Biomedical subjects

B A Miller

Publications and source records attributed to B A Miller.

At least 19 recordsLinked to original sources

PubMed1999

Identification of the erythropoietin receptor domain required for calcium channel activation.

Erythropoietin (Epo) activates a voltage-independent Ca2+ channel that is dependent on tyrosine phosphorylation. To identify the domain(s) of the Epo receptor (Epo-R) required for Epo-induced Ca2+ influx, Chinese hamster ovary (CHO) cells were transfected with wild-type or mutant Epo receptors subcloned into pTracer-cytomegalovirus vector. This vector contains an SV40 early promoter, which drives expression of the green fluorescent protein (GFP) gene, and a cytomegalovirus immediate-early promoter driving expression of the Epo-R. Successful transfection was verified in single cells by detection of GFP, and intracellular Ca2+ ([Ca]i) changes were simultaneously monitored with rhod-2. Transfection of CHO cells with pTracer encoding wild-type Epo-R, but not pTracer alone, resulted in an Epo-induced [Ca]i increase that was abolished in cells transfected with Epo-R F8 (all eight cytoplasmic tyrosines substituted). Transfection with carboxyl-terminal deletion mutants indicated that removal of the terminal four tyrosine phosphorylation sites, but not the tyrosine at position 479, abolished Epo-induced [Ca]i increase, suggesting that tyrosines at positions 443, 460, and/or 464 are important. In CHO cells transfected with mutant Epo-R in which phenylalanine was substituted for individual tyrosines, a significant increase in [Ca]i was observed with mutants Epo-R Y443F and Epo-R Y464F. The rise in [Ca]i was abolished in cells transfected with Epo-R Y460F. Results were confirmed with CHO cells transfected with plasmids expressing Epo-R mutants in which individual tyrosines were added back to Epo-R F8 and in stably transfected Ba/F3 cells. These results demonstrate a critical role for the Epo-R cytoplasmic tyrosine 460 in Epo-stimulated Ca2+ influx.

Animals↗

PubMed1999

A homolog of the fungal nuclear migration gene nudC is involved in normal and malignant human hematopoiesis.

The filamentous fungus Aspergillus nidulans nudC gene has an essential function in movement of nuclei following mitosis and is required for normal colony growth. Here, the molecular cloning and role in hematopoiesis of a human gene (designated HnudC) homologous to A. nidulans nudC is reported. The amino terminus of the larger human protein (HNUDC = 45 kDa) does not overlap with A. nidulans NUDC (22 kDa). However, NUDC and the C-terminal 94 amino acids of HNUDC are 67% identical. The C-terminal region of the HnudC gene fully complements the A. nidulans temperature-sensitive nudC3 mutation, suggesting that nudC has an essential function in cell growth that is conserved from filamentous fungi to humans. In initial studies, HNUDC levels were much higher in erythroid precursors compared to most other human tissues. Therefore, the potential role of HnudC in hematopoiesis was explored. In normal human bone marrow, HNUDC protein and mRNA are highly expressed in early myeloid and erythroid precursors and decline as these cells terminally differentiate. To determine whether hematopoietic growth factors induce HnudC expression, TF-1 cells were stimulated by granulocyte-macrophage colony-stimulating factor. This induced a significant increase in HNUDC protein and HnudC mRNA, suggesting that enhancement of HnudC expression in response to growth factor stimulation may be mediated at the transcription level. Furthermore, HNUDC was significantly enhanced in lysates of bone marrow aspirates from patients with acute myelogenous and acute lymphoblastic leukemia compared to aspirates from normal controls, suggesting that HnudC is involved in malignant hematopoietic cell growth as well. These data demonstrate that HNUDC is highly expressed in normal and malignant human hematopoietic precursors and suggest it is of functional importance in the proliferation of these cells.

Antibody Specificity↗

PubMed1999

Mothers' alcohol and other drug problems and their punitiveness toward their children.

