Showing papers by "University of California, San Francisco published in 1996"
TL;DR: Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by otherIre1p molecules as a result of oligomerization.
Abstract: The transmembrane kinase Ire1p is required for activation of the unfolded protein response (UPR), the increase in transcription of genes encoding endoplasmic reticulum (ER) resident proteins that occurs in response to the accumulation of unfolded proteins in the ER. Ire1p spans the ER membrane (or the nuclear membrane with which the ER is continuous), with its kinase domain localized in the cytoplasm or in the nucleus. Consistent with this arrangement, it has been proposed that Ire1p senses the accumulation of unfolded proteins in the ER and transmits the signal across the membrane toward the transcription machinery, possibly by phosphorylating downstream components of the UPR pathway. Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by other Ire1p molecules as a result of oligomerization. In addition to its kinase domain, a C-terminal tail domain of Ire1p is required for induction of the UPR. The role of the tail is probably to bind other proteins that transmit the unfolded protein signal to the nucleus.
12,185 citations
TL;DR: The work from the authors' laboratories reviewed herein was supported by grants from the National Cancer Institute.
6,895 citations
TL;DR: An overview of the definitions, clinical features, and epidemiology of the acute respiratory distress syndrome is provided and advances in the areas of pathogenesis, resolution, and treatment are discussed.
Abstract: The acute respiratory distress syndrome is a common, devastating clinical syndrome of acute lung injury that affects both medical and surgical patients. Since the last review of this syndrome appeared in the Journal, 1 more uniform definitions have been devised and important advances have occurred in the understanding of the epidemiology, natural history, and pathogenesis of the disease, leading to the design and testing of new treatment strategies. This article provides an overview of the definitions, clinical features, and epidemiology of the acute respiratory distress syndrome and discusses advances in the areas of pathogenesis, resolution, and treatment. Historical Perspective and Definitions . . .
5,002 citations
TL;DR: Among women with low bone mass and existing vertebral fractures, alendronate is well tolerated and substantially reduces the frequency of morphometric and clinical vertebra fractures, as well as other clinical fractures.
3,730 citations
TL;DR: After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
Abstract: Background Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. Methods We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial — the Beta-Carotene and Retinol Efficacy Trial — involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. Results A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P = 0.02), as compared with the placebo group. There were no statistically significant ...
3,417 citations
TL;DR: Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.
Abstract: Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.
3,166 citations
TL;DR: β-catenin regulates gene expression by direct interaction with transcription factors such as LEF-1, providing a molecular mechanism for the transmission of signals from cell-adhesion components or wnt protein to the nucleus.
Abstract: The cytoplasmic proteins beta-catenin of vertebrates and armadillo of Drosophila have two functions: they link the cadherin cell-adhesion molecules to the cytoskeleton, and they participate in the wnt/wingless signal pathway. Here we show, in a yeast two-hybrid screen, that the architectural transcription factor LEF-1 (for lymphoid enhancer-binding factor) interacts with beta-catenin. In mammalian cells, coexpressed LEF-1 and beta-catenin form a complex that is localized to the nucleus and can be detected by immunoprecipitation. Moreover, LEF-1 and beta-catenin form a ternary complex with DNA that splays an altered DNA bend. Microinjection of LEF-1 into XenoPus embryos induces axis duplication, which is augmented by interaction with beta-catenin. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as LEF-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus.
2,761 citations
Women & Children's Hospital of Buffalo1, Cleveland Clinic2, Georgetown University3, Walter Reed Army Institute of Research4, University of California, San Francisco5, University at Buffalo6, University of Colorado Denver7, Biogen Idec8, Oregon Health & Science University9, Good Samaritan Hospital10, Kaiser Permanente11
TL;DR: Interferon beta‐ la had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium‐enhanced lesions on brain magnetic resonance images.
Abstract: The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase I11 trial of interferon beta-la. Interferon beta-la, 6.0 million units (30 μg), was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-la treatment produced a significant delay in time to sustained EDSS progression (p equals; 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-la-treated group. Patients treated with interferon beta-la also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (pvalues ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-la-treated patients. There were no major adverse events related to treatment. Interferon beta- la had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the hndamen- tal course of relapsing multiple sclerosis.
