Showing papers by "University of Texas Medical Branch published in 1996"
TL;DR: The reliability of the Functional Independence Measure (FIMSM) for adults was examined using procedures of meta-analysis and demonstrated acceptable reliability across a wide variety of settings, raters, and patients.
1,159 citations
TL;DR: Intraperitoneal cisplatin significantly improves survival and has significantly fewer toxic effects in patients with stage III ovarian cancer and residual tumor masses of 2 cm or less.
Abstract: Background Intravenous platinum-based chemotherapy is the standard primary therapy for advanced ovarian cancer. We conducted a phase 3 trial to compare the effects of intraperitoneal and intravenous cisplatin on the survival of women with previously untreated, stage III, epithelial ovarian cancer. Methods The patients underwent an initial exploratory laparotomy and resection of all tumor masses larger than 2 cm. Within four weeks after surgery, six courses of intravenous cyclophosphamide (600 mg per square meter of body-surface area per course) plus either intraperitoneal cisplatin (100 mg per square meter) or intravenous cisplatin (100 mg per square meter) were administered at three-week intervals. Results Of 654 randomized patients, 546 were eligible for the study. The estimated median survival was significantly longer in the group receiving intraperitoneal cisplatin (49 months; 95 percent confidence interval, 42 to 56) than in the group receiving intravenous cisplatin (41 months; 95 percent confidence ...
1,154 citations
TL;DR: This commentary is to institute a dialog that will lead to a better understanding of the strengths and weaknesses of the above methods, and to propose guidelines that should lead to more uniform and thus fairer judging of the studies that provide estimates of neuron or synapse numbers.
Abstract: Neuron and synapse numbers are important assays in neuroscience. These numbers are estimated by one of four methods: 1) profile counts, 2) assumption-based methods, 3) serial reconstructions, and 4) stereological methods. The criteria for these methods are diverse. This creates a disparity in that some reviewers accept estimates from any of these methods, while others accept only specific methods. An equally important issue is the diversity of sampling strategies, since unbiased estimates of neuronal or synaptic numbers are contingent upon both counting and sampling techniques. The purpose of this commentary is to institute a dialog that will lead to a better understanding of the strengths and weaknesses of the above methods, and to propose guidelines that should lead to more uniform and thus fairer judging of the studies that provide estimates of neuron or synapse numbers. In addition, adoption of more uniform standards for obtaining unbiased numerical estimates should result in the generation of an unbiased database that will be of considerable use in future studies.
981 citations
967 citations
TL;DR: These studies demonstrate that β-polymerase functions specifically in base-excision repair in vivo, and establishes embryonic fibroblast cell lines homozygous for a deletion mutation in the gene encoding DNA polymerase-β.
Abstract: Synthesis of DNA by DNA polymerase-beta is distributive on single-stranded DNA templates, but short DNA gaps with a 5' PO4 in the gap are filled processively to completion. In vitro studies have suggested a role of beta-polymerase in different types of DNA repair. However, the significance of these studies to the in vivo role of beta-polymerase has remained unclear. Because genetic studies are essential for determining the physiological role of a gene, we established embryonic fibroblast cell lines homozygous for a deletion mutation in the gene encoding DNA polymerase-beta. Extracts from these cell lines were found to be defective in uracil-initiated base-excision repair. The beta-polymerase-deleted cells are normal in viability and growth characteristics, although they exhibit increased sensitivity to monofunctional DNA-alkylating agents, but not to other DNA-damaging agents. Both the deficiency in base-excision repair and hypersensitivity to DNA-alkylating agents are rescued following stable transfection with a wild-type beta-polymerase minitransgene. These studies demonstrate that beta-polymerase functions specifically in base-excision repair in vivo.
811 citations
TL;DR: The examples demonstrate that the parent compounds and their metabolites cause both nongenotoxic cell proliferative effects as well as direct and indirect genotoxic effects, which illustrates the complex nature of estrogen carcinogenesis.
