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Biomedical subjects

L Greenbaum

Publications and source records attributed to L Greenbaum.

At least 19 recordsLinked to original sources
PubMed2006

Why do young women smoke? I. Direct and interactive effects of environment, psychological characteristics and nicotinic cholinergic receptor genes.

Despite the health hazards, cigarette smoking is disproportionately frequent among young women. A significant contribution of genetic factors to smoking phenotypes is well established. Efforts to identify susceptibility genes do not generally take into account possible interaction with environment, life experience and psychological characteristics. We recruited 501 female Israeli students aged 20-30 years, obtained comprehensive background data and details of cigarette smoking and administered a battery of psychological instruments. Smoking initiators (n=242) were divided into subgroups with high (n=127) and low (n=115) levels of nicotine dependence based on their scores on the Fagerstrom Tolerance Questionnaire and genotyped with noninitiators (n=142) for single nucleotide polymorphisms (SNPs) in 11 nicotinic cholinergic receptor genes. We found nominally significant (P<0.05) allelic and genotypic association with smoking initiation of SNP rs2072660 and multilocus haplotypes (P<0.007-0.05) in CHRNB2 and nominal (P<0.05) allelic or genotypic association of SNPs in CHRNA7 (rs1909884), CHRNA9 (rs4861065) and CHRNB3 (rs9298629) with nicotine dependence. Employing logistic regression and controlling for known risk factors, the best-fitting model for smoking initiation encompassed a 5 SNP haplotype in CHRNB2, neuroticism and novelty seeking (P=5.9 x 10(-14), Nagelkerke r(2)=0.30). For severity of nicotine dependence, two SNPs in CHRNA7 (rs1909884 and rs883473), one SNP in CHRNA5 (rs680244) and the interaction of a SNP in CHRNA7 (rs2337980) with neuroticism, were included in the model (P=2.24 x 10(-7), Nagelkerke r(2)=0.40). These findings indicate that background factors, psychological characteristics and genetic variation in nicotinic cholinergic receptors contribute independently or interactively to smoking initiation and to severity of nicotine dependence in young women.

Adult↗
PubMed2004

Differentiation-dependent photodynamic therapy regulated by porphobilinogen deaminase in B16 melanoma.

Protoporphyrin IX (PpIX) synthesis by malignant cells is clinically exploited for photodiagnosis and photodynamic therapy following administration of 5-aminolevulinic acid (ALA). The expression and activity of the housekeeping porphobilinogen deaminase (PBGD) was correlated to PpIX synthesis in differentiating B16 melanoma cells. Differentiation was stimulated by two inducers, butyrate and hexamethylene bisacetamide (HMBA), both of which promote the formation of typical melanosomes and melanin, as well as morphological changeover. A marked decrease in total PBGD activity and PpIX synthesis was observed following stimulation by butyrate, while HMBA induced an opposite effect. In contrast, ferrochelatase levels remained unchanged. Photodynamic inactivation of the cells undergoing differentiation was largely dependent on the PpIX accumulation, which was modulated by the two inducers butyrate and HMBA. Fluorescence immunostaining with anti-PBGD antibodies revealed a major PBGD fraction in the nucleus and a minor fraction in the cytosol. This nuclear localisation pattern was confirmed by expression of PBGD fused to green fluorescence protein. We suggest that efficient photodynamic therapy of cancer facilitated by ALA administration can be enhanced using combined therapeutic modalities.

Acetamides↗
PubMed2002

Nuclear distribution of porphobilinogen deaminase (PBGD) in glioma cells: a regulatory role in cancer transformation?