2,459 citations
TL;DR: Maintaining normothermia intraoperatively is likely to decrease the incidence of infectious complications in patients undergoing colorectal resection and to shorten their hospitalizations.
Abstract: Background Mild perioperative hypothermia, which is common during major surgery, may promote surgical-wound infection by triggering thermoregulatory vasoconstriction, which decreases subcutaneous oxygen tension. Reduced levels of oxygen in tissue impair oxidative killing by neutrophils and decrease the strength of the healing wound by reducing the deposition of collagen. Hypothermia also directly impairs immune function. We tested the hypothesis that hypothermia both increases susceptibility to surgical-wound infection and lengthens hospitalization. Methods Two hundred patients undergoing colorectal surgery were randomly assigned to routine intraoperative thermal care (the hypothermia group) or additional warming (the normothermia group). The patients' anesthetic care was standardized, and they were all given cefamandole and metronidazole. In a double-blind protocol, their wounds were evaluated daily until discharge from the hospital and in the clinic after two weeks; wounds containing culture-positive pu...
2,442 citations
TL;DR: Heritable mutations in BCNS patients and a somatic mutation in a sporadic BCC were identified in a human homolog of the Drosophila patched (ptc) gene, which appears to be crucial for proper embryonic development and for tumor suppression.
Abstract: The basal cell nevus syndrome (BCNS) is characterized by developmental abnormalities and by the postnatal occurrence of cancers, especially basal cell carcinomas (BCCs), the most common human cancer. Heritable mutations in BCNS patients and a somatic mutation in a sporadic BCC were identified in a human homolog of the Drosophila patched (ptc) gene. The ptc gene encodes a transmembrane protein that in Drosophila acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues. The human PTC gene appears to be crucial for proper embryonic development and for tumor suppression.
1,898 citations
TL;DR: Innate immunity has been considered only to provide rapid, incomplete antimicrobial host defense until the slower, more definitive acquired immune response develops but may have an additional role in determining which antigens the acquired immune system responds to and the nature of that response.
Abstract: Innate immunity has been considered only to provide rapid, incomplete antimicrobial host defense until the slower, more definitive acquired immune response develops. However, innate immunity may have an additional role in determining which antigens the acquired immune system responds to and the nature of that response. Knowledge of the molecules and pathways involved may create new therapeutic options for infectious and autoimmune diseases.
TL;DR: It is shown that the N-terminus of nNOS, which contains a PDZ protein motif, interacts with similar motifs in postsynaptic density-95 protein (PSD-95) and a related novel protein, PSD-93.
TL;DR: This work acknowledges key intellectual contributions from Jody Rosenblatt and Julie Theriot (protrusion, Listeria motility) and attempted to fairly represent different laboratories, systems, and opinions.
TL;DR: It is shown that repeated administration of only the recombinant human ob protein, leptin, into homozygous female ob/ob mice can correct their sterility, thus resulting in ovulation, pregnancy and parturition.
Abstract: The sterility of male and female homozygous ob/ob mice is a recognized feature of the ob mutation (1). Whereas ob/ob males can occasionally reproduce if maintained on a restricted diet, ob/ob females are always sterile (2). Thinning of the ob/ob females to normal weight by diet-restriction failed to correct their sterility. Early sexual development is normal in ob/ob females; however, ovulation never follows and the mice remain prepuberal indefinitely with no occurrence of oestrus cycles. Reproductive hormones are reduced in ob/ob females (3) demonstrating a functional defect from the hypothalamic-pituitary axis (4-6). The ovaries of ob/ob females are capable of producing viable eggs when transplanted into lean female recipients (7). Reconstitution of reproductive functions in the ob/ob female necessitates delivery of hypothalamic extracts to the third ventricle (8) and administration of pituitary extract (9), gonadotropic hormones (10), progesterone (11) and relaxin (12). These previous findings demonstrate that the sterility of ob/ob females is caused by an insufficiency of hormones at the hypothalamic-pituitary level rather than physical hindrance of copulatory activity, pregnancy and parturition caused by excess adipose tissue. We show here that repeated administration of only the recombinant human ob protein, leptin, into homozygous female ob/ob mice can correct their sterility, thus resulting in ovulation, pregnancy and parturition.