Abstract: In western society, the causes of several cancers--including breast, endometrium, ovary, liver, and prostate--have been linked to inappropriate and/or prolonged exposure to synthetic or endogenous steroidal hormones. In this review, we discuss the mechanisms of estrogen carcinogenesis with a focus on estrogen metabolism to 16 alpha-hydroxy estrone and 2- and 4-hydroxy catechol estrogens and the potential effects of these metabolites in vitro and in vivo on hamster liver and kidney and rat liver carcinogenesis models. The examples demonstrate that the parent compounds and their metabolites cause both nongenotoxic cell proliferative effects as well as direct and indirect genotoxic effects, which illustrates the complex nature of estrogen carcinogenesis. These effects, in combination with the metabolic state of the tissue and the timing of its exposure, may determine the cell type (organ) of tumor development and the severity of disease.
634 citations
TL;DR: This work has shown that alternative tissue-specific processing of primary mRNA from the α-CT/CGRP gene in rats generates two distinct peptides, CT and CGRP, which are the most potent endogenous vasodilatory peptides that have been discovered.
Abstract: I. Introduction THE calcitonin (CT) and calcitonin gene-related peptide (CGRP) are derived from the CT/CGRP gene, which is localized in chromosome 11. Alternative splicing of the primary RNA transcript leads to the translation of CGRP and CT peptides in a tissue-specific manner. This alternative tissue-specific processing of primary mRNA from the α-CT/CGRP gene in rats generates two distinct peptides, CT and CGRP (1, 2). CGRP is a 37-amino acid neuropeptide expressed predominantly in the nervous system and CT is expressed mainly in the thyroid gland. CGRP receptors, widely distributed in the body, are the most potent endogenous vasodilatory peptides that have been discovered. Derived from the C cells of the thyroid gland, CT is the most potent peptide inhibitor of osteoclast-mediated bone resorption and is involved primarily in protecting the skeleton during periods of “calcium stress” such as growth, pregnancy, and lactation (3). In 1961, Copp and colleagues (4) postulated the existence of the calcium-lo...
482 citations
Journal Article•
TL;DR: The observation that MG channels can be chemically blocked and/or activated by a wide range of compounds requires revision of the long-standing conclusion of Paintal that mechanotransduction is a process that has a low susceptibility to chemical influence.
Abstract: In this article, the actions, mechanisms and applications of various ions and drugs that interact with MG channels have been discussed. At present, no compound has been found that displays the high specificity and affinity exhibited by tetrodotoxin or alpha-bungarotoxin that proved so useful in the functional and structural characterization of the voltage-gated Na+ channel and the acetylcholine receptor channel, respectively. Nevertheless, three different classes of compounds have been discovered since Paintal's review that clearly block MG channels. These compounds, represented by amiloride, gentamicin and gadolinium, act mainly on the SA cation channel, which appears to be shared by many nonsensory and some mechanosensory cells. Each class of compound can be distinguished by the voltage and concentration dependence of the block and most likely involves different mechanisms of blocking action. In general, the MG channel blocker pharmacology indicates a variety of "receptor sites" on MG channels. The recognition and acceptance of such receptors should provide added impetus for continued screening for more potent drugs, venoms and toxins. In the case of activators, little is understood of the mechanisms by which the various amphipathic and amphiphilic compounds stimulate MG channels, although different bilayer and protein mechanisms have been evoked. Even less is understood of the role the new class of MG K+ channel and their modulation by fatty acids plays in physiological and perhaps pathological processes. However, given that K+ channels in general tend to reduce the excitability of nerve and muscle, plausible roles include fatty acid regulation of vascular tone and control of neuronal network excitability. In both cases, more detailed understanding is required regarding the physiological stimuli that modulate these channels through their fatty acid receptors. It may turn out that recognition and/or development of cell-type specific agents that activate such MG channels will possess high therapeutic potential. In any case, the observation that MG channels can be chemically blocked and/or activated by a wide range of compounds requires revision of the long-standing conclusion of Paintal that mechanotransduction is a process that has a low susceptibility to chemical influence.
426 citations
University of Texas Health Science Center at Houston1, NewYork–Presbyterian Hospital2, University of South Alabama3, University of Texas Southwestern Medical Center4, Washington University in St. Louis5, Harborview Medical Center6, University of Cincinnati7, Louisiana State University8, University of Alabama at Birmingham9, University of Texas Medical Branch10
TL;DR: Wound assessment over time showed that thin split-thickness autografts plus allograft dermal matrix were equivalent to thicker split- Thirteen-day take rates of the dermal Matrix were statistically equivalent to the control autografteds.
