The future of academic urologists.
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Academic Medical Centers↗
Biomedical subjects
C Lee
Publications and source records attributed to C Lee.
Spontaneous subcapsular and intrarenal hematoma demonstrated by various diagnostic modalities and monitored by ultrasonography until complete resolution.
A patient with acute right abdominal pain and nausea underwent various diagnostic imaging studies, including ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), technetium-99m DTPA renal study, and contrast arteriogram. The 99mTc renal study showed a linear photopenic area along the lateral cortical aspect of the right kidney and a focal cortical defect in the left kidney. These lesions corresponded to the findings of US, CT, MRI, and contrast angiography. Because of a suspected malignant mass, a CT-guided aspiration biopsy of the right kidney was performed that resulted in bloody fluid without malignant cells. The patient's condition was diagnosed as intrarenal and subcapsular renal hematoma. The patient was treated conservatively and followed up with CT and US studies. Sequential CT and US demonstrated gradual reduction of the size of the hematoma, and complete resolution was confirmed by US 1.5 years later. As long as underlying pathology can be ruled out, conservative management of spontaneous renal subcapsular hematoma is recommended.
Aged↗
Methotrexate for cesarean scar pregnancy after in vitro fertilization and embryo transfer. A case report.
BACKGROUND: Cesarean scar pregnancy is an exceedingly rare occurrence. We present the first case of cesarean scar pregnancy following in vitro fertilization-embryo transfer (IVF-ET). CASE: A 40-year-old woman with a history of a previous cesarean section presented with five years of unexplained infertility. The patient complained of abdominal pain 16 days after embryo transfer. Ultrasonography revealed a gestational sac with cardiac activity located outside the lower segment of the uterus. Dilatation and curettage was performed due to misdiagnosis of inevitable abortion. Two weeks later, repeated sonography demonstrated a sacculus, 4.07 x 4.07 cm, within the uterine isthmus with only 7.1 mm of thickness separating the sac from the urinary bladder. Normal cervical length without ballooning was noted. Cesarean scar pregnancy was diagnosed. Local injection of methotrexate (MTX) under ultrasound guidance was performed. Plasma beta-hCG levels declined from 23,328 to 8 mlU/mL within two months. CONCLUSION: For women with cesarean scar pregnancy who desire fertility, conservative treatment using MTX is an excellent choice.
Abortifacient Agents, Nonsteroidal↗
In vitro models of prostate apoptosis: clusterin as an antiapoptotic mediator.
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Animals↗
EMDR for treatment of PTSD. The EMDR International Association Research Committee.
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Attitude of Health Personnel↗
Beliefs about outcomes for mental disorders: a comparative study of primary health practitioners and psychiatrists in Singapore.
OBJECTIVES: To compare responses to a mental health literacy survey assessing the likely outcome of three major mental disorders by primary health practitioners (OPD doctors and GPs) and by psychiatrists in Singapore. METHODS: We used two vignettes of Major Depression and Schizophrenia developed in an Australian study. In addition, a third vignette of Mania was developed locally and included. The respondents were required to choose one of the set of prognostic options if the patients received or did not receive professional help, to rate the likely impact of the disorder, and to assess the likelihood of the patient being discriminated against. Psychiatrists' responses were obtained by surveying staff at Woodbridge Hospital, while the primary health practitioners were required to respond to a postal survey. RESULTS: The response rate for the psychiatrists was 70% (69/99), while the Primary health practitioners had an overall response rate of 38% (264/691). The response from OPDs being 51% (77/151) and that of the GPs being 35% (189/540). There was evidence of disorder specificity, with schizophrenia judged as having the worst outcome and depression the best outcome in response to treatment. There was also evidence of group specificity, with the psychiatrists most optimistic and the OPD doctors least optimistic about the outcome following professional intervention. The majority of both the primary health practitioners and the psychiatrists judged that patients would be discriminated against, more so for schizophrenia and mania than for depression. Compared to the OPD doctors, a lower percentage of GPs felt that the patients would be discriminated against. CONCLUSION: Primary health practitioners in Singapore hold more negative views than Singapore psychiatrists about the outcome of professional intervention for three major psychiatric disorders. This finding has implications for education and training for primary health practitioners as well as for treatment of psychiatric patients in the primary health setting.