Recently, considerable interest has been directed to red-fluorescence photodiagnosis of brain and other tumours during surgery using the protoporphyrin IX natural precursor, 5-aminolaevulinic acid. In the present study we focused on the role of the rate-limiting enzyme porphobilinogen deaminase in glioma C6 cell activity, differentiation and sub-cellular distribution. Over-expression of the human housekeeping porphobilinogen deaminase in the glioma cells, using the housekeeping-porphobilinogen deaminase plasmid, induced a G1 cell cycle attenuation accompanied by increases in enzyme activity and c6 differentiation toward astrocytes. Visualisation of subcellular localisation of the porphobilinogen deaminase using the independent techniques of fluorescence immuno-staining with specific anti-human porphobilinogen deaminase antibodies and cellular expression of porphobilinogen deaminase fused to green fluorescent protein, revealed (unexpectedly) a major fraction of porphobilinogen deaminase in the nucleus and only a minor fraction in the cytoplasm. Both C and N terminals of porphobilinogen deaminase fused to green fluorescent protein revealed a major fraction of the newly synthesized fused porphobilinogen deaminase in the nucleus. Furthermore, newborn rat brain cells grown in a primary culture showed the same localisation pattern of porphobilinogen deaminase in the nuclei. Stimulation of C6 glioma cell differentiation by butyrate induced a marked decrease in porphobilinogen deaminase both in the nucleus and in the cytoplasm as determined by Western blotting and fluorescence immuno-localisation. These findings suggest a possible dual role for housekeeping porphobilinogen deaminase in fast dividing glioma cells, one related to the porphyrin synthesis pathway and another coupled to nuclear function, which might be linked to tumorigenesis.

Animals↗
PubMed2002

Pregnancy and transvaginal septation.

Patients with an imperforate transverse vaginal septum typically present in adolescence with primary amenorrhea and require surgical correction. Pregnancy in these women is associated with a high spontaneous abortion rate, but no association with incompetent cervix has been reported. We describe a patient with a high transverse vaginal septum and a short cervix requiring transabdominal cerclage.

Adult↗
PubMed2001

Rectus sheath hematoma in pregnancy.

Although spontaneous hemorrhage into the sheath of the rectus abdominis muscle is uncommon in pregnancy, rectus sheath hematomas (RSHs) should be considered in patients who present with an acute onset of abdominal pain in the latter half of pregnancy or the immediate postpartum period. Both sonography and CT are useful in diagnosing RSHs. We report a case of pregnancy-associated RSH initially suspected of being a degenerating leiomyoma or torsed ovary. Sonography showed a large mass of mixed echogenicity with no internal vascularity. CT confirmed that the lesion was suprafacial.

Abdominal Pain↗
PubMed2001

The use of mycophenolate mofetil suspension in pediatric renal allograft recipients.

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC0-12) of 27.2 microg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.

Adolescent↗
PubMed2000

Reproducible erythroid aplasia caused by mycophenolate mofetil.

Anemia secondary to mycophenolate mofetil (MMF) was recently described in experimental animals. A clinical association between MMF and anemia has been observed, but there are no proven reports. We describe a girl with chronic graft failure who developed erythroid aplasia under immunosuppression with MMF. She showed prompt resolution when MMF was discontinued and a recurrence of this clinical course when MMF was restarted. As re-challenge with a medication is the most definitive approach for showing a direct relationship between the drug and the side effect, this case clearly demonstrates that MMF can cause erythroid aplasia.

Adolescent↗
PubMed2000

Mitochondrial localization and photodamage during photodynamic therapy with tetraphenylporphines.

The subcellular localization sites of TPPS4 and TPPS1 and the subsequent cellular site damage during photodynamic therapy were investigated in CT-26 colon carcinoma cells using spectroscopic and electron microscopy techniques. The association of both porphyrins with the mitochondria was investigated and the implications of this association on cellular functions were determined. Spectrofluorescence measurements showed that TPPS4 favors an aqueous environment, while TPPS1 interacts with lipophilic complexes. The subcellular localization sites of each sensitizer were determined using spectral imaging. Mitochondrial-CFP transfected cells treated with porphyrins revealed localization of TPPS1 in the peri-nuclear region, while TPPS4 localized in the mitochondria, inducing structural damage and swelling upon irradiation, as shown by transmission electron microscopy. TPPS4 fluorescence was detected in isolated mitochondria following irradiation. The photodamage induced a 38% reduction in mitochondrial activity, a 30% decrease in cellular ATP and a reduction in Na(+)/K(+)-ATPase activity. As a result, cytosolic concentrations of Na(+) and Ca(2+) increased, and the level of K(+) decreased. In contrast, the lipophilic TPPS1 did not affect mitochondrial structure or function and ATP content remained unchanged. We conclude that TPPS4 induces mitochondrial structural and functional photodamage resulting in an altered cytoplasmic ion concentration, while TPPS1 has no effect on the mitochondria.