OBJECTIVE: The relationship between mothers' alcohol or other drug (AOD) problems and their punitiveness toward their children is examined in this study. METHOD: Women (N = 170) were recruited from five different sources, including clinical interventions and the community. Women's punitiveness toward their children was assessed by three different maternal self-report measures: Conflict Tactics Scale, Parental Punitiveness Scale and Child Abuse Potential Inventory. Women's histories of AOD problems, violent victimization and hostility were assessed using standardized assessment tools. RESULTS: Women were categorized by their AOD problems as follows: current problem (22.4%), past only problem (44.7%) or no problems (32.9%). Results indicate that mothers with current or past AOD problems are more punitive toward their children, controlling for potentially confounding demographic factors. Mothers' histories of partner violence and parental violence also predicted higher levels of mother-to-child punitiveness. However, histories of childhood sexual abuse predicted lower levels of mothers' punitiveness. Hostility served as a predictor of mothers' punitiveness and moderated some of the relationships between their AOD problems and their punitiveness. CONCLUSIONS: Findings suggest that women with AOD problems are more likely to be punitive toward their children, but other factors may also contribute to this risk. Treatment and prevention interventions need to be developed to decrease the risk of violent victimization among children whose mothers have alcohol and other drug problems.

Adolescent↗

PubMed1998

Duration of antiviral prophylaxis during nursing home outbreaks of influenza A: a comparison of 2 protocols.

BACKGROUND: We performed a randomized trial of 2 protocols guiding the duration of antiviral chemoprophylaxis during outbreaks of influenza A in a rural, 700-bed nursing home for veterans and their spouses with 14 nursing units in 4 buildings. METHODS: Half of all residents volunteered to participate. Nursing units were randomized, and the effectiveness of short-term (minimum, 14 days and 7 days without the onset of a case in the building) vs long-term (minimum, 21 days and 7 days without the onset of a case in the 4-building facility) prophylaxis was compared using amantadine hydrochloride in the influenza seasons of 1991-1992 and 1993-1994 and rimantadine hydrochloride in the influenza season of 1994-1995. A "case" is defined as an incident of a respiratory tract illness and the isolation of an influenza virus organism. We compared the number of cases after the discontinuation of short- vs long-term chemoprophylaxis. Prospective surveillance identified residents with new respiratory tract symptoms, and specimens for viral cultures were obtained even in the absence of temperature elevation. RESULTS: We documented influenza A virus activity during 3 seasons (32, 68, and 12 patients, respectively). During the 1991-1992, 1993-1994, and 1994-1995 influenza seasons, the patients on 11 floors were assigned to receive short-term chemoprophylaxis and those on 10 floors were assigned to long-term chemoprophylaxis. Only in 1993-1994 did chemoprophylaxis extend beyond 14 or 21 days when new cases continued beyond 14 days. Amantadine-resistant strains were circulating at that time. None of the participants in the prospective, controlled study had influenza develop after the termination of short- or long-term chemoprophylaxis. CONCLUSION: Antiviral chemoprophylaxis can be administered for the longer duration of 14 days or, in the absence of new culture-confirmed illness in the nursing building, for 7 days.

Aged↗

PubMed1998

Bcl-3 expression and nuclear translocation are induced by granulocyte-macrophage colony-stimulating factor and erythropoietin in proliferating human erythroid precursors.

Bcl-3 is a proto-oncogene involved in the chromosomal translocation t(14;19) found in some patients with chronic lymphocytic leukemia. It shares structural similarities with and is a member of the IkappaB family of proteins. In this report, involvement of Bcl-3 in hematopoietic growth factor-stimulated erythroid proliferation and differentiation was examined. In TF-1 cells, an erythroleukemia cell line, granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo) greatly enhanced Bcl-3 expression at both the protein and mRNA levels in association with stimulation of proliferation. Bcl-3 protein was also highly expressed in early burst-forming unit-erythroid (BFU-E)-derived erythroid precursors (day 7) and decreased during maturation (days 10 and 14), suggesting that Bcl-3 is involved in normal erythroid proliferation. In these hematopoietic cells, Bcl-3 was hyperphosphorylated. GM-CSF and Epo modulated the subcellular localization of Bcl-3. Upon stimulation of TF-1 cells with GM-CSF or Epo, the nuclear translocation of Bcl-3 was dramatically enhanced. Overexpression of Bcl-3 in TF-1 cells by transient transfection along with the NF-kappaB factors p50 or p52 resulted in significant induction of an human immunodeficiency virus-type 1 (HIV-1) kappaB-TATA-luceriferase reporter plasmid, demonstrating that Bcl-3 has a positive role in transactivation of kappaB-containing genes in erythroid cells. Stimulation with GM-CSF enhanced c-myb mRNA expression in these cells. Bcl-3 in nuclear extracts of TF-1 cells bound to a kappaB enhancer in the c-myb promoter together with NF-kappaB2/p52 and this binding activity was enhanced by GM-CSF stimulation. Furthermore, cotransfection of Bcl-3 with p52 or p50 in TF-1 cells resulted in significant activation of a c-myb kappaB-TATA-luceriferase reporter plasmid. These findings suggest that Bcl-3 may participate in the transcriptional regulation of certain kappaB-containing genes involved in hematopoiesis, including c-myb.