Attitude of Health Personnel↗
An element with palindromic structure is required for the expression of TBP (TATA box-binding protein) gene in Drosophila melanogaster.
Previously we showed that the 5'-flanking regions between -261 and -207 of the Drosophila melanogaster TBP (TATA box binding protein) gene is important for its expression. We further made serial deletion mutants in this region and analyzed their promoter activities using the transient transfection assay. We found that the 16 bp deletion from -261 to -245 greatly reduces the promoter activity of the Drosophila TBP gene. The 16 bp DNA element contains half of a 11 bp long palindromic sequence, CTTTT-GAAAAG. Disruption of the palindromic sequence by site-directed mutagenesis severely affected promoter activity. In addition, the electrophoretic mobility shift assay showed that the oligonucleotide containing the palindromic sequence can make specific DNA/protein complexes when it was mixed with the Drosophila nuclear extract, suggesting that it interacts with nuclear protein(s). Our data suggest that the palindromic sequence has a critical role in the expression of the Drosophila TBP gene.
Animals↗
Cyclooxygenase knockout mice: models for elucidating isoform-specific functions.
The development of cyclooxygenase (COX) deficient mice has allowed investigation into the individual physiological roles of the COX-1 and COX-2 isoforms. In the following article, the phenotypes of the two Ptgs (genes coding for COX-1 and COX-2) knockouts are summarized, and recent studies to investigate the effects of COX deficiency on cancer susceptibility, inflammatory response, gastric ulceration, and female reproductive processes are discussed. Also, the development and potential uses of mice deficient in both COX isoforms and mice containing only a single copy of one isoform are discussed. Additionally, when the data permit, the effects of genetic ablation of COX activity are compared with those of pharmacological inhibition of COX activity by nonsteroidal anti-inflammatory drugs. The data suggest that prostaglandins derived via the individual COX isoforms have separate as well as common functions. However, for the maintenance of normal physiology, it appears that deficiency of COX-2 has more profound effects than deficiency of COX-1.
Animals↗
Restricted receptor segregation into membrane microdomains occurs on human T cells during apoptosis induced by galectin-1.
Galectin-1 induces apoptosis of human thymocytes and activated T cells by an unknown mechanism. Apoptosis is a novel function for a mammalian lectin; moreover, given the ubiquitous distribution of the oligosaccharide ligand recognized by galectin-1, it is not clear how susceptibility to and signaling by galectin-1 is regulated. We have determined that galectin-1 binds to a restricted set of T cell surface glycoproteins, and that only CD45, CD43, and CD7 appear to directly participate in galectin-1-induced apoptosis. To determine whether these specific glycoproteins interact cooperatively or independently to deliver the galectin-1 death signal, we examined the cell surface localization of CD45, CD43, CD7, and CD3 after galectin-1 binding to human T cell lines and human thymocytes. We found that galectin-1 binding resulted in a dramatic redistribution of these glycoproteins into segregated membrane microdomains on the cell surface. CD45 and CD3 colocalized on large islands on apoptotic blebs protruding from the cell surface. These islands also included externalized phosphatidylserine. In addition, the exposure of phosphatidylserine on the surface of galectin-1-treated cells occurred very rapidly. CD7 and CD43 colocalized in small patches away from the membrane blebs, which excluded externalized phosphatidylserine. Receptor segregation was not seen on cells that did not die in response to galectin-1, including mature thymocytes, suggesting that spatial redistribution of receptors into specific microdomains is required for triggering apoptosis.
Antigens, CD↗
Characterization of the Stat5 protease.
