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Biomedical subjects

J Siegel

Publications and source records attributed to J Siegel.

At least 19 recordsLinked to original sources
PubMed2001

Ultrafast laser-induced phase transitions in amorphous GeSb films.

Time-resolved measurements of the spectral dielectric function reveal new information about ultrafast phase transitions induced by femtosecond laser pulses in Sb-rich amorphous GeSb films. The excitation generates a nonthermal phase within 200 fs. The dielectric function of this phase differs from that of the crystalline phase, contrary to previous suggestions of a disorder-to-order transition. The observed dielectric function is close to that of the liquid phase, indicating an ultrafast transition from the amorphous phase to a different disordered state.

Journal Article↗
PubMed2001

Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey.

Erionite present in stones used to build the villages of Karain and Tuzköy, Turkey, mined from nearby caves, is purported to cause mesothelioma in half of the villagers. We constructed genetic epidemiology maps to test whether some villagers were genetically predisposed to mesothelioma. Analysis of a six-generation extended pedigree of 526 individuals showed that mesothelioma was genetically transmitted, probably in an autosomal dominant way. This finding should lead to preventive strategies to lower the incidence of mesothelioma in future generations, and close monitoring of high-risk individuals might allow early detection and cure.

Adult↗
PubMed2000

Maximum suppression of HIV replication leads to the restoration of HIV-specific responses in early HIV disease.

OBJECTIVES: It is predicted that HIV-infected individuals in early HIV disease are the most likely group to achieve immune reconstitution following highly active antiretroviral treatment. We assessed whether suppression of HIV replication in this group would improve immune function. METHODS: Seventeen antiretroviral-naïve patients in early HIV disease were evaluated for immune function and lymphocyte phenotyping using standard immunological assays. RESULTS: Absolute CD4+ T-cell number increased from a median of 550 to 800 x 10(6) cells/l while CD8+ T-cell numbers were reduced. The decrease in CD8+ cells correlated with a decrease in the CD8+ memory phenotype. Kinetics of CD4+ naïve and memory T-cell rise indicated that 80% of the maximum CD4+ naïve increase was achieved within 18 weeks whereas maximum CD4+ memory T-cell rise was achieved within 36 weeks. Activation markers (HLA-DR, CD38) and an apoptosis-related marker (CD95) were reduced on CD4+ and CD8+ T cells. Lymphocyte proliferation responses to tetanus toxoid, alloantigen, and anti-CD3/CD28 were restored in patients that were initially unresponsive. At baseline, 31% of the patients responded to HIV p24, which increased to 69% post-therapy. The inducible RANTES response was normalized following therapy whereas inducible interferon-gamma, interleukin (IL)-12, and MIP1beta were elevated. The depressed inducible IL-10 response, however, was not altered after therapy. CONCLUSIONS: This is one of the first studies to demonstrate the restoration of HIV-1 specific responses in non-acute HIV infection, suggesting early intervention with potent antiretroviral therapy may reverse immune-mediated damage not seen with treated patients who have more advanced disease.

Adolescent↗
PubMed2000

No association between body mass index and beta(3)-adrenergic receptor variant (W64R) in children with premature pubarche and adolescent girls with hyperandrogenism.