Abstract: A multicenter clinical study assessed the ability of an acellular allograft dermal matrix to function as a permanent dermal transplant in full-thickness and deep partial-thickness burns. The study consisted of a pilot phase (24 patients) to identify the optimum protocol and a study phase (43 patients) to evaluate graft performance. Each patient had both a test and a mirror-image or contiguous control site. At the test site, the dermal matrix was grafted to the excised wound base and a split-thickness autograft was simultaneously applied over it. The control site was grafted with a split-thickness autograft alone. Fourteen-day take rates of the dermal matrix were statistically equivalent to the control autografts. Histology of the dermal matrix showed fibroblast infiltration, neovascularization, and neoepithelialization without evidence of rejection. Wound assessment over time showed that thin split-thickness autografts plus allograft dermal matrix were equivalent to thicker split-thickness autografts.
417 citations
TL;DR: It is found that microsomes prepared from human mammary adenocarcinoma and fibroadenoma predominantly catalyze the metabolic 4-hydroxylation of estradiol, which may indicate a mechanistic role of 4-Hydroxyestradiol in tumor development.
Abstract: Estrogen is a known risk factor in human breast cancer. In rodent models, estradiol has been shown to induce tumors in those tissues in which this hormone is predominantly converted to the catechol metabolite 4-hydroxyestradiol by a specific 4-hydroxylase enzyme, whereas tumors fail to develop in organs in which 2-hydroxylation predominates. We have now found that microsomes prepared from human mammary adenocarcinoma and fibroadenoma predominantly catalyze the metabolic 4-hydroxylation of estradiol (ratios of 4-hydroxyestradiol/2-hydroxyestradiol formation in adenocarcinoma and fibroadenoma, 3.8 and 3.7, respectively). In contrast, microsomes from normal tissue obtained either from breast cancer patients or from reduction mammoplasty operations expressed comparable estradiol 2- and 4-hydroxylase activities (corresponding ratios, 1.3 and 0.7, respectively). An elevated ratio of 4-/2-hydroxyestradiol formation in neoplastic mammary tissue may therefore provide a useful marker of benign or malignant breast tumors and may indicate a mechanistic role of 4-hydroxyestradiol in tumor development.
400 citations
TL;DR: Among patients presenting with acute ischemic chest pain without persistent ST-segment elevation, blacks appeared to have less severe coronary disease, received revascularization less frequently, and had less recurrent ischemia compared with nonblacks, which suggests that more aggressive strategies should be directed to those patients with the greatest likelihood of adverse outcomes.
Abstract: Objective. —To investigate the natural history and response to treatment of patients with unstable angina or non—Q-wave myocardial infarction (MI). Design. —Inception cohort. Setting. —Patients in general community, primary care, or referral hospitals. Patients. —All patients with an episode of unstable exertional chest pain or chest pain at rest presumed to be ischemic in origin lasting 5 minutes or more but without persisting ST-segment elevation greater than 30 minutes or the development of Q-waves were identified and enumerated in 18 participating hospitals. A subset of enumerated patients was selected to be followed prospectively using specific sampling strategies that would provide adequate numbers of black, women, and elderly (aged ≥75 years) patients for comparison with their respective counterparts. Main Outcome Measures.—The primary analysis compared the incidence of death or Ml at 42 days after entry into the prospective study according to race, sex, and age. Other outcomes considered were recurrent ischemia and the combined outcomes of death, Ml, or recurrent ischemia by 42 days after entry. Results. —A total of 8676 admissions with unstable angina or non—Q-wave Ml were enumerated and, of these, 3318 patients were selected for the prospective study. The direct adjusted mean age of the 3318 patients was 63.8 years. There were 943 blacks and 2375 nonblacks. Compared with nonblacks, blacks were less likely to be treated with intensive anti-ischemic therapy for their qualifying anginal episode and less likely to undergo invasive procedures (risk ratio [RR], 0.65; 95% confidence interval [CI], 0.58 to 0.72;P Conclusions. —Among patients presenting with acute ischemic chest pain without persistent ST-segment elevation, blacks appeared to have less severe coronary disease, received revascularization less frequently, and had less recurrent ischemia compared with nonblacks. Women also were found to have less severe coronary disease and were treated less intensely than men, but experienced similar outcomes. Elderly patients had more severe coronary disease than younger patients on coronary angiography, but were more likely to be treated medically, and they experienced far more adverse outcomes. These data suggest that more aggressive strategies should be directed to those patients with the greatest likelihood of adverse outcomes. (JAMA. 1996;275:1104-1112)
TL;DR: This model was tested among 116 child and adolescent psychiatric inpatients and suggested that a nonhierarchical arrangement of the 3 factors may be preferable to a hierarchical one.
