Biomedical subjects

R Kaufman

Publications and source records attributed to R Kaufman.

At least 19 recordsLinked to original sources

PubMed2001

Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy.

From 1940 through the 1960s, diethylstilbestrol (DES), a synthetic oestrogen, was given to pregnant women to prevent pregnancy complications and losses. Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and a combined analysis of two cohorts of women who were exposed to DES during pregnancy. The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence. The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07-1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer.

Breast Neoplasms↗

PubMed2001

Prediction of aspiration in patients with newly diagnosed untreated advanced head and neck cancer.

OBJECTIVES: To determine the prevalence of aspiration in patients with newly diagnosed nontreated advanced head and neck cancer and to determine the ability of the clinical examination to predict aspiration in this patient population. DESIGN: A descriptive prevalence study of the presence of aspiration in patients with advanced (stages III and IV) head and neck cancer and a prospective correlation study between variables of the clinical evaluation with the criterion standard videofluoroscopy. SETTING: Regional veterans affairs medical center. PATIENTS: A consecutive sample of 27 patients without previous treatment or tracheostomy. INTERVENTIONS: All patients underwent evaluation by an otolaryngologist and speech pathologist prior to videofluoroscopy. MAIN OUTCOME MEASURES: Variables in the dysphagia evaluation (consisting of a directed medical history, physical examination, and food challenge), the self-rated 45-item questionnaire, and the clinicians "educated prediction" of aspiration were analyzed with reference to aspiration on videofluoroscopy using univariant analysis. RESULTS: The prevalence of aspiration determined by videofluoroscopy was 41% (11 of 27 patients). Two (6%) of 32 items in the medical history, 1 (4%) of 25 items in the physical examination, and 8 (50%) of 16 items in the food challenge were found to be statistically significantly correlated (P<.05) with aspiration on videofluoroscopy by univariate analysis. Nine (25%) of 45 items in the self-rated questionnaire were correlated with aspiration on videofluoroscopy. The clinicians' educated prediction of aspiration was not correlated with aspiration determined by videofluoroscopy. CONCLUSIONS: Clinical evaluation alone is inadequate in predicting patients who aspirated, determined objectively by videofluoroscopic swallowing study. Further study is needed to develop an efficient dysphagia evaluation to identify patients at risk for aspiration.

Aged↗

PubMed2001

Clarifying the discussion on brain death.

Definitions of death are based on subjective standards, priorities, and social conventions rather than on objective facts about the state of human physiology. It is the meaning assigned to the facts that determines when someone may be deemed to have died, not the facts themselves. Even though subjective standards for the diagnosis of death show remarkable consistency across communities, they are extrinsic. They are driven, implicitly or explicitly, by ideas about what benefits the community rather than what benefits the individual. The differences that do exist across communities generally reduce to questions about legitimacy and not fact. The questions at the core of the debate about brain death are better framed by asking: "Whom ought we deem to be dead?" rather than: "Who is dead." The rationale for equating brain death with death, therefore, extends well beyond somatic and biological concepts of death.

Bioethics↗

PubMed2000

Incidence of squamous neoplasia of the cervix and vagina in des-exposed daughters.

PURPOSE: Women exposed to diethylstibestrol (DES) in utero are known to have an excess risk of clear cell adenocarcinoma of the vagina and cervix, in addition to vaginal epithelial changes, but the effect on the incidence of squamous neoplasia is uncertain. This study evaluated the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to diethylstilbestrol.METHODS: A cohort comprising 3899 DES-exposed and 1374 unexposed daughters was followed for thirteen years (1982-1995) for pathology-confirmed diagnoses of high-grade squamous neoplasia. A pathologist blinded to exposure status reviewed seventy-seven percent of cases. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (CI) controlling for age, calendar year, screening history and other covariates.RESULTS: The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.12 (1.19-3.77). Adjustment for screening history had little effect, but when the analysis was restricted to a group highly screened before 1982, the risk was reduced. Risk estimates were higher among women exposed earlier in gestation; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.82 (1.43-5.53).CONCLUSIONS: The findings support an association between in utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out.

Journal Article↗

PubMed1998

ATP-stimulated smooth muscle cell proliferation requires independent ERK and PI3K signaling pathways.