OBJECTIVE: To determine if the Trp(64)Arg (W64R) variant of the beta(3)-adrenergic receptor (ADRB3) could be used as a genetic marker to define risk for polycystic ovary syndrom (PCOS) and/or obesity in children and adolescents. DESIGN: Association study. SETTING: Academic research environment. PATIENT(S): Children referred for evaluation of premature pubic hair (n = 63), adolescent girls referred for evaluation of hirsutism and/or oligomenorrhea (n = 33), and healthy adult controls (n = 67). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Relationship of body mass index (BMI) to presence or absence of W64R variant and frequency of W64R variant in our patient population. RESULT(S): Body mass index (kg/m(2)) was determined for 63 children (55 girls and 8 boys) and 33 adolescent girls. Presence or absence of the W64R variant was assayed by polymerase chain reaction (PCR) amplification followed by allele-specific restriction fragment digest. Twelve subjects and 11 healthy controls were found to be heterozygous for the W64R variant. One subject was found to be homozygous for the W64R variant. Allele frequency for the W64R variant was comparable between patients and controls. Among the patients, mean BMI values were not different between carriers and noncarriers. CONCLUSION(S): Although other studies suggest that the W64R variant is associated with the development of obesity and insulin resistance, we cannot demonstrate that it has a major effect on BMI in children with premature pubarche or in adolescent girls with hyperandrogenism. Serial observations are necessary to determine if this variant predicts the development of obesity and/or PCOS in adulthood.

Adolescent↗
PubMed2000

Childhood physical and sexual abuse as risk factors for heavy drinking among African-American women: a prospective study.

OBJECTIVE: This study examines the associations among characteristics of child sexual abuse. childhood physical abuse, lack of parental care, and heavy drinking in a relatively young, urban population of African-American women all of whom have documented histories of child sexual abuse. METHODOLOGY: The sample consists of 113 African American child victims who were brought to a city hospital emergency room for treatment and collection of forensic evidence in the 1970s and re-interviewed as adults in the 1990s. RESULTS: The results of this research suggest that multiple incidents of child sexual abuse, more than the characteristics of such abuse is an important predictor of adult heavy alcohol use and binge drinking. These results remain even after controlling for the effects of parental drinking behavior. CONCLUSION: Although the victim of multiple child sexual assaults is more likely to suffer force and penetration, these analyses suggest that it is the multiple victimization and not the force or penetration that drives the relationship between child sexual assault and drinking behaviors.

Adolescent↗
PubMed1999

SHIP-mediated inhibition of K562 erythroid differentiation requires an intact catalytic domain and Shc binding site.

Growing evidence supports a role for the SHIP inositol 5'-phosphatase in the negative regulation of a variety of receptor-mediated signaling pathways in hematopoietic cells. SHIP expression among cultured cell lines was examined and found to be restricted to cells of hematopoietic origin, with the exception of the K562 erythroleukemia cell line, in which SHIP protein and mRNA were undetectable. The absence of endogenous SHIP in K562 cells provided a useful system to study the role of SHIP in growth and differentiation. When stably expressed in K562 cells, SHIP was found to be constitutively tyrosine phosphorylated and associated with endogenous Shc and Grb-2. Stable expression of SHIP did not affect growth of the cells but resulted in decreased synthesis of hemoglobin protein and epsilon-globin mRNA in response to hemin, an inducer of erythroid differentiation. This effect was not due to increased cell death in the SHIP-expressing lines following hemin stimulation, but was likely the result of an impaired differentiation program in these cells. Mutational analysis indicated that SHIP must retain both an intact catalytic domain and Shc binding site to efficiently inhibit K562 erythroid differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Role of reactive oxygen intermediates in activation-induced CD95 (APO-1/Fas) ligand expression.

Activation-induced cell death of T lymphocytes requires the inducible expression of CD95 (APO-1/Fas) ligand, which triggers apoptosis in CD95-bearing target cells by an autocrine or paracrine mechanism. Although execution of the CD95 death pathway is largely independent of reactive oxygen intermediates, activation-induced cell death is blocked by a variety of antioxidants. In the present study, we investigated the involvement of redox processes in the regulation of CD95 ligand (CD95L) expression in Jurkat T cells. We show that various antioxidants potently inhibited the transcriptional activation of CD95L following T cell receptor ligation or stimulation of cells with phorbol ester and ionomycin. Conversely, a prooxidant such as hydrogen peroxide alone was able to increase CD95L expression. As detected by Western blot and cytotoxicity assays, functional expression of CD95L protein was likewise diminished by antioxidants. Inhibition of CD95L expression was associated with a decreased DNA binding activity of nuclear factor (NF)-kappaB, an important redox-controlled transcription factor. Moreover, inhibition of NF-kappaB activity by a transdominant IkappaB mutant attenuated CD95L expression. Our data suggest that, although reactive oxygen intermediates do not act as mediators in the execution phase of CD95-mediated apoptosis, they are involved in the transcriptional regulation of CD95L expression.