Abstract: The tripartite model of depression and anxiety suggests that depression and anxiety have shared (generalized negative affect) and specific (anhedonia and physiological hyperarousal) components. In one of the 1st studies to examine the structure of mood-related symptoms in youngsters, this model was tested among 116 child and adolescent psychiatric inpatients, ages 8-16 (M = 12.46; SD = 2.33). Consistent with the tripartite model, a 3-factor (Depression, Anxiety, and Negative Affect) model represented the observed data well. Follow-up analyses suggested that a nonhierarchical arrangement of the 3 factors may be preferable to a hierarchical one.
Journal Article•
TL;DR: The emergence of these two newly recognized tickborne infections as threats to human health is probably due to increased clinical cognizance, but as in other emergingtickborne infections, it is likely that the rapid increase in identified cases signals a true emergence of disease associated with a changing vector-host ecology.
Abstract: Ehrlichiae are small, gram-negative, obligately intracellular bacteria that reside within a phagosome. The first human ehrlichial infection was recognized in the United States in 1987. It was later shown to be caused by a new species, Ehrlichia chaffeensis. In 1994, an ehrlichial pathogen within neutrophils that is closely related to the known veterinary pathogens E. equi and E. phagocytophila was found to infect humans. Molecular methods were required to detect, characterize, and identify these fastidious and uncultivated bacteria. Subsequently, E. chaffeensis infection was documented in more than 400 patients in 30 states, Europe, and Africa. Likewise, approximately 170 cases of human granulocytic ehrlichiosis have been diagnosed, most since 1994, predominantly in the upper midwestern and northeastern states, but also in northern California. The disease caused by ehrlichiae is generally undifferentiated but is often associated with leukopenia, thrombocytopenia, and elevated serum hepatic transaminase levels in tick-exposed patients. Infection ranges from subclinical to fatal; tetracycline appears to be an effective therapy. The emergence of these two newly recognized tickborne infections as threats to human health is probably due to increased clinical cognizance, but as in other emerging tickborne infections, it is likely that the rapid increase in identified cases signals a true emergence of disease associated with a changing vector-host ecology.
TL;DR: It is concluded that chemokines are produced in the airways, and that an increased recovery of MCP-1, RANTES, and MIP-1alpha is observed in allergic asthmatic patients.
Abstract: Chemokines are cytokines that induce chemotaxis of inflammatory cells. We studied the presence of chemokines in bronchoalveolar lavage fluid (BALF) obtained from nine allergic asthmatic patients and six nonsmoking normal individuals. The cells were pelleted, and ribonucleic acid (RNA) was extracted by using RNAzol B. BALF was assayed for monocyte chemoattractant protein-1 (MCP-1), regulated upon activation in normal T cells, expressed, probably secreted (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha) and interleukin-8 (IL-8) by enzyme-linked immunosorbent assay (ELISA). The levels of MCP-1, RANTES, and MIP-1alpha were significantly higher in the asthma patients than in the control subjects (p<0.04). The concentrations of RANTES and MCP-1 correlated with the lymphocyte count in the BAL specimens (r = 0.61 and 0.68, respectively). BALF showed eosinophil chemotactic activity in vitro that was blocked by anti-RANTES and anti-MCP-3 antibodies. The total cellular RNA was reverse-transcribed and the complementary deoxyribonucleic acid (cDNA) was amplified with the polymerase chain reaction (PCR) for MCP-1, MCP-3, RANTES, MIP-1alpha, IL-8, and beta-actin. We found that messenger ribonucleic acids (mRNAs) for MCP-1, MCP-3, RANTES, MIP-1alpha, and IL-8 were produced by BAL cells from most asthmatic and normal subjects. We conclude that chemokines are produced in the airways, and that an increased recovery of MCP-1, RANTES, and MIP-1alpha is observed in allergic asthmatic patients.
TL;DR: Comparing across a range of variables, including Axis I diagnoses from the revised 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders, revealed that multiple attempters presented a more severe clinical picture and, accordingly, elevated suicide risk compared with attEMPters and ideators.