TL;DR: The development of the Stress-Related Growth Scale (SRGS) and its use in a study examining determinants of stress-related positive outcomes for college students showed that the SRGS has acceptable internal and test-retest reliability and that scores are not influenced by social desirability.
Abstract: This article reports the development of the Stress-Related Growth Scale (SRGS) and its use in a study examining determinants of stress-related positive outcomes for college students. Study 1 analyses showed that the SRGS has acceptable internal and test-retest reliability and that scores are not influenced by social desirability. Study 2 analyses showed that college students' SRGS responses were significantly related to those provided by friends and relatives on their behalf. Study 3 analyses tested the determinants of stress-related growth longitudinally. Significant predictors of the SRGS were (a) intrinsic religiousness; (b) social support satisfaction; (c) stressfulness of the negative event; (d) positive reinterpretation and acceptance coping; and (e) number of recent positive life events. The SRGS was also positively related to residual change in optimism, positive affectivity, number of socially supportive others, and social support satisfaction, lending further support to the validity of this new scale. Results have implications for current theory on stress-related positive outcomes.
TL;DR: It is shown that at postnatal day 0 (P0), GDNF-deficient mice have deficits in dorsal root ganglion, sympathetic and nodose neurons, but not in hindbrain noradrenergic or midbrain dopaminergic neurons, and GDNF is important for the development and/or survival of enteric, sympathetic, and sensory neurons and the renal system, but is not essential for catecholaminergic neuron in the central nervous system (CNS).
Abstract: GLIAL cell-line derived neurotrophic factor (GDNF) is a potent survival factor for embryonic midbrain dopaminergic1, spinal motor2, cranial sensory3, sympathetic, and hindbrain noradrenergic4 neurons, and is available to these cells in vivo. It is therefore considered a physiological trophic factor and a potential therapeutic agent for Parkinson's disease5,6, amyotrophic lateral sclerosis7, and Alzheimer's disease4. Here we show that at postnatal day 0 (P0), GDNF-deficient mice have deficits in dorsal root ganglion, sympathetic and nodose neurons, but not in hindbrain noradrenergic or midbrain dopaminergic neurons. These mice completely lack the enteric nervous system (ENS), ureters and kidneys. Thus GDNF is important for the development and/or survival of enteric, sympathetic and sensory neurons and the renal system, but is not essential for catecholaminergic neurons in the central nervous system (CNS).
TL;DR: Results establish netrin-1 as a guidance cue that likely collaborates with other diffusible cues to guide axons in vivo and evidence is provided for a distinct trochlear axon chemorepellent produced by floor plate cells.
TL;DR: The evolutionary trace method is a systematic, transparent and novel predictive technique that identifies active sites and functional interfaces in proteins with known structure and provides an evolutionary perspective for judging the functional or structural role of each residue in protein structure.
TL;DR: Results based on the pre-specified analytic method are presented, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention are presented.
Abstract: Risk Factors for Lung Cancer and for Intervention Effects in CARET, the Beta-Carotene and Retinol Efficacy Trial Gilbert S. Omenn, Gary E. Goodman, Mark D. Thornquist, John Balmes, Mark R. Cullen, Andrew Glass, James P. Keogh, Frank L. Meyskens, Jr., Barbara Valanis, James H. Williams, Jr., Scott Barnhart, Martin G. Cherniack, Carl Andrew Brodkin, Samuel Hammar* Background: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in (3-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an al- cohol chemical form of vitamin A), and people having higher serum p-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg (3-carotene and 25 000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18 314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg P-carotene and 25 000 IU retinyl palmitate). Promptly after the January 18,1996, announcement that the CARET active in- tervention had been stopped, we published preliminary find- ings from CARET regarding cancer, heart disease, and total mortality. Purpose: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the interven- tion. Methods: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for p-carotene con- centration. An Endpoints Review Committee evaluated end- point reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were es- timated by use of Cox regression models; tests were per- formed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 1550 ARTICLES a value, and all P values were derived from two-sided statis- tical tests. Results: According to CARET'S pre-specified analysis, there was an RR of 136 