Adenocarcinoma↗
PubMed2000

Green fluorescent protein photobleaching: a model for protein damage by endogenous and exogenous singlet oxygen.

Characterization of protein damage during photosensitization of chlorin e6-treated cells was performed using the green fluorescent protein (GFP). The GFP-chromophore damage caused by singlet oxygen was studied in COS 7 kidney cells and E. coli bacteria following light irradiation. Electron spin resonance (ESR) revealed the generation of endogenous singlet oxygen (1O2) by photoactivated GFP, an effect similar to that produced by the exogenous photosensitizer chlorin e6. A light dose-dependent photobleaching effect of GFP was pronounced at low pH or upon photosensitization with chlorin e6. However, the 1O2 quenchers beta-carotene and sodium azide minimized GFP photo-bleaching. Gel electrophoresis of photosensitized GFP followed by fluorescence multi-pixel spectral imaging revealed the binding of chlorin e6 to GFP, affecting the photobleaching efficacy. Fluorescence multi-pixel spectral imaging of GFP-transfected COS 7 cells demonstrated the presence of GFP in the cytoplasm and nucleus, while chlorin e6 was found to be concentrated in the perinuclear vesicles. Exposure of the cells to light induced GFP photobleaching in the close vicinity of chlorin e6 vesicles. We conclude that photoactivated GFP generates endogenous 1O2, inducing chromophore damage, which can be enhanced by the cooperation of exogenous chlorin e6.

Animals↗
PubMed1996

Rapid activation of latent transcription factor complexes reflects initiating signals in liver regeneration.

Liver regeneration following partial hepatectomy represents a physiologic response to a growth stimulus occurring in the intact animal. Understanding what growth factors and cytokines trigger liver regeneration will provide insights into recovery from hepatic injury mediated by viruses and toxins, and promote an understanding of normal cellular growth control. The modification of pre-existing latent transcription factors in the remnant liver by extracellular signals immediately post-hepatectomy provides a mechanism for the transcriptional activation of primary or immediate early growth response genes, thereby establishing a transcriptional cascade. Two factors activated within minutes to hours post-hepatectomy in a protein synthesis-independent fashion include PHF/NF-kappaB and Stat3. Interestingly, these factors are commonly activated by cytokines such as TNFalpha, IL-1 and IL-6 suggesting that there may be a connection between cytokine release and the onset of liver regeneration. In addition to these known transcription factor complexes, we have used a reporter gene assay in transgenic mice to attempt to identify promoter sequences that are responsible for the transcriptional activation of the liver-restricted IGFBP-1 immediate early gene within minutes posthepatectomy. Studies so far indicate that an upstream region of 800 bp is able to confer both tissue-restricted expression and induction during liver regeneration. Identification of the transcriptional activators or liver regeneration factors responsible for this induction will result in further dissection of the initiating signals.

Journal Article↗
PubMed1995

Changes in kininogens and kallikrein in the plasma, brain, and uterus during pregnancy in the rat.

Bradykinin is a potent inducer of uterine smooth muscle contractions in rodents and primates. Hence, the purpose of the present study was to characterize the various components of the kinin system in the plasma, uterus, hypothalamus, and anterior pituitary of the rat during pregnancy to determine whether the kinin system is involved in the regulation of uterine contractility during pregnancy. To achieve this aim, timed pregnant rats were used, groups of animals (n = 6 per group) were killed on days 5, 15, 20, 21, and 22, and measurements of kininogen and kallikrein activity were performed on plasma and selected tissues. A nonpregnant control group was also used, consisting of a group of 10 randomly cycling rats. The results of the study revealed that total kininogen levels in the plasma rose during pregnancy (days 15-22) to peak on day 22, the day of parturition. This rise was due to increases primarily in T-kininogen compared to low mol wt (LMW) kininogen. Total kininogen levels in the hypothalamus were undetectable during pregnancy; however, anterior pituitary kininogen levels increased markedly from days 15-22. Hypothalamic kallikrein activity was very markedly increased from days 5-20 only to drop on days 21 and 22 of pregnancy. Uterine total kininogen levels were low from days 5-20 of pregnancy, only to undergo a marked elevation on days 21 and 22 (the day of parturition). This elevation on day 21 was due to increased T- and LMW kininogen levels. Uterine LMW kininogen levels were elevated on day 21, followed by a marked fall on day 22. This fall was most likely due to increased bradykinin production from LMW kininogen, because uterine kallikrein activity was significantly elevated on days 21 and 22. The increased production of bradykinin in the uterus on the day of parturition could play a significant role in the mechanism responsible for activation of uterine contractions during this event.