Abstract: The relationships among suicide ideators, attempters, and multiple attempters were explored in 332 psychiatric patients referred specifically for suicidal ideation or behavior. Previous researchers have subsumed multiple attempters under the general category of attempters. However, comparisons across a range of variables, including Axis I diagnoses from the revised 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1987) depressive and anxiety symptoms, suicidal ideation, hopelessness, problem solving, and a range of personality features revealed that multiple attempters presented a more severe clinical picture and, accordingly, elevated suicide risk compared with attempters and ideators. Observed differences between groups were maintained when attempters with "questionable intent" (i.e., those making equivocal attempts) were excluded from the analyses. Language: en
TL;DR: In this paper, in vitro optical properties as a function of pressure with a visible-IR spectrophotometer are measured and there was an increase in absorption and scattering coefficients among most of the compressed specimens.
Abstract: Tissue optical properties are necessary parameters for prescribing light dosimetry in photomedicine. In many diagnostic or therapeutic applications where optical fiber probes are used, pressure is often applied to the tissue to reduce index mismatch and increase light transmittance. In this paper, we have measured in vitro optical properties as a function of pressure with a visible-IR spectrophotometer. A spectral range of 400-1800 mm with a spectral resolution of 5 nm was used for all measurements. Skin specimens of a Hispanic donor and two Caucasian donors were obtained from the tissue bank. Bovine aorta and sclera, and porcine sclera came from a local slaughter house. Each specimen, sandwiched between microscope slides, was compressed by a spring-loaded apparatus. Then diffuse reflectance and transmittance of each sample were measured at no load and at approximately 0.1, 1, and 2 kgf/cm/sup 2/. Under compression, tissue thicknesses were reduced up to 78%. Generally speaking, the reflectance decreased while the overall transmittance increased under compression. The absorption and reduced scattering coefficients were calculated using the inverse adding doubling method. Compared with the no-load controls, there was an increase in absorption and scattering coefficients among most of the compressed specimens.
TL;DR: The data indicate that there is no major difference in allelic distribution of both genes between the ethnic populations and the multiplex PCR assay used in this study has the advantage of reducing the time, effort and cost required to carry out such analysis.
TL;DR: Capacitance measurements and the single-cell immunoblot assay found that the somata underwent robust exocytosis upon depolarization and released substance P, in response to KCl stimulation, suggesting that soma release is Ca(2+)-dependent.
TL;DR: Findings suggest that the epidemic in Venezuela during 1995 resulted from the re-emergence of an epizootic serotype IC VEE virus, and raises the possibility of a serotypes IC enzootic transmission cycle in northern Venezuela.
Journal Article•
TL;DR: In this article, the effects of soya consumption on circulating steroid hormones in six healthy females 22-29 years of age were examined, starting within 6 days after the onset of menses, the subjects ingested a 12-oz portion of soymilk with each of three meals daily for 1 month on a metabolic unit.
Abstract: Soybean consumption is associated with reduced rates of breast, prostate, and colon cancer, which is possibly related to the presence of isoflavones that are weakly estrogenic and anticarcinogenic. We examined the effects of soya consumption on circulating steroid hormones in six healthy females 22-29 years of age. Starting within 6 days after the onset of menses, the subjects ingested a 12-oz portion of soymilk with each of three meals daily for 1 month on a metabolic unit. Daily isoflavone intakes were approximately 100 mg of daidzein (mostly as daidzin) and approximately 100 mg of genistein (mostly as genistin). Serum 17 beta-estradiol levels on cycle days 5-7, 12-14, and 20-22 decreased by 31% (P = 0.09), 81% (P = 0.03), and 49% (P = 0.02), respectively, during soya feeding. Decreases persisted for two or three menstrual cycles after withdrawal from soya feeding. The luteal phase progesterone levels decreased by 35% during soya feeding (P = 0.002). Dehydroepiandrosterone sulfate levels decreased progressively during soya feeding by 14-30% (P = 0.03). Menstrual cycle length was 28.3 +/- 1.9 days before soymilk feeding, increased to 31.8 +/- 5.1 days during the month of soymilk feeding (P = 0.06), remained increased at 32.7 +/- 8.4 days (P = 0.11) at one cycle after termination of soymilk feeding, and returned to pre-soya diet levels five to six cycles later. These results suggest that consumption of soya diets containing phytoestrogens may reduce circulating ovarian steroids and adrenal androgens and increase menstrual cycle length. Such effects may account at least in part for the decreased risk of breast cancer that has been associated with legume consumption.