Antioxidants↗
PubMed1998

Human immunodeficiency virus type 1 cDNA integration: new aromatic hydroxylated inhibitors and studies of the inhibition mechanism.

Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA is a required step for viral replication. Integrase, the virus-encoded enzyme important for integration, has not yet been exploited as a target for clinically useful inhibitors. Here we report on the identification of new polyhydroxylated aromatic inhibitors of integrase including ellagic acid, purpurogallin, 4,8, 12-trioxatricornan, and hypericin, the last of which is known to inhibit viral replication. These compounds and others were characterized in assays with subviral preintegration complexes (PICs) isolated from HIV-1-infected cells. Hypericin was found to inhibit PIC assays, while the other compounds tested were inactive. Counterscreening of these and other integrase inhibitors against additional DNA-modifying enzymes revealed that none of the polyhydroxylated aromatic compounds are active against enzymes that do not require metals (methylases, a pox virus topoisomerase). However, all were cross-reactive with metal-requiring enzymes (restriction enzymes, a reverse transcriptase), implicating metal atoms in the inhibitory mechanism. In mechanistic studies, we localized binding of some inhibitors to the catalytic domain of integrase by assaying competition of binding by labeled nucleotides. These findings help elucidate the mechanism of action of the polyhydroxylated aromatic inhibitors and provide practical guidance for further inhibitor development.

Anthracenes↗
PubMed1998

Cross-reactivity of the monoclonal antibody 9E10 with murine c-MYC.

The C-terminal regions of the human and the murine c-MYC consist of a common conserved sequence, the amino acids (a.a.) 418-439 with one terminal exchange (C438G). The pre-C-terminal region of both proteins, a.a. 408-417, exhibit four exchanges. A commercially available monoclonal antibody, 9E10, raised against the C-terminal a. a. 408-439 of human c-MYC, is declared to recognize specifically and exclusively human c-MYC. However, in an immunofluorescence assay we observed, in addition to the reaction with a human cell line (SV80), reactivity with the murine cell line L929. In analogy, a rabbit polyclonal antiserum raised against a peptide which corresponds to the murine pre-C-terminus of c-MYC, a.a. 408-417, showed also cross-reactivity in immunofluorescence. The immunostaining with both anti-bodies in the human and the murine cell line was competed by the peptide, corresponding to the murine pre-C-terminal a.a. 408-417, whereas the staining of both cell lines with an antiserum raised against the conserved N-terminal region of c-MYC was not competed by this peptide. The cross-reactivity of 9E10 with murine c-MYC was confirmed by Western blot using two additional cell lines. In conclusion, our findings indicate that 9E10 which is generally regarded as specific for human c-MYC cross-reacts with denaturated murine c-MYC.

Antibodies, Monoclonal↗
PubMed1998

Heart transplantation in patients with heparin-induced thrombocytopenia on the Novacor left ventricular assist system.

We report on two patients with development of heparin-induced thrombocytopenia with thrombosis while on the Novacor left ventricular assist system. Heart transplantation was successfully performed in both patients with heparin used for cardiopulmonary bypass after careful monitoring of heparin-associated antibodies. The approach to the patients' management and potential alternatives for anticoagulation are discussed.

Anticoagulants↗
PubMed1998

Doctor-patient relationship in oncological illness: the "talking medicine".