Immature myeloid cells have been shown to transduce signals through a carboxyl-terminally truncated isoform of Stat5. This functionally distinct signal transducer and activator of transcription isoform is generated through a unique protein-processing event. Evaluation of numerous cell lines has determined that there is a direct correlation between the expression of truncated Stat5 and protease activity. Moreover, protease activity is found only in the myeloid and not in lymphoid progenitors. To further characterize the protease small quantities have been purified to near homogeneity. Studies on this purified material indicate that the protease has an apparent molecular mass of approximately 25 kDa and is active over a wide range of pH values. The protease will also cleave both activated (i.e. tyrosine-phosphorylated) and inactivate Stat5. Although this activity is sensitive to phenylmethylsulfonyl fluoride, it is notably not sensitive to several other serine protease inhibitors. Additional studies have led to the identification of the unique site where the protease cleaves Stat5. Mutagenesis of this site renders Stat5 resistant to cleavage. Consistent with the model that Stat5 cleavage is important for early myeloid development, introduction of a "non-cleavable" isoform of Stat5 into FDC-P1 cells (a myeloid progenitor line) leads to significant phenotypic changes.
3T3 Cells↗
Growth factors in expressed prostatic fluid from men with prostate cancer, BPH, and clinically normal prostates.
BACKGROUND: Although growth factors such as epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, and TGF-beta are important regulators of prostate cell growth in vitro and in animal models, evidence to support their role in human prostate cancer development remains sparse. We previously showed that men without prostate cancer have concentrations of EGF and TGF-alpha in expressed prostatic fluid (EPF) that are individually distinct and stable over time. This study addressed whether growth factor levels in EPF are associated with the presence or progression of prostate cancer. METHODS: We measured levels of immunoreactive EGF, TGF-alpha, and TGF-beta1 in stored EPF samples from three age-matched groups: 19 men with untreated, histologically diagnosed prostate cancer (CaP), 38 with benign prostate hyperplasia (BPH), and 19 with normal prostate glands (NPD). RESULTS: Median TGF-alpha was lower in the BPH group (0.45 ng/ml) than in either CaP (0.63 ng/ml) or NPD (0.58 ng/ml) groups (P = 0.03 and 0.12, respectively). For EGF, the median was lowest in the CaP group and highest in the NPD group (92.5 ng/ml vs. 175.5 ng/ml, P = 0.006). For TGF-beta1, the median level in CaP was 2.7 times higher than the median level among all controls (6.65 ng/ml vs. 2.46 ng/ml, P = 0.002). Growth factor levels were not associated with tumor stage or Gleason score. However, the single case with distant metastases had TGF-beta1 levels 23-fold higher than the CaP median. CONCLUSIONS: The results suggest that at the time of CaP diagnosis, EGF levels in EPF are significantly lower, and TGF-beta1 levels significantly higher, than normal. Marked overexpression of TGF-beta1 in advanced CaP might be reflected in extremely high EPF levels.
Aged↗
Anatomical characteristics and three-dimensional model of the dog dorsal lateral geniculate body.
The morphological and laminar characteristics of the dorsal lateral geniculate nucleus (LGN) and medial interlaminar nucleus (MIN) of the domestic dog (Canis familiaris) were studied by three-dimensional computer reconstruction of labeled retinal afferents following intraocular HRP injections. As previously reported, the dog LGN consisted of layers A, A1, C, C1, C2, and C3. Layers A, C, and C2 receive contralateral-eye inputs, and layers A1 and C1 ipsilateral inputs. The dog MIN was found to have four orderly interdigitating layers; layers 1, 2, 3, and 4, medial to lateral. MIN layers 1 and 3 received contralateral inputs, and layers 2 and 4 ipsilateral inputs. Layer 1 had the largest soma of all LGN/MIN layers. LGN layer A was partially separated into medial and lateral subdivisions by a cleft free of somata. The overall three-dimensional shape of the lateral geniculate body was like the letter C, with the convex part of the C directed posteriorly. The relative volume of the MIN was smaller than in the cat; the canine MIN comprised 8.3% of the combined volume of layers A, A1 and the MIN, while that of the cat comprised 14.2% as estimated from Sanderson's map. The volume of all contralateral-eye layers, combining both LGN and MIN, was 31.2 mm(3) (78%), and that for ipsilateral layers was 8.6 mm(3) (22%). The ratio of ipsilateral to contralateral laminar volumes is much lower in the dog than in the cat.