TL;DR: Small children and domestic livestock are at increased risk of oleander poisoning, and experimental and established therapeutic measures involved in detoxification are discussed.
TL;DR: A new rodent model of chronic central pain following spinal cord trauma is reported and somatosensory thresholds for non‐noxious mechanical and radiant heat which elicit paw withdrawal (flexor reflex) are significantly lowered following SCI.
Abstract: Spinal cord injury (SCI) results in variable motor recoveries and chronic central pain syndromes develop in the majority of SCI patients. To provide a basis for further studies, we report a new rodent model of chronic central pain following spinal cord trauma. Male Sprague-Dawley rats (N = 10) were hemisectioned at T13 and were tested both preoperatively and postoperatively and compared to sham-operated controls (N = 10) for locomotor function, and mechanical and thermal thresholds of both paw withdrawal and supraspinal responses. Results support the development and persistence of allodynia which persists for 160 days. Locomotor function was tested using the Basso, Beattie and Bresnahan (BBB) open field test and only the limb ipsilateral to the hemisection was affected, demonstrating acute flaccid paralysis with motor recovery which approached normal values by postoperative day (POD) 15. Prior to the hemisection, the rats showed little to no paw withdrawal response to von Frey stimulation of 4.41 mN or 9.41 mN in both forelimbs and hindlimbs. Postoperatively, responses in both ipsilateral and contralateral forelimbs and hindlimbs increased over time and the increase was statistically significant compared to intra-animal presurgical and sham control values (P < 0.05). There were no significant side-to-side differences in limb responses preoperatively or beyond POD 15. The forelimbs and hindlimbs responded to von Frey hair strengths of 122 mN preoperatively and postoperatively with similar withdrawal frequencies that were not statistically significant. Preoperatively, the paw withdrawal latency to heat stimuli was 22.9 +/- 3.0 (mean +/- SE) and 20.1 +/- 3.1 sec for the hindlimbs and forelimbs, respectively. Postoperatively, the mean hindlimb and forelimb latency of paw withdrawals decreased to 11.9 +/- 1.8 and 9.2 +/- 2.5 sec, respectively. This decrease in thermal thresholds is statistically significant when compared to intra-animal preoperative and sham control values (P < 0.05). These data indicate that somatosensory thresholds for non-noxious mechanical and radiant heat which elicit paw withdrawal (flexor reflex) are significantly lowered following SCI. To further support the development and persistence of chronic pain following hemisection, supraspinal responses such as paw lick, head turns, attacking the stimulus, and vocalizations were elicited in response to mechanical and thermal stimuli and were statistically significant compared to presurgical intra-animal or sham control values (P < 0.05). Hemisected animals vocalized to von Frey hair bending forces of 49.8 with a mean of 6.0 +/- 1.2 times out of 10 stimuli compared to intra-animal presurgical and sham control values of zero. Supraspinal responses of hemisected animals to thermal stimuli occurred at lower temperatures that were statistically significant compared to sham control or preoperative values (P < 0.05). These chronic changes in thresholds to both mechanical and thermal stimuli represent the development and persistence of mechanical and thermal allodynia after SCI.
TL;DR: Crystal structures of human pol beta complexed with blunt-ended segments of DNA show that, although the crystals belong to a different space group, the DNA is nevertheless bound in the pol beta binding channel in the same way as the DNA in previously reported structures of rat pol beta complexes with a template-primer and ddCTP.
Abstract: Mammalian DNA polymerase β (pol β) is a small (39 kDa) DNA gap-filling enzyme that comprises an amino-terminal 8-kDa domain and a carboxy-terminal 31-kDa domain. In the work reported here, crystal structures of human pol β complexed with blunt-ended segments of DNA show that, although the crystals belong to a different space group, the DNA is nevertheless bound in the pol β binding channel in the same way as the DNA in previously reported structures of rat pol β complexed with a template−primer and ddCTP [Pelletier, H., Sawaya, M. R., Kumar, A., Wilson, S. H., & Kraut, J. (1994) Science 264, 1891−1903]. The 8-kDa domain is in one of three previously observed positions relative to the 31-kDa domain, suggesting that the 8-kDa domain may assume only a small number of stable conformations. The thumb subdomain is in a more open position in the human pol β−DNA binary complex than it is in the rat pol β−DNA−ddCTP ternary complex, and a closing thumb upon nucleotide binding could represent the rate-limiting confo...