Vascular smooth muscle cells respond to the purinergic agonist ATP by increasing intracellular calcium concentration and increasing the rate of cell proliferation. In many cells the extracellular signal-regulated kinase (ERK) cascade plays an important role in cellular proliferation. We have studied the effect of extracellular ATP on ERK activation and cell proliferation. ATP binding to a UTP-sensitive P2Y nucleotide receptor activates ERK1/ERK2 in a time- and dose-dependent manner in coronary artery smooth muscle cells (CASMC). ATP-induced activation of ERK1/ERK2 is dependent on the dual-specificity kinase mitogen-activated protein kinase/ERK kinase (i.e., MEK) but independent of phosphatidylinositol 3-kinase (PI3K) activity. We provide evidence that both ERK1/ERK2 and PI3K activities are required for CASMC proliferation. Thus ATP-stimulation of CASMC proliferation requires independent activation of both the ERK and PI3K signaling pathways.

Adenosine Triphosphate↗

PubMed1998

Training environment for inferior vena caval filter placement.

This paper describes a Virtual Environment system designed to aid in training interventional radiologists in inferior vena cava filter placement. It is being developed as part of a VE simulator for a number of surgical and interventional radiology procedures at the Laboratory for Advanced Computer Applications in Medicine at the George Washington University. In this procedure a filter is placed in the inferior vena cava to prevent blood clots from the lower portion of the body from reaching the lungs and causing a pulmonary embolus. The simulation is designed to provide both tutorial and testing modes for the filter placement procedure.

Algorithms↗

PubMed1997

The efficacy and safety of Skinner herpes simplex vaccine towards modulation of herpes genitalis; report of a prospective double-blind placebo-controlled trial.

A randomised, placebo-controlled, multi-centre trial of intracellular subunit herpes simplex virus (HSV) type 1 vaccine NFU.Ac.HSV-1(S-)MRC (Skinner vaccine) was conducted at three medical centres in the United States. Subjects with documented herpes genitalis of at least 1-year duration and a history of six or more genital HSV recurrences in the 12 months prior to study entry were randomised to receive vaccine or placebo at 0, 1 and 2 months. Vaccination induced significant neutralising, enzyme-linked immunosorbent assay and lymphocyte transformation response to HSV-1 antigen. The frequency of recurrences was reduced in the vaccinated female patients at both 3 and 6 months following vaccination with an overall reduction in patients of both sexes which did not reach statistical significance. Recurrence severity was reduced as measured by decreased number of lesions and associated symptoms per recurrence (P = 0.04). The data suggest that clinical manifestations of latent HSV genital infection may be modified by therapeutic immunisation.

Adult↗

PubMed1997

HER-2/neu gene amplification status in prostate cancer by fluorescence in situ hybridization.

HER-2/neu expression has been established as a prognostic factor in breast and other cancers. In prostate cancer (PC), a similar predictive role has been hindered by variable immunohistochemical (IHC) results. The authors studied DNA amplification of the HER-2/neu gene on 4-microm sections obtained from 62 formalin-fixed, paraffin-embedded PCs by fluorescence in situ hybridization (FISH). The results were compared with HER-2/neu protein expression as determined by IHC and correlated by logistic regression analysis with Gleason tumor grade, DNA ploidy, serum prostate specific antigen (PSA), and pathological stage. The HER-2/neu gene was localized using the Oncor (Gaithersburg, MD) digoxigenin-labeled unique sequence probe. Amplified PCs had at least 20 malignant cells, with 5 or more copies of the sequence. Amplification of HER-2/neu correlated with Gleason score (P = .0001). The mean Gleason score of unamplified tumors was 5.7 and that of amplified tumors was 7.5. Nondiploid tumors had a significantly greater rate of HER-2/neu amplification compared with diploid tumors (P = .0003). Of the 62 cases evaluated by IHC and FISH, 18 cases (29%) were overexpressed by IHC, and 27 cases (44%) were amplified by FISH. A trend for similar HER-2/neu status in each PC by the two methods did not reach statistical significance (P = .23). HER-2/neu amplification by FISH was associated with advanced pathological stage; however, this relationship reached only near-statistical significance (P = .06). There was no correlation of HER-2/neu amplification by FISH with patient age or preoperative serum PSA levels. The authors conclude that HER-2/neu gene amplification status can be determined by FISH on archival prostate cancer specimens, significantly correlates with high tumor grade and nondiploid DNA content, and is more frequently encountered in tumors with advanced pathological stage. Also, FISH is more sensitive than IHC for detection of abnormalities in the HER-2/neu gene, and further studies should be undertaken to determine whether a FISH-based HER-2/neu detection method may prove of importance in the prediction of prognosis and planning of therapy in prostate cancer patients.