Animals↗
PubMed1994

Structure and localization of the IGFBP-1 gene and its expression during liver regeneration.

Insulin-like growth factor-binding protein-1s are important modulators of the insulin-like growth factors that may have both positive and negative effects on the ability of insulin-like growth factors to stimulate cell growth. The IGFBP-1 gene is one of the most highly induced immediate-early genes after partial hepatectomy. The IGFBP-1 gene is also expressed at a high level during fetal liver development and in response to nutritional changes and diabetes. Therefore it may have important roles in liver growth and metabolism. To begin to examine the regulation of this gene, we cloned and sequenced the entire mouse IGFBP-1 gene. Its structure is highly similar to that of the human gene, and, in addition to the exonic regions, the two genes are highly conserved in specific regions in the promoter and first intron. Analysis of this conservation allows us to predict important regulatory sites that define the tissue specific and insulin-mediated regulation of the gene and identify potential sites that might be important for the transcriptional induction during liver regeneration. The mouse gene is located on mouse chromosome 11; it is found at the boundary between regions in the mouse genome homologous to human chromosomes 22 and 7. We found IGFBP-1 mRNA in both parenchymal and nonparenchymal RNA after partial hepatectomy. Using in situ hybridization of IGFBP-1 mRNA in regenerating rat liver tissue, we demonstrated IGFBP-1 transcripts in several cell types. We found that IGFBP-1 gene induction after partial hepatectomy is paralleled by protein expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Differential effect of interleukin 1 on naive and memory CD4+ T cells.

Freshly derived murine CD4+ T cells are divided into naive and memory cells based on the expression of CD45 isoforms. Cross-linking the T cell receptor CD3 complex either by plastic-bound anti-CD3 antibodies or the antibody presented on non-lymphoid Fc gamma receptor type II-positive Chinese hamster ovary cells in absence of competent antigen-presenting cells fails to activate naive cells to either secrete cytokines or to proliferate. In contrast, memory cells secrete their characteristic cytokines [interleukin (IL) 2, IL4, and interferon-gamma] and show significant proliferation to this stimulus. IL 1 however, is required for their optimal clonal expansion. Differential expression of IL 1 receptor mRNA in memory cells also correlate with their responsiveness to IL 1. Thus, these data reveal a basic difference in the requirements for activation of naive and memory CD4+ T cells.

Animals↗
PubMed1989

Monoclonal antibodies to murine CD3 epsilon define distinct epitopes, one of which may interact with CD4 during T cell activation.

The TCR is comprised of two variable chains that confer specificity, called alpha:beta or gamma:delta, physically associated with five different molecules that comprise the complex known as CD3. Antibodies to this complex are very useful, as they react with all T lymphocytes. A rat mAb to mouse CD3 has been prepared. It reacts with 100% of T cells in all mouse strains tested but with no other cell type. It binds to the CD3 epsilon chain. This antibody activates cloned T cell lines and normal T cells, provided suitable accessory cells and signals are present. This antibody detects a determinant similar to but not identical with those detected by two previously reported hamster anti-CD3 epsilon antibodies. This antibody fixes C efficiently, and it is thus useful for depletion of T cells from bulk populations. Activation of T cells by one of the three different anti-CD3 epsilon antibodies was inhibited by the Fab fragment of anti-CD4, similar to the effects of anti-CD4 Fab on two previously reported anti-TCR V region antibodies that bind a CD3 epsilon-associated epitope. This further defines a site involving TCR V regions and CD3 epsilon with which CD4 appears to associate during T cell activation.

Animals↗