B-Cell Lymphoma 3 Protein↗

PubMed1998

NF-kappaB transcription factors are involved in normal erythropoiesis.

NF-kappaB/Rel designates a widely distributed family of transcription factors involved in immune and acute phase responses. Here, the expression and function of NF-kappaB factors in erythroid proliferation and differentiation were explored. In an erythroleukemia cell line, TF-1, high levels of p105/p50, p100/p52, p65, and IkappaBalpha were detected 24 hours after growth factor deprivation. In response to granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation, significant induction of p52 expression was observed. GM-CSF also induced nuclear translocation of both p52 and p65. No induction of NF-kappaB factors was observed with erythropoietin stimulation of TF-1 cells. Overexpression of p52 and p65 in TF-1 cells by transient transfection resulted in significant induction of a kappaB-TATA-luciferase reporter plasmid, showing that these factors are functional in vivo in erythroid cells. To determine whether NF-kappaB factors may play a role in normal erythropoiesis, levels of these factors were determined in burst-forming unit-erythroid (BFU-E)-derived cells at different stages of differentiation. The NF-kappaB factors p105/p50, p100/p52, and p65 were highly expressed in early BFU-E-derived precursors, which are rapidly proliferating, and declined during maturation. Furthermore, nuclear levels of NF-kappaB factors p50, p52, and p65 were higher in less mature precursors (day 10 BFU-E-derived cells) compared with more differentiated (day 14) erythroblasts. In nuclear extracts from day 10 BFU-E-derived cells, p50, p52, and p65 were able to form complexes, which bound to kappaB sites in the promoters of both the c-myb and c-myc genes, suggesting that c-myb and c-myc may be among the kappaB-containing genes regulated by NF-kappaB factors in normal erythroid cells. Taken together, these data show that NF-kappaB factors are modulated by GM-CSF and suggest they function to regulate specific kappaB containing genes involved in erythropoiesis.

Cell Division↗

PubMed1998

Increased incidence of cancer in infants in the U.S.: 1980-1990.

BACKGROUND: During the decade between 1980-1990, the rate of cancer in children in the U.S. increased. It is unknown whether cancer in infancy, which is biologically and clinically different from cancer in older children, also increased. METHODS: To evaluate changes in cancer incidence in infants in the U.S. age < 1 year, data from the Surveillance, Epidemiology, and End Results (SEER) program and the U.S. Bureau of the Census were used to construct age specific, population-based cancer incidence rates. RESULTS: Overall, the annual cancer rate in infants increased from 189 cases per million infants between 1979-1981 to 220 between 1989-1991. At both timepoints, female infants had higher cancer rates than male infants. Although the rates for female infants remained stable at 223 between 1979-1981 versus 236 between 1989-1991, rates for male infants increased from 158 to 205 during the same timepoints. Male infants had increased rates of central nervous system (CNS) tumors (P < 0.05), neuroblastoma, and retinoblastoma; female infants had increased rates of teratomas (P < 0.01) and hepatoblastomas. Between 1979-1981, the three most common types of cancer in infants were neuroblastoma, leukemia, and renal tumors (27%, 15%, and 14%, respectively), and were neuroblastoma, CNS tumors, and leukemia between 1989-1991 (27%, 15%, and 13%, respectively). CONCLUSIONS: This study shows that the rate of certain types of cancer in infants in the U.S. is increasing. Studies of both genetic and environmental factors are needed to explain these increased rates and the changing distribution of cancer in the first year of life.

Female↗

PubMed1998

Evaluating cluster alarms: a space-time scan statistic and brain cancer in Los Alamos, New Mexico.