Adult↗

PubMed1996

Decreased levels of CD44 protein and mRNA in prostate carcinoma. Correlation with tumor grade and ploidy.

BACKGROUND: CD44, a transmembrane protein, is associated with cell-cell and cell-matrix interaction and with tumor growth and metastasis. Expression of both standard form and variant isoforms of CD44 protein has been associated with aggressive behavior and metastasis in various tumors, but has not been characterized in prostate adenocarcinoma (PAC). METHODS: The expression of CD44 standard (CD44s) and splice variant v3, v4/5, v6, v7/8, and v10 proteins were studied in 109 PACs and correlated with tumor grade, DNA ploidy, and mRNA levels. Monoclonal antibodies against the various CD44 proteins were applied to microwave irradiated, formalin fixed, paraffin embedded sections. The DNA content of the tumors was evaluated by the Feulgen method with the CAS200 Image Analyzer. Total RNA exhibiting 18s and 28s bands was derived from two benign prostatic tissues and 5 PACs exhibiting decreased levels of CD44 protein by immunohistochemistry. The RNA was analyzed with reverse transcriptase polymerase chain reaction using CD44 specific primers. RESULTS: The basal cells of the benign prostatic acini revealed uniform membranous staining for CD44s, v3, and v6 in 95-97% of cases. Similar staining was observed for v4/5, v7/8, and v10 in 40%, 30%, and 2% of cases, respectively. Secretory epithelial cells of the benign prostatic acini showed predominant expression of CD44s (97% of cases). Staining for CD44 variant proteins (v3, v4/5, v6, v7/8, and v10) in this location ranged from 9-22% of cases. Approximately 70% of the PACs showed significant loss of CD44s expression, which correlated with high tumor grade (Gleason > or = 7) (P = 0.01) and aneuploid status (P = 0.002). In 93-98% of the PACS, there was a complete lack of membranous expression for all CD44 variant isoforms. The metastatic PACS did not show preferential expression of either the standard form or any variant isoform. The cDNA from the normal prostates yielded a prominent CD44 standard form polymerase chain reaction product at 482 base pair (bp) and variant isoforms at approximately 650 and 850 bp. No CD44 products could be amplified from the subset of five PAC cDNAs, even when present at four-fold excess. CONCLUSIONS: PACS exhibit down-regulation of CD44 protein expression, which correlates with high tumor grade and aneuploidy. v6 and v3 isoforms were preferentially expressed in the basal cells of benign prostatic acini. Based on a subset of cases, loss of CD44 protein expression is associated with decreased abundance of CD44 mRNA.

Adenocarcinoma↗

PubMed1996

Multimodality therapy of an acquired factor V inhibitor.

Acquired inhibitors of factor V are rare causes of clinical bleeding, whose severity ranges from mild to life-threatening. Optimal treatment of patients with factor V inhibitors is uncertain. We report on our successful treatment approach in a patient with spontaneous, life-threatening intracranial bleeding caused by a factor V inhibitor. The patient deteriorated after initial treatment with fresh-frozen plasma and platelet transfusions. He was subsequently treated with a combination of plasma exchange and chemotherapy, which led to complete recovery. Our experience suggests that plasma exchange may be life-saving in cases of severe bleeding caused by factor V inhibitors. The use of plasmapheresis in conjunction with chemotherapy is an efficacious and well-tolerated treatment and should be considered in patients with factor V inhibitors.

Aged↗

PubMed1996

Catabolism of dopamine and 5-hydroxytryptamine by monoamine oxidase in the ixodid tick, Amblyomma hebraeum.