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associa- tions of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol in- take has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum p-carotene concentrations. Conclusions: CARET participants receiving the combination of P-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for p-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Preven- tion Study in 29 133 male smokers in Finland. Implications: Individuals at high risk of developing lung cancer, i.e., cur- rent smokers and asbestos-exposed workers, should be dis- couraged from taking supplemental P-carotene (and the combination of p-carotene with vitamin A). Safety and ef- ficacy should be demonstrated before recommending use of vitamin supplements in any population. [J Natl Cancer Inst * Affiliations of authors: G. S. Omenn, S. Bamhart, C A. Brodkin, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, and Departments of Environmental Health and Medicine, University of Washington, Seattle; G. E. Goodman, Division of Public Health Sciences. Fred Hutchinson Cancer Research Center, Departments of Environmental Health and Medicine, University of Washington, and Swedish Hospital Tumor Institute, Seattle; M. D. Thomquist, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, J. Balmes, Department of Medicine, University of California at San Francisco; M. R. Cullen, M. G. Chemiack, Department of Medicine, Yale University, New Haven, CT; A. Glass, B. Valanis, Kaiser Permanente Center for Health Research, Portland, OR; J. P. Keogh, Department of Medicine, University of Maryland, Baltimore; F. L Meyskens, Jr., J. H. Williams, Jr., Department of Medicine and Cancer Center, University of California/Irvine, Orange; S. Hammar, Departments of Environmen- tal Health and Pathology, University of Washington. Correspondence to: Gilbert S. Omenn, M.D., Ph.D., Fred Hutchinson Cancer Research Center, 1124 Columbia St., MP-859, Seattle, WA 98104. See Notes section following References. Journal of the National Cancer Institute, Vol. 88, No. 21, November 6, 1996
TL;DR: A speech processing algorithm was developed to create more salient versions of the rapidly changing elements in the acoustic waveform of speech that have been shown to be deficiently processed by language-learning impaired (LLI) children as discussed by the authors.
Abstract: A speech processing algorithm was developed to create more salient versions of the rapidly changing elements in the acoustic waveform of speech that have been shown to be deficiently processed by language-learning impaired (LLI) children. LLI children received extensive daily training, over a 4-week period, with listening exercises in which all speech was translated into this synthetic form. They also received daily training with computer "games" designed to adaptively drive improvements in temporal processing thresholds. Significant improvements in speech discrimination and language comprehension abilities were demonstrated in two independent groups of LLI children.
TL;DR: It is proposed that after the cationic lipid/DNA complex is internalized into cells by endocytosis it destabilization induces flip-flop of anionic lipids from the cytoplasmic-facing monolayer, which laterally diffuse into the complex and form a charge neutral ion pair with the cationsic lipids.
Abstract: To understand how DNA is released from cationic liposome/DNA complexes in cells, we investigated which biomolecules mediate release of DNA from a complex with cationic liposomes. Release from monovalent[1,2-dioleoyl-3(1)-1(trimethylammonio)propane] or multivalent (dioctadecylamidoglycylspermine) lipids was quantified by an increase of ethidium bromide (EtBr) fluorescence. Plasmid sensitivity to DNAse I degradation was examined using changes in plasmid migration on agarose gel electrophoresis. Physical separation of the DNA from the cationic lipid was confirmed and quantified on sucrose density gradients. Anionic liposomes containing compositions that mimic the cytoplasmic-facing monolayer of the plasma membrane (e.g. phosphatidylserine) rapidly released DNA from the complex. Release occurred near a 1/1 charge ratio (-/+) and was unaffected by ionic strength or ion type. Water soluble molecules with a high negative linear charge density such as dextran sulfate or heparin also released DNA. However, ionic water soluble molecules such as ATP, tRNA, DNA, poly(glutamic acid), spermidine, spermine, or histone did not, even at 100-fold charge excess (-/+). On the basis of these results, we propose that after the cationic lipid/DNA complex is internalized into cells by endocytosis it destabilizes the endosomal membrane. Destabilization induces flip-flop of anionic lipids from the cytoplasmic-facing monolayer, which laterally diffuse into the complex and form a charge neutral ion pair with the cationic lipids. This results in displacement of the DNA from the cationic lipid and release of the DNA into cytoplasm. This mechanism accounts for a variety of observations on cationic lipid/DNA complex-cell interactions.