OBJECTIVES: This article presents a space-time scan statistic, useful for evaluating space-time cluster alarms, and illustrates the method on a recent brain cancer cluster alarms in Los Alamos, NM. METHODS: The space-time scan statistic accounts for the preselection bias and multiple testing inherent in a cluster alarm. Confounders and time trends can be adjusted for. RESULTS: The observed excess of brain cancer in Los Alamos was not statistically significant. CONCLUSIONS: The space-time scan statistic is useful as a screening tool for evaluating which cluster alarms merit further investigation and which clusters are probably chance occurrences.

Brain Neoplasms↗

PubMed1998

Use of competing conceptions of risk in animal agriculture.

This study considers a theory of risk as a means of coping with risk and uncertainty that have become a growing reality for animal agriculture. Microbial contaminations of food, waste management, animal products in the human diet, and transmissible spongiform encephalopathies (TSE) incorporate different conceptions of risk and require different approaches to handling the uncertainty involved. A dichotomous schema is suggested to assist understanding risk that may be adapted to recognizing and handling risk. The polar aspects of the proposal are the probabilistic approach at one end and the contextual understanding at the other. Probabilist conceptions of risk presume that risk is determined by probability and consequence. Contextual conceptions presume that management, law, regulation, media, and public perceptions, as well as the severity of the consequence, will figure prominently in decision making in the face of uncertainty. Relative emphasis on probabilistic characteristics shapes distinct understandings of risk that can be plotted between the poles. We are proposing that these conceptualizations need not be issues only for debate but also for recognition of the probabilistic or contextual nature of the risk. Specific actions and policy may be constructed on the basis of the conceptualization. The bovine spongiform encephalopathy/new variant Creutzfeldt-Jakob disease complex is examined philosophically and methodologically as a contextual challenge to animal agriculture and associated industries. As such, the TSE serve as a case study of effective application of risk theory to risks in animal agriculture.

Animal Husbandry↗

PubMed1998

Relationships between experiences of parental violence during childhood and women's self-esteem.

The interrelationships between experience of parental verbal aggression and physical violence during childhood and the development of low self-esteem during adulthood were explored separately for the father-daughter and mother-daughter relationships. Data were collected from 472 women between the ages of 18 and 45 during in-depth interviews drawn from five sources: outpatient alcoholism treatment, DWI (Driving While Intoxicated) education programs, shelter for battered women, outpatient mental health treatment, and randomly from the community. Control variables included respondents' alcohol problems and help-seeking behavior, parental alcohol problems, number of changes in childhood family (e.g., divorce), and respondents' race and social class. Controlling for these variables, experiences of father-to-daughter verbal aggression, moderate violence, and severe violence were found related to lower self-esteem in adulthood for women. Conversely, controlling for these variables, experiences of mother-to-daughter verbal aggression, moderate violence, and severe violence were not found related to lower self-esteem in adulthood for women.

Adolescent↗

PubMed1998

Exposure assessment for a study of workers exposed to acrylonitrile.

Procedures used to develop estimates of exposure to acrylonitrile for a cohort study (>25000 workers in 8 monomer, fiber, and resin companies from 1952 to 1983) are presented. Visits to the companies were made, interviews of workers were conducted, historical records were made, and measurements were taken. On the basis of similar tasks, locations, other exposures, and a similar distribution of exposures to acrylonitrile, 3600 exposure groups were formed. Special procedures were used to reduce the misclassification of workers performing tasks that varied in time but that were inadequately reflected in the job title. A software program organized and retained all exposure information on each exposure group. Quantitative estimates of acrylonitrile exposure were developed using a hierarchical approach in a software program that documented the derivation of each estimate and facilitated data review. Two of the estimation methods were evaluated in a comparison with measurement data.

Acrylonitrile↗

PubMed1998

Trends: immigration and technology.

America is experiencing a new wave of immigration that many say will be larger than the one beginning just before 1900. But this immigration is more global in origin and will result in making many states so diverse that there is no "majority" culture. Immigration will fuel the economy and will be particularly advantageous to those businesses that can recognize and respond to the needs of the new immigrant groups.

Cultural Diversity↗

PubMed1997

Expression of SCL is normal in transfusion-dependent Diamond-Blackfan anemia but other bHLH proteins are deficient.