TL;DR: The present review provides an overview of recent advances in the field of opiate and opioid immunoregulatory processes and speculates as to their significance in diverse biological systems.
Abstract: The discovery of the ability of the nervous system to communicate through "public" circuits with other systems of the body is attributed to Ernst and Berta Scharrer, who described the neurosecretory process in 1928. Indeed, the immune system has been identified as another important neuroendocrine target tissue. Opioid peptides are involved in this communication (i.e., neuroimmune) and with that of autoimmunoregulation (communication between immunocytes). The significance of opioid neuropeptide involvement with the immune system is ascertained from the presence of novel δ, μ., and κ receptors on inflammatory cells that result in modulation of cellular activity after activation, as well as the presence of specific enzymatic degradation and regulation processes. In contrast to the relatively uniform antinociceptive action of opiate and opioid signal molecules in neural tissues, the presence of naturally occurring morphine in plasma and a novel μ3 opiate-specific receptor on inflammatory cells adds to the growing knowledge that opioid and opiate signal molecules may have antagonistic actions in select tissues. In examining various disorders (e.g., human immunodeficiency virus, substance abuse, parasitism, and the diffuse inflammatory response associated with surgery) evidence has also been found for the involvement of opiate/opioid signaling in prominent mechanisms. In addition, the presence of similar mechanisms in man and organisms 500 million years divergent in evolution bespeaks the importance of this family of signal molecules. The present review provides an overview of recent advances in the field of opiate and opioid immunoregulatory processes and speculates as to their significance in diverse biological systems.
TL;DR: β-pol and DNA ligase I are components of a multiprotein complex that performs BER, and it is concluded that β-Pol and DNAligase I were co-immunoprecipitated from the testis nuclear extract with anti β-pol IgG.
TL;DR: This review identifies the types of tumors for which patients with Fanconi's anemia are at risk and indicates that older patients have an ever‐increasing risk for development of solid tumors.
Abstract: Patients with Fanconi's anemia (FA) are at a high risk for development of malignancies. It is well-known that leukemia occurs in approximately 10% of cases, with increasing risk with age. Less commonly recognized is the risk for myelodysplastic syndromes (approximately 5%); the relationship between myelodysplasia and evolution to leukemia remains speculative. What also needs to be emphasized is that older patients have an ever-increasing risk for development of solid tumors, with at least 5% reported to have liver tumors (male:female ratio, 2:1) and an equal number of other cancers (female:male ratio, 3:1, even after exclusion of gynecologic malignancies). Hematologists have tended to focus on aplastic anemia and leukemia. As FA patients live longer, more of the other malignancies will occur, perhaps related to cord blood or bone marrow transplant, or treatment with cytokines. This review identifies the types of tumors for which patients with Fanconi's anemia are at risk.
Journal Article•
TL;DR: These findings demonstrate for the first time that hydrogen peroxide, a cellular oxidant, possess the ability to activate EGFR-mediated signaling events in VSMC, which may be important in oxidant stress-induced cellular responses.
Abstract: Protein tyrosine phosphorylation events play determinant roles in cellular processes such as proliferation and differentiation. We have recently reported that hydrogen peroxide, an active oxygen species and a cellular oxidant, stimulates growth response events in vascular smooth muscle cells (VSMC). To understand the mechanisms by which oxidant stress modulates these growth response events, we have studied the effect of hydrogen peroxide on protein tyrosine phosphorylation events in VSMC. Our findings show that hydrogen peroxide stimulates tyrosine phosphorylation of several proteins including epidermal growth factor receptor (EGFR) in VSMC. Hydrogen peroxide-induced tyrosine phosphorylation of EGFR was found to be time dependent; with a threefold increase at 5 min and a 20-fold increase at 30 min of treatment as compared to control levels. Hydrogen peroxide treatment of VSMC also resulted in a time-dependent increase in tyrosine phosphorylation of SHC proteins. In addition, hydrogen peroxide-induced tyrosine-phosphorylated EGFR formed a complex with SHC-Grb2-SOS. These events were followed by activation of Ras and extracellular signal-regulated protein kinases (ERKs) group of mitogen-activated protein kinases (MAPKs). Together these findings demonstrate for the first time that hydrogen peroxide, a cellular oxidant, possess the ability to activate EGFR-mediated signaling events in VSMC. These EGFR-mediated signaling events may be important in oxidant stress-induced cellular responses.