TL;DR: Children with language-based learning impairments with major deficits in their recognition of some rapidly successive phonetic elements and nonspeech sound stimuli were engaged in adaptive training exercises mounted as computer "games" designed to drive improvements in their "temporal processing" skills.
Abstract: Children with language-based learning impairments (LLIs) have major deficits in their recognition of some rapidly successive phonetic elements and nonspeech sound stimuli. In the current study, LLI children were engaged in adaptive training exercises mounted as computer "games" designed to drive improvements in their "temporal processing" skills. With 8 to 16 hours of training during a 20-day period, LLI children improved markedly in their abilities to recognize brief and fast sequences of nonspeech and speech stimuli.
TL;DR: The development of a system for the lytic growth of this virus in a latently infected B cell line and the first ultrastructural visualization of the virus are reported, which will facilitate the detailed study of the molecular biology of viral replication, the testing of antiviral drugs and the development of diagnostic tests for viral infection.
Abstract: Kaposi's sarcoma (KS) is the leading neoplasm of AIDS patients, and HIV infection is known to be a major risk factor for its development. However, KS can occur in the absence of HIV infection and the risk of KS development varies widely even among HIV-infected patients, with homosexual men with AIDS being 20 times more likely to develop KS than AIDS-afflicted children or hemophiliacs. These and other data strongly suggest that a sexually transmitted agent or co-factor may be involved in KS pathogenesis. Recently, DNA sequences corresponding to the genome of a novel member of the herpesvirus family have been identified within AIDS-KS biopsies, and several reports indicate that these sequences are also present in all forms of HIV-negative KS. These and other findings suggest this new agent, referred to as KS-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), as a candidate for the putative etiologic cofactor. However, the role of this agent in KS remains hotly debated. Further progress in understanding its biology has been severely hampered by the lack of a cell culture system for virus growth. Here we report the development of a system for the lytic growth of this virus in a latently infected B cell line and present the first ultrastructural visualization of the virus. This system will facilitate the detailed study of the molecular biology of viral replication, the testing of antiviral drugs and the development of diagnostic tests for viral infection.
TL;DR: It has been shown that an increased level of CuZn-superoxide dismutase and antiapoptotic protein Bcl-2 in the brains of transgenic mice protects neurons from ischemic/reperfusion injury, whereas a deficiency in CuZN- superoxide dismUTase or mitochondrial Mn-super poisoning exacerbates isChemic brain damage.
Abstract: Background and Purpose Oxygen free radicals or oxidants have been proposed to be involved in acute central nervous system injury that is produced by cerebral ischemia and reperfusion. Because of the transient nature of oxygen radicals and the technical difficulties inherent in accurately measuring their levels in the brain, experimental strategies have been focused on the use of pharmacological agents and antioxidants to seek a correlation between the exogenously supplied specific radical scavengers (ie, superoxide dismutase and catalase) and the subsequent protection of cerebral tissues from ischemic injury. However, this strategy entails problems (hemodynamic, pharmacokinetic, toxicity, blood-brain barrier permeability, etc) that may cloud the data interpretation. This mini-review will focus on the oxidant mechanisms in cerebral ischemic brain injury by using transgenic and knockout mice as an alternative approach. Methods Transgenic and knockout mutants that either overexpress or are deficient in antio...
TL;DR: Results indicate that DCC is a receptor or a component of a receptor that mediates the effects of netrin-1 on commissural axons, and they complement genetic evidence for interactions between DCC and netrin homologs in C. elegans and Drosophila.
TL;DR: The number and proportion of Americans living with chronic conditions, and the magnitude of their costs, including direct costs (annual personal health expenditures) and indirect costs to society (lost productivity due to chronic conditions and premature death) are determined.