For any physician, sympathetic interaction with his/her patients should remain a central concern. It is his/her task to understand the patient's hopes, fears, anxieties and social situation, as well as to understand himself and his own motives and attitudes, which can often be identified as helplessness. Continually advancing technology, rationalization, time, and the pressure for success leave less and less room for such considerations in medical practice. While patients often consider their medical care as very good, they, however, complain that the emotional support is often insufficient. Thus, for the benefit of both the doctor and the patient, every physician has to assure compassion in his relationship with the patients. Medical doctors taking care of cancer patients do not need only thorough medical training but also additional training in psychosomatic medicine.

Adult↗
PubMed1997

Butyrate modulates DNA-damage-induced p53 response by induction of p53-independent differentiation and apoptosis.

Butyrate, a physiologically occurring agent, has been reported to decrease constitutively high expressed p53 levels in transformed cells. To elucidate whether butyrate also inhibits DNA-damage-induced p53 response we investigated the effects of butyrate and the anticancer drug mitomycin C in normal C3H10T1/2 cells harbouring wild-type p53. In comparison with p53-deficient fibroblasts we examined p53 protein level, cell cycle arrest, differentiation, and apoptosis. Butyrate induced G1 phase arrest, differentiation, and p53-independent increase in p21(waf1/cip1) protein. Moreover, butyrate induced p53-independent apoptosis, which was, as well as p53-mediated apoptosis, associated with a dose-dependent increase in Bax and c-Myc protein. Pretreatment with butyrate repressed dose-dependently mitomycin-C-induced p53 accumulation and interfered with p53-dependent cell cycle arrest. Butyrate further partially inhibited p53-mediated apoptosis, but low doses of butyrate were more effective than higher concentrations. This was reflected in an enhanced decrease in c-Myc and Bax protein in response to mitomycin C with low concentrations of butyrate. Our data indicate that the differentiation stimulus of butyrate, in association with p21(waf1/cip1) induction, and apoptosis, may explain antineoplastic effects of butyrate. Co-carcinogenic features of butyrate may result from inhibition of p53-mediated DNA damage response.

Animals↗
PubMed1997

Modulation of cutaneous nociceptor activity by electrical stimulation in the brain stem does not inhibit the nociceptive excitation of dorsal horn neurons.

In anesthetized cats, recordings were obtained from single lumbar dorsal horn neurons and from primary afferent fibers of the posterior tibial nerve excited by controlled noxious radiant heating of glabrous hindpaw skin. Electrical stimulation in four brain stem regions (periaqueductal gray and lateral reticular formation in the midbrain, raphe and reticular formation in the medulla) during noxious skin heating markedly reduced the nociceptive excitation of the dorsal horn neurons. In contrast, such brain stem stimulation had small and variable effects upon the noxious heat-evoked activity in the primary afferent fibers; both increases and decreases were observed. The brain stimulation also produced transient changes in blood pressure, suggesting that circulatory effects may underlie the mechanism of nociceptor modulation. It is concluded that brain stem stimulation can modulate cutaneous nociceptor activity, but that this modulatory effect on nociceptor inflow is too small and inconsistent to explain the marked descending inhibition of the nociceptive excitation of dorsal horn neurons.

Action Potentials↗
PubMed1997

Augmenting and reducing of visual evoked potentials in high- and low-sensation seeking humans, cats, and rats.

High- and low-sensation seeking behaviors in human and cat are shown to be correlated with visual evoked potential (VEP) augmenting and reducing, respectively. Demonstration of this relationship in RHA/Verh and RLA/Verh rats provides a heuristic animal model with which to investigate the physiological and genetic basis of this relationship. Recent work is described which shows that VEP augmenting and reducing is a true cortical phenomenon and not merely a reflection of differences occurring at the thalamus. Recent evidence is discussed that suggests the role of diffuse subcortical monoaminergic projections to the cortex as the neurochemical basis for sensation seeking behaviors controlled by prefrontal and limbic cortex and perhaps the correlated VEP augmenting/reducing responses recorded from the posterior cortex.

Animals↗