Animals↗
Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.
Neurons containing the neuropeptide orexin (hypocretin) are located exclusively in the lateral hypothalamus and send axons to numerous regions throughout the central nervous system, including the major nuclei implicated in sleep regulation. Here, we report that, by behavioral and electroencephalographic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only known monogenic model of narcolepsy. Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neurons. We propose that orexin regulates sleep/wakefulness states, and that orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation.
Age of Onset↗
The AU-rich 3' untranslated region of human MDR1 mRNA is an inefficient mRNA destabilizer.
The human multidrug resistance gene MDR1 encodes a membrane-bound protein, referred to as P-glycoprotein, that acts as a pump to extrude toxins from cells. The 3' untranslated region (3'UTR) of the human MDR1 mRNA is very AU-rich (70%) and contains AU-rich sequences similar to those shown to confer rapid decay on c-myc, c-fos, and lymphokine mRNAs. We tested the ability of the MDR1 3'UTR to act as an mRNA destabilizing element in the human hepatoma cell line HepG2. The MDR1 mRNA has an intermediate half-life of 8 h in HepG2 cells compared to a half-life of 30 min for c-myc mRNA. The MDR1 mRNA half-life was prolonged to >20 h upon treatment with the protein synthesis inhibitor cycloheximide. We constructed expression vectors containing the human beta-globin coding region with the 3'UTR from either MDR1 or c-myc. The c-myc 3'UTR increased the decay of the chimeric mRNA, but the MDR1 3'UTR had no effect. We tested the ability of MDR1 3'UTR sequences to compete for interaction with AU-binding proteins in cell extracts; MDR1 RNA probes had a fivefold lower affinity for AU-binding proteins that interact with the c-myc AU-rich 3'UTR. Overall, our data suggest that the MDR1 3'UTR does not behave as an active destabilizing element in HepG2 cells.
3' Untranslated Regions↗
Localization in the nucleolus and coiled bodies of protein subunits of the ribonucleoprotein ribonuclease P.
The precise location of the tRNA processing ribonucleoprotein ribonuclease P (RNase P) and the mechanism of its intranuclear distribution have not been completely delineated. We show that three protein subunits of human RNase P (Rpp), Rpp14, Rpp29 and Rpp38, are found in the nucleolus and that each can localize a reporter protein to nucleoli of cells in tissue culture. In contrast to Rpp38, which is uniformly distributed in nucleoli, Rpp14 and Rpp29 are confined to the dense fibrillar component. Rpp29 and Rpp38 possess functional, yet distinct domains required for subnucleolar localization. The subunit Rpp14 lacks such a domain and appears to be dependent on a piggyback process to reach the nucleolus. Biochemical analysis suggests that catalytically active RNase P exists in the nucleolus. We also provide evidence that Rpp29 and Rpp38 reside in coiled bodies, organelles that are implicated in the biogenesis of several other small nuclear ribonucleoproteins required for processing of precursor mRNA. Because some protein subunits of RNase P are shared by the ribosomal RNA processing ribonucleoprotein RNase MRP, these two evolutionary related holoenzymes may share common intranuclear localization and assembly pathways to coordinate the processing of tRNA and rRNA precursors.
Amino Acid Sequence↗
Butenolide endothelin antagonists with improved aqueous solubility.
Continued development around our ETA-selective endothelin (ET) antagonist 1 (CI-1020) has led to the synthesis of analogues with improved aqueous solubility profiles. Poor solubility characteristics displayed by 1 required a complex buffered formulation in order to conduct iv studies. To overcome the use of specific iv formulations for preclinical studies on additional drug candidates, analogues with improved aqueous solubility were desired. Several analogues were synthesized with substitution patterns that allowed for the formation of either acid or base addition salts. These derivatives had dramatically improved aqueous solubility. In addition, these analogues retained equivalent or improved ETA receptor selectivity and antagonist potency, versus 1, both in vitro and in vivo. Compound 29, which contains as a substituent the sodium salt of a sulfonic acid, has an ETA IC50 = 0.38 nM, ETA selectivity of 4200-fold, and ETA functional activity of KB = 7.8, all of which are similar or superior to those of 1. Compound 29 also has vastly superior aqueous solubility and solubility duration, compared to 1. Furthermore, 29 after iv infusion displays improved activity to 1 in preventing acute hypoxia-induced pulmonary hypertension in rats with an ED50 = 0.3 microg/kg/h.
