regulation of MRP gene expression. Our data also provide a link between the malignant and chemoresistant phenotypes of this childhood malignancy.

ATP-Binding Cassette Transporters↗
PubMed1999

Use of tumor-specific gene expression for the differential diagnosis of neuroblastoma from other pediatric small round-cell malignancies.

The differential diagnosis of neuroblastoma from other small round-cell tumors of childhood, although clinically of great importance, is sometimes difficult due to the almost indistinguishable appearance of such tumors by conventional microscopy. Because neuroblastomas are characterized by the synthesis of catecholamines, we investigated the possibility that expression of genes involved in this pathway could serve as a molecular marker for this disease. A reverse transcriptase polymerase chain reaction assay was used to analyze expression of tyrosine hydroxylase and dopa decarboxylase in 84 pediatric malignancies including 55 neuroblastomas, 6 Ewing's sarcomas/primitive neuroectodermal tumors, 7 lymphomas, 6 leukemias, 2 rhabdomyosarcomas, 6 osteosarcomas, and 2 phaeochromocytomas. Of the 55 neuroblastoma samples analyzed, 54 expressed clearly detectable levels of both genes. The one sample that did not express either of the genes was rediagnosed both clinically and by molecular genetic analysis as a Ewing's sarcoma. Of the 29 non-neuroblastoma tumor samples examined, the only tumor samples that expressed clearly detectable levels of both tyrosine hydroxylase and dopa decarboxylase were phaeochromocytomas. Like neuroblastomas, these tumors are characterized by high levels of catecholamines. These findings suggest that expression of genes involved in catecholamine biosynthesis may be useful for differentiating neuroblastoma from other small round-cell tumors of childhood.

Child, Preschool↗
PubMed1999

T-cell depletion of allogeneic bone marrow using anti-alphabetaTCR monoclonal antibody: prevention of graft-versus-host disease without affecting engraftment potential in rats.

Bone marrow chimerism may solve two major limitations in the transplantation of solid organs and cellular grafts: (1) the requirement for life-long immunosuppressive therapy, and (2) acute and chronic rejection. When untreated bone marrow is transplanted into major histocompatibility complex (MHC)-disparate rats, lethal graft-vs-host disease (GVHD) occurs in the majority of recipients. T-cell depletion using anti-CD3 and anti-CD5 monoclonal antibody (mAb) to avoid GVHD led to an increased occurrence of failure of engraftment. We previously identified a cellular population in mouse bone marrow that facilitates engraftment of highly purified hematopoietic stem cells (HSC) across complete MHC barriers. In light of the fact that facilitating cells have a CD8+/CD3+/TCR- phenotype and mostly coexpress CD5, we evaluated in this study whether T-cell depletion of rat bone marrow using anti-alphabetaTCR mAb would retain engraftment potential yet avoid GVHD. T-cell depletion of bone marrow was performed using anti-alphabetaTCR mAb and immunomagnetic beads. Recipients were conditioned with 1100 or 1000 cGy of total body irradiation and reconstituted with 100 x 10(6) T-cell depleted (TCD) MHC- and minor antigen-disparate bone marrow cells. Animals were monitored clinically and histologically for GVHD. Chimerism was assessed by flow cytometry. Immunomagnetic bead depletion resulted in a reduction of T cells from 1.92%+/-0.21% to 0.10%+/-0.04% of total bone marrow. T-cell depletion did not remove facilitating cells (CD8+/alphabetaTCR-/gammadeltaTCR-/NK3.2.3-) from bone marrow. Further, the engraftment potential of TCD bone marrow was not affected, as 100% of animals engrafted and high levels of donor chimerism were detectable. Animals reconstituted with TCD bone marrow showed no clinical evidence of GVHD and histology revealed none to minimal changes, whereas recipients transplanted with untreated bone marrow succumbed to severe lethal GVHD. T-cell depletion using antialphabetaTCR mAb and immunomagnetic beads selectively removes T cells from the bone marrow graft while sparing facilitating cells that are required for engraftment of allogeneic bone marrow across MHC barriers. Moreover, the cells required for engraftment of HSC do not produce GVHD.

Animals↗
PubMed1999

Double-blind comparison of lansoprazole 15 mg, lansoprazole 30 mg and placebo as maintenance therapy in patients with healed duodenal ulcers resistant to H2-receptor antagonists.

BACKGROUND: Maintenance antisecretory therapy is often used to prevent duodenal ulcer recurrence and control symptoms. This study compared the efficacy and safety of lansoprazole 15 mg and 30 mg daily with placebo in preventing ulcer recurrence in patients with a recent history of duodenal ulcer disease. METHODS: Fifty-six patients were treated with either lansoprazole 15 mg, 30 mg or placebo o.m. RESULTS: Within 1 month of study initiation, 27% (four out of 15) of placebo-treated patients experienced ulcer recurrence as compared to 13% (two out of 15) and 6% (one out of 18) of lansoprazole 15 mg and 30 mg treated patients, respectively. Median time to first ulcer recurrence was > 12 months in lansoprazole patients. At Month 12, significantly (P < 0.001) more lansoprazole 15 mg patients (70%) and lansoprazole 30 mg patients (85%) remained healed. Eighty-two per cent of lansoprazole 15 mg and 76% of lansoprazole 30 mg patients remained asymptomatic during the entire study period. All placebo patients became symptomatic, experienced ulcer recurrence, or withdrew from the study by month six. The incidence of adverse events was comparable among the three treatment groups. CONCLUSIONS: Lansoprazole safely and effectively reduces duodenal ulcer recurrence and ulcer-related symptoms.

2-Pyridinylmethylsulfinylbenzimidazoles↗