Basic helix-loop-helix proteins, which are tissue specific (SCL) or broadly expressed (E proteins), interact positively to regulate erythroid specific genes. Here, expression of SCL and two broadly expressed E proteins, E47 and HEB, was high early in erythroid differentiation and declined during maturation. Stimulation of erythroid progenitors/precursors with stem cell factor (SCF) enhanced SCL and E protein levels, one mechanism by which SCF may increase erythroid proliferation. Interactions between SCL and E proteins are competed by Id2, which binds and sequesters E proteins. Upregulation of Id2, demonstrated here late in erythroid differentiation, may downregulate genes involved in erythroid proliferation/differentiation. We examined expression of bHLH proteins in transfusion-dependent patients with Diamond-Blackfan anemia (DBA) to determine if these interactions are disrupted. In erythroblasts from patients, expression of SCL protein and mRNA was normal and SCL increased in response to SCF. However, E47 and HEB protein levels were significantly decreased. Id2 was strongly expressed in patients. Through reduction of SCL/E protein heterodimer formation, abnormal levels of bHLH transcription factors may affect expression of erythroid specific genes, such as beta globin. Stimulation of Diamond-Blackfan cells with SCF partially compensated for this defect, enhancing expression of E47, HEB, and SCL. SCF may function to increase SCL/E protein heterodimer formation, which may be one of the mechanisms through which SCF stimulates erythroid proliferation/differentiation in DBA.

Basic Helix-Loop-Helix Proteins↗

PubMed1997

Breast cancer clusters in the northeast United States: a geographic analysis.

High breast cancer mortality rates have been reported in the northeastern part of the United States, with recent attention focused on Long Island, New York. In this study, the authors investigate whether the high breast cancer mortality is evenly spread over the Northeast, in the sense that any observed clusters of deaths can be explained by chance alone, or whether there are clusters of statistical significance. Demographic data and age-specific breast cancer mortality rates for women were obtained for all 244 counties in 11 northeastern states and for the District of Columbia for 1988-1992. A recently developed spatial scan statistic is used, which searches for clusters of cases without specifying their size or location ahead of time, and which tests for their statistical significance while adjusting for the multiple testing inherent in such a procedure. The basic analysis is adjusted for age, with further analyses examining how the results are affected by incorporating race, urbanicity, and parity as confounding variables. There is a statistically significant and geographically broad cluster of breast cancer deaths in the New York City-Philadelphia, Pennsylvania, metropolitan area (p = 0.0001), which has a 7.4% higher mortality rate than the rest of the Northeast. The cluster remains significant when race, urbanicity, and/or parity are included as confounding variables. Four smaller subclusters within this area are also significant on their own strength: Philadelphia with suburbs (p = 0.0001), Long Island (p = 0.0001), central New Jersey (p = 0.0001), and northeastern New Jersey (p = 0.0001). The elevated breast cancer mortality on Long Island might be viewed less as a unique local phenomenon and more as part of a more general situation involving large parts of the New York City-Philadelphia metropolitan area. The several known and hypothesized risk factors for which we could not adjust and that may explain the detected cluster are most notably age at first birth, age at menarche, age at menopause, breastfeeding, genetic mutations, and environmental factors.

Breast Neoplasms↗

PubMed1997

Human papillomavirus type 16 DNA in esophageal carcinomas from Alaska Natives.

The possible etiological role of human papillomavirus (HPV) in esophageal carcinogenesis was evaluated in Alaska Natives in whom the incidence of esophageal cancer is 1.3 and 3.8 times higher than in US Caucasian men and women, respectively. Fixed paraffin-embedded esophageal tissues from 32 cases of squamous-cell carcinoma (SCC) and 3 cases of adenocarcinoma (AC) diagnosed between 1957 and 1988 were analyzed by polymerase chain reaction (PCR) and in situ hybridization for HPV DNA sequences. Detection of the human beta-globin gene by PCR was used as a control for sufficiency of DNA and its potential for amplification in the tissue samples. Twenty-five of the tumor tissues were considered adequate for PCR analyses; HPV DNA was detected in 10 of 22 SCCs and was not found in 3 ACs. Seven of the 10 HPV-positive tissues contained sequences from the E6 gene of HPV type 16. Koilocytosis, an epithelial change consistent with HPV infection, was found in 80% of the esophageal squamous-cell tumors with HPV DNA and in 75% of those without HPV DNA. The detection of amplifiable cellular DNA was related to recentness of diagnosis; however, the detection of HPV DNA within amplifiable specimens was not related to recentness of diagnosis. A 413-bp sequence from the L1 open reading frame of HPV 16 from esophageal tissue of 2 patients was identical to sequences previously identified in cervical cells from other Alaska Natives. Our results provide molecular evidence of HPV infection, especially type 16, in archival esophageal cancer tissues from 45% of those patients whose specimens contain adequate DNA for PCR analysis.