Animals↗
Transforming growth factor-beta in benign and malignant prostate.
BACKGROUND: The present review summarizes the cellular action of TGF-beta in benign and malignant growth of the prostate. METHODS: TGF-beta is a pleiotropic growth factor. It plays an important role in the regulation of growth and differentiation in many cells. In benign prostatic epithelia, its action is mediated through a paracrine mechanism. It inhibits proliferation and induces apoptosis in prostatic epithelia. It provides a mechanism to maintain epithelial homeostasis in the prostate. In prostatic stroma, its continual action leads to smooth muscle differentiation. This effect of TGF-beta may regulate the development of prostatic smooth muscle nodules in benign prostatic hyperplasia. RESULTS: As prostatic epithelial cells undergo malignant transformation, two major events occur regarding TGF-beta action. These include the loss of expression of functional TGF-beta receptors and overproduction of TGF-beta in malignant cells. The loss of expression of functional TGF-beta receptors provides a growth advantage to cancer cells over their benign counterparts. The overproduction of TGF-beta by cancer cells has a multitude of adverse consequences. TGF-beta can promote extracellular matrix production, induce angiogenesis, and inhibit host immune function. The biological consequence of these activities is an enhanced tumorigenicity in prostate cancer. Results of our recent studies with a rat prostate cancer model suggest that the immunosuppressive effect of TGF-beta seems to be the primary cause of tumor progression. This is because, if these cancer cells were engineered to reduce the production of TGF-beta, tumor growth was inhibited in syngeneic hosts but not in immune compromised hosts. CONCLUSIONS: Our future research should take advantage of this knowledge to devise therapeutic strategies aimed at eradicating prostate cancer.
Androgens↗
The intracellular domain of interferon-alpha receptor 2c (IFN-alphaR2c) chain is responsible for Stat activation.
Type I IFNs activate the Jak-Stat signal transduction pathway. The IFN-alpha receptor 1 (IFN-alphaR1) subunit and two splice variants of the IFN-alphaR2 subunit, IFN-alphaR2c and IFN-alphaR2b, are involved in ligand binding. All these receptors have been implicated in cytokine signaling and, specifically, in Stat recruitment. To evaluate the specific contribution of each receptor subunit to Stat recruitment we employed chimeric receptors with the extracellular domain of either IFN-gammaR2 or IFN-gammaR1 fused to the intracellular domains of IFN-alphaR1, IFN-alphaR2b, and IFN-alphaR2c. These chimeric receptors were expressed in hamster cells. Because human IFN-gamma exhibits no activity on hamster cells, the use of the human IFN-gamma receptor extracellular domains allowed us to avoid the variable cross-species activity of the type I IFNs and eliminate the possibility of contributions of endogenous type I IFN receptors into the Stat recruitment process. We demonstrate that Stat recruitment is solely a function of the IFN-alphaR2c intracellular domain. When chimeric receptors with the human IFN-gammaR1 extracellular domain and various human IFN-alpha receptor intracellular domains were expressed in hamster cells carrying the human IFN-gammaR2 subunit, only the IFN-alphaR2c subunit was capable of supporting IFN-gamma signaling as measured by MHC class I induction, antiviral protection, and Stat activation. Neither the IFN-alphaR2b nor the IFN-alphaR1 intracellular domain was able to recruit Stats or support IFN-gamma-induced biological activities. Thus, the IFN-alphaR2c intracellular domain is necessary and sufficient to activate Stat1, Stat2, and Stat3 proteins.
Animals↗