Journal Article•
TL;DR: Analysis of DNA adducts induced by malondialdehyde provided evidence that lipid peroxidation products can accumulate in human breast tissues and reach relatively high levels in the breast tissues of women with breast cancer.
Abstract: The etiology of the majority of human breast cancers is unknown; however, oxidative stress and lipid peroxidation have been suggested to play a role in breast carcinogenesis. To address this possibility, DNA adducts induced by malondialdehyde (MDA), an end product of lipid peroxidation, were analyzed in surgical specimens of normal breast tissues of 51 breast cancer patients using the nuclease P1-enhanced version of the 32P-postlabeling assay. Normal breast tissue samples from 28 noncancer patients receiving reduction mammoplasty served as controls. Two previously characterized putative MDA-deoxyadenosine (dA) and one MDA-deoxyguanosine adduct were detected in all tissue samples examined. Normal breast tissues from cancer patients exhibited significantly higher levels of the putative MDA adducts [median (42.5) and range (2.2-202.8) of relative adduct labeling x 10(9) values] than those found in noncancer controls (median, 15.67; range, 2.4-382.1; P = 0.0001, Mann-Whitney U test). Ten of the 51 cancer patients and 1 of the 28 controls were found to contain the putative MDA adducts at the level of > 1/10(7) nucleotides, a frequency comparable to that found in human liver. Age and body mass did not significantly influence the levels of these adducts. However, the presence of a previously detected benzo(a)pyrene-like DNA adduct in the breast tissues was associated with higher levels of the putative MDA-dA adducts in cancer patients (P = 0.012). The level of the putative MDA-dA adducts was significantly lower in smokers and former smokers compared to nonsmokers among cases after adjusting for age, body mass index, and status of the benzo(a)pyrene-like adduct (P = 0.009). Tumor tissues (n = 11) displayed significantly lower levels of the putative MDA adducts (median, 10.2; range, 5.3-20.6) than their corresponding normal adjacent tissues (median, 25.5; range, 10.5-138; P < 0.01). These findings provide evidence that lipid peroxidation products can accumulate in human breast tissues and reach relatively high levels in the breast tissues of women with breast cancer. There seems to be an interaction between these endogenous DNA modifications and carcinogen exposure-induced DNA adducts. Detection and quantitation of the putative MDA-DNA adducts may potentially be a useful tool in the understanding of breast cancer etiology.
TL;DR: It is suggested that afferent signals from injured and intact fibers play distinctively different roles in neuropathicPain: inputs from injured afferents maintain all components of neuropathic pain, while those from intact afferentS mediate evoked pain such as mechanical and cold allodynia.
Abstract: This study was conducted to determine the contribution of peripheral inputs from injured and intact afferent fibers to behavioral signs of neuropathic pain, using a previously developed neuropathic rat model. Neuropathic injury was produced by tightly ligating the left L5 and L6 spinal nerves; this procedure induced rats to display neuropathic pain behaviors in the ipsilateral hindlimb. The behaviors included signs of mechanical and cold allodynia, as well as ongoing pain. Five days after neuropathic injury, peripheral inputs from injured segments (L5 and L6) or intact segments (L3 and L4) were blocked by either transection of the dorsal roots or application of a local anesthetic (bupivacaine) to the roots. Dorsal rhizotomy of the injured segments reduced all components of neuropathic pain behaviors. In contrast, dorsal rhizotomy of the uninjured segments abolished behavioral signs of mechanical and cold allodynia, but signs of ongoing pain were preserved. Blocking afferent inputs by application of bupivacaine mimicked the results of dorsal rhizotomy, in a reversible manner. These results suggest that afferent signals from injured and intact fibers play distinctively different roles in neuropathic pain: inputs from injured afferents maintain all components of neuropathic pain, while those from intact afferents mediate evoked pain such as mechanical and cold allodynia. An hypothesis is proposed to explain the results of the present as well as other published studies.