Adenocarcinoma↗

PubMed1997

Human papillomavirus types 52 and 58 are prevalent in cervical cancers from Chinese women.

A substantial body of evidence has confirmed human papillomavirus (HPV) infection as an etiologic agent in human cervical cancer. To evaluate the association between HPV and cervical cancer in Chinese women, we examined tumor specimens from women who lived in Shanghai, People's Republic of China. Biopsies from 40 women, diagnosed with either squamous-cell carcinoma (n = 35) or adenocarcinoma (n = 5) were tested for HPV DNA by PCR. The HPV types present in tumors were determined either by hybridization of PCR products with HPV type-specific probes or by PCR-based sequencing. A total of 35 of the 40 cervical cancer specimens (87.5%) contained HPV DNA. The following distribution and types were detected: 7.5% HPV 16, 10% HPV 18, 20% HPVs 16 and 18, 15% HPV 52, 15% HPV 58, 12.5% HPVs 52 and 58 and 7.5% unclassified HPVs. In this population of Chinese women with cervical cancer, HPV 52 and 58 were as prevalent as the "high-risk" (for cervical cancer) viruses HPVs 16 and 18.

Adenocarcinoma↗

PubMed1997

Modulation of calcium channels in human erythroblasts by erythropoietin.

Erythropoietin (Epo) induces a dose-dependent increase in intracellular free Ca2+ ([Ca2+]i) in human erythroblasts, which is dependent on extracellular Ca2+ and blocked by high doses of nifedipine or Ni2+. In addition, pretreatment of human erythroblasts with mouse antihuman erythropoietin receptor antibody but not mouse immunopure IgG blocked the Epo-induced [Ca2+]i increase, indicating the specificity of the Ca2+ response to Epo stimulation. In this study, the erythropoietin-regulated calcium channel was identified by single channel recordings. Use of conventional whole cell patch-clamp failed to detect Epo-induced whole cell Ca2+ current. To minimize washout of cytosolic constituents, we next used nystatin perforated patch, but did not find any Epo-induced whole cell Ca2+ current. Using Ba2+ (30 mmol/L) as charge carrier in cell-attached patches, we detected single channels with unitary conductance of 3.2 pS, reversal potential of +72 mV, and whose unitary current (at +10 mV) increased monotonically with increasing Ba2+ concentrations. Channel open probability did not appreciably change over the voltage range (-50 to +30 mV) tested. Epo (2 U/mL) increased both mean open time (from 4.27 +/- 0.75 to 11.15 +/- 1.80 ms) and open probability (from 0.26 +/- 0.06 to 2.56 +/- 0.59%) of this Ba(2+)-permeable channel. Our data strongly support the conclusion that the Epo-induced [Ca2+]i increase in human erythroblasts is mediated via Ca2+ entry through a voltage-independent Ca2+ channel.

Animals↗

PubMed1997

Alcohol, drugs, and violence in children's lives.

This chapter reviews the current state of knowledge concerning the interrelationship between the cycle of alcohol and other drugs (AOD) use and the cycle of violence. This issue is framed in terms of two questions. The first is the extent to which AOD use by the perpetrator is related to the perpetration of violence toward children, defined here as including both physical and sexual abuse. The second question is whether the experience of abuse during childhood is related to the subsequent development of the abuse of alcohol and other drugs. The review indicates that parental AOD abuse is related to physical and sexual abuse. However, because most perpetrators are not parents, the relationship is not yet clear. The data do support the link between experiencing childhood violence and the development of later AOD abuse. Theoretical explanations for each link are reviewed and mediating variables are identified. The review concludes with a presentation of methodological issues and the directions for future research.

Alcoholism↗