The purpose of this study was to assess biogenic amine catabolism in Amblyomma hebraeum Koch (an African cattle tick). We assayed haemolymph and saliva for a variety of biogenic amines (usually following injection of substrate into the haemolymph) in partially fed females using HPLC coupled to electrochemical detection. Dopamine (DA) and 5-hydroxytryptamine (5-HT) were rapidly converted to dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) respectively, indicating that monoamine oxidase (MAO) constitutes a major catabolic pathway for biogenic amines in this species. We could not detect N-acetylated or gamma-glutamyl conjugated metabolites of these important neurotransmitters. [In a few samples we looked for but could not detect homovanillic acid or 3-methoxytyramine (O-methylated metabolites of DOPAC and DA respectively).] Deprenyl was about 44-72 times more potent an inhibitor of MAO than clorgyline when either DA or 5-HT was offered as substrate, suggesting that this MAO is of the MAOB type. Conversion of DA to DOPAC was also detected in several tissues incubated with DA in vitro; in descending order of MAO activity (pmol mg-1 h-1 at about 18 degrees C) tissues tested were: skeletal muscle (approximately 100), Malpighian tubule (approximately 50), ovary (approximately 45), salivary gland (approximately 30), midgut (approximately 20), and haemolymph (approximately 4-5). This study suggests that ticks differ considerably from insects in utilizing MAO as an important metabolic pathway for biogenic amines.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

A generalized HLA prediction model for related donor matches.

This article derives a generalized probabilistic model for predicting HLA matches from a population of family members consisting of all blood-related descendants of one pair of patient's grandparents, excluding parents and siblings, for three subsequent generations. This consists of the patient's children, blood-related aunts/uncles, first cousins, first cousins once removed and nephews/nieces. (It is assumed that the patient's siblings and parents were tested prior but did not produce a match.) The model uses family pedigree information and haplotype frequency data to estimate the likelihood of a match. Results are given for many ethnic groupings. These results indicate that such a family search frequently approximates or exceeds the 0.25 success rate of a single sibling search when the patient possesses a common haplotype within the patient's ethnic population, and the family members are also of the same ethnic origin. Families of the same lineage averaging more than two children/nuclear family substantially exceed the 0.25 rate. The results degrade only modestly for the two children/nuclear family scenario when first cousins once removed are excluded from the search. Among the study's larger nations of Japan, the United States and the United Kingdom, approximately 15-20% of the population can potentially benefit from such searches. These percentages are much higher for the study's smaller countries.

HLA Antigens↗

PubMed1996

Increased bcl-2 protein levels in prostatic adenocarcinomas are not associated with rearrangements in the 2.8 kb major breakpoint region or with p53 protein accumulation.

bcl-2, an inhibitor of programmed cell death (apoptosis), is present in high levels in a subset of prostatic adenocarcinomas. In this study, 42 prostatic adenocarcinomas were analyzed to determine whether increased bcl-2 levels are associated with rearrangements in the 2.8-kb major breakpoint region, an association known to occur in certain follicular lymphomas featuring a t(14:18) translocation. Immunostaining for bcl-2 and p53 proteins was performed on formalin-fixed, paraffin-embedded tumor specimens using murine anti-human bcl-2 and p53 monoclonal antibodies in all 42 cases. Genomic DNA from paired frozen samples of each tumor was subjected to digestion with HindIII and EcoRI and the products analyzed on a Southern blot with a 2.8-kb-digoxigenin-labeled major breakpoint region probe. Comparisons between groups were evaluated with the Fisher exact test. Diffuse, strong cytoplasmic immunoreactivity for bcl-2 was present in the epithelial cells of tumor glands in 16 of 42 cases (38%), including 8 of 19 low grade (Gleason score 6 and below) and 8 of 23 high grade (Gleason score 7 and above) prostatic adenocarcinoma. Southern blotting demonstrated a normal 2.8-kb germline DNA fragment in every case, with no evidence of rearrangement. Nuclear p53 staining was present in 10 of 24 high grade and 0 of 18 low grade tumors (P < 0.001). Only four cases exhibited positivity for both bcl-2 and p53, and there was no association of bcl-2 positivity with co-expression of the p53 protein (P = 0.58). We conclude that aberrations in the function of either bcl-2 or p53 could possibly modify the apoptotic pathway resulting in the extended survival of tumor cells. Also, increased bcl-2 levels in prostatic adenocarcinomas occur in the absence of detectable rearrangements in the major breakpoint region.

Adenocarcinoma↗

PubMed1995

Measles virus and C3 binding sites are distinct on membrane cofactor protein (CD46).

The human complement regulatory protein membrane cofactor protein (CD46) is the cellular receptor for measles virus (MV), whereas decay accelerating factor (DAF; CD55), a structurally similar complement regulatory protein, does not bind MV. To characterize the interaction between MV and CD46, mutants of the CD46 protein and hybrid molecules between CD46 and DAF were tested for their ability to act as MV receptors. The transmembrane domain and cytoplasmic tail of CD46 were not required for receptor function as cells expressing the CD46 extracellular domain linked to the glycosyl-phosphatidylinositol tail of DAF were rendered susceptible to MV infection. Chimeric proteins exchanging the four extracellular short consensus repeat (SCR) domains between CD46 and DAF indicated that only molecules with both SCR1 and SCR2 from CD46 allowed a productive MV infection. Further, monoclonal antibodies (mAbs) against SCR1 or SCR2 of CD46 blocked MV infection, whereas a mAb against SCR3 and SCR4 did not. The latter mAb blocks C3b/C4b binding (which maps to SCR3 and SCR4) whereas the former mAbs do not. Thus, our data indicate that both SCR1 and SCR2 make up the MV receptor determinant in CD46. These results also suggest avenues for development of therapeutic agents to inhibit MV binding and thus infection and disease.

Animals↗

PubMed1995

Characterization of the echovirus 7 receptor: domains of CD55 critical for virus binding.

CD55, or decay-accelerating factor (DAF), is a cell surface glycoprotein which regulates complement activity by accelerating the decay of C3/C5 convertases. Recently, we and others have established that this molecule acts as a cellular receptor for echovirus 7 and related viruses. DAF consists of five domains: four short consensus repeats (SCRs) and a serine/threonine-rich region, attached to the cell surface by a glycosylphosphatidyl inositol anchor. Chinese hamster ovary cells stably transfected with deletion mutants of DAF or DAF-membrane cofactor protein recombinants were analyzed for virus binding. The results indicate that the binding of echovirus 7 to DAF specifically requires SCR2, SCR3, and SCR4. There is also a nonspecific requirement for the S/T-rich region which probably functions to project the binding region away from the cell membrane. The three nonpeptide modifications of DAF, N-linked glycosylation, O-linked glycosylation, and the glycosylphosphatidyl inositol anchor, are not required for virus binding. The SCRs of membrane cofactor protein, the closest known relative of DAF, cannot substitute for those of DAF with retention of virus binding activity. The monoclonal antibody used to identify DAF as an echovirus receptor, and which inhibits binding of the virus (monoclonal antibody 854), binds to SCR3.

Animals↗

PubMed1995

HLA prediction model for extended family matches.

This article derives a probabilistic model for predicting HLA matches from a population of extended family members. (Extended family members are defined as either first cousins or blood-related aunts or uncles). The model uses family pedigree information and haplotype frequency data to estimate the likelihood of a match. Results are given for many ethnic groupings. A case study is also described. This technique is most applicable when all family members are of the same ethnic origin, which increases the likelihood of a match among a small number of family members, and the patient possesses a haplotype having a frequency exceeding 10%, within the patient's ethnic population. Under such conditions, an extended family search can frequently approximate the success rate of a single sibling search.

Adult↗

PubMed1994

Comparison of three immunoassays for the determination of N-acetylprocainamide. Determination of false elevations by a polyclonal antibody-based method.

The performance of the ROCHE FP NAPA reagent, a newly reformulated monoclonal antibody-based fluorescence polarization immunoassay (FPIA) for N-acetylprocainamide, was compared with two commercially available polyclonal antibody-based immunoassays, the Abbott TDx and Syva EMIT. Although excellent correlation was observed between the ROCHE FP NAPA reagent and the Syva EMIT reagent, a positive bias was observed in the correlation between the ROCHE FP NAPA reagent and the Abbott TDx reagent. The bias in the TDx method was investigated further by the concurrent high-performance liquid chromatography (HPLC) analysis of patient samples. Insignificant differences (p < 0.05) were observed between the HPLC and ROCHE FP values. The TDx system, however, yielded significantly higher (p < 0.0005) results than did HPLC.

Acecainide↗

PubMed1994

Inclusion of a sensitivity control to add a quality-control parameter and improve reproducibility in BCR, immunoglobulin, and T-cell receptor gene-rearrangement studies.

Molecular analyses to determine clonality of T and B cells in malignant lymphoma and leukemia and to detect the (9;22) translocation in chronic myelogenous leukemia are commonly used in clinical molecular biology laboratories. We describe the inclusion of a sensitivity control in each of these assays derived from DNA of well-characterized cell lines. The inclusion of such a sample adds an important quality-control parameter to ensure assay-to-assay reproducibility and to satisfy accreditation and regulatory requirements.

Blotting, Southern↗