Abstract: Objectives. —To determine (1) the number and proportion of Americans living with chronic conditions, and (2) the magnitude of their costs, including direct costs (annual personal health expenditures) and indirect costs to society (lost productivity due to chronic conditions and premature death). Design. —Analysis of the 1987 National Medical Expenditure Survey for prevalence and direct health care costs; indirect costs based on the 1990 National Health Interview Survey andVital Statistics of the United States. Setting. —US population. Participants. —For the estimate of prevalence and direct costs, the National Medical Expenditure Survey sample of persons who reported health conditions associated with (1) use of health services or supplies or (2) periods of disability. Interventions. —None. Main Outcome Measures. —The number of persons with chronic conditions, their annual direct health care costs, and indirect costs from lost productivity and premature deaths. Results. —In 1987, 90 million Americans were living with chronic conditions, 39 million of whom were living with more than 1 chronic condition. Over 45% of non-institutionalized Americans have 1 or more chronic conditions and their direct health care costs account for three fourths of US health care expenditures. Total costs projected to 1990 for people with chronic conditions amounted to $659 billion—$425 billion for direct health care costs and $234 billion in indirect costs. Conclusions. —The prevalence and costs of chronic conditions as a whole have rarely been estimated. Because the number of persons with limitations due to chronic conditions is more regularly reported in the literature, the total prevalence of chronic conditions has perhaps been minimized. The majority of persons with chronic conditions are not disabled, nor are they elderly. Chronic conditions affect all ages. Because persons with chronic conditions have greater health needs at any age, their costs are disproportionately high.
TL;DR: It is proposed that the complex regulation of Hac1p expression serves to provide multiple levels at which the UPR can be controlled.
TL;DR: Despite greater toxicity, the use of MMC in a definitive CR regimen for anal cancer is justified, particularly in patients with large primary tumors.
Abstract: Purpose: Definitive chemoradiation (CR) has replaced radical surgery as the preferred treatment of epidermoid carcinoma of the anal canal. To determine the importance of mitomycin (MMC) in the standard CR regimen and to assess the role of salvage CR in patients who have residual tumor following CR, a phase III randomized trial was undertaken by the Radiation Therapy Oncology Group (RTOG)/Eastern Cooperative Oncology Group (ECOG). Patients andMethods: Between August 1988 and December 1991, 310 patients were randomized to receive either radiotherapy (RT) and fluorouracil (5-FU) or radiotherapy, 5-FU, and MMC. Of 291 assessable patients, 145 received 45 to 50.4 Gy of pelvic RT plus 5-FU at 1,000 mg/m 2 /d for 4 days, and 146 received RT, 5-FU, and MMC (10 mg/m 2 per dose for two doses). Patients with residual tumor on posttreatment biopsy were treated with a salvage regimen that consisted of additional pelvic RT (9 Gy), 5-FU, and cisplatin (100 mg/m 2 ). E PIDERMOID CARCINOMAS of the anal region I comprise only 1% to 2% of large bowel cancers and 3.9% of anorectal carcinomas.' Nevertheless, these neoplasms have dramatically increased in importance over the past 20 years as a model for organ preservation with the use of concomitant radiation (RT) and chemotherapy in lieu of radical surgery. 2 Before the application of chemoradiation (CR) regimens, the 5-year survival rate of patients with anal epidermoid malignancies managed by radical surgery ranged from 40% to 60% and local relapse was common.34 The combined modality regimen initially described by Nigro et a 5 in 1974 was a preoperative regimen that subsequently evolved into a definitive treatment program by 1983.67 More than 500 patients treated with CR using fluorouracil (5-FU) infusion and mitomycin (MMC) have been reported over the past 18 years. 6 ' 2
TL;DR: Frequency of chronic pelvic pain is undiagnosed, although it affects approximately one in seven U.S. women, and its association with health-related quality of life, work productivity, and health care utilization is examined.
TL;DR: A biomarker is desirable in quantitating systemic exposure both in smokers and nonsmokers to constituents of tobacco smoke to reflect exposure to toxic constituents of smoke that are of concern.
Abstract: A biomarker is desirable in quantitating systemic exposure both in smokers and nonsmokers to constituents of tobacco smoke. Self-report measures in smokers, such as cigarettes smoked per day, are highly imprecise owing to individual differences in how cigarettes are smoked, with ranges of nicotine intake per cigarette from 0.3 to 3.0 mg (1, 2). Self-report measures, such as hours per day exposed to environmental tobacco smoke (ETS) by nonsmokers, are also likely to be imprecise indicators of intake of tobacco smoke owing to variations in the number of cigarettes smoked, proximity of nonsmokers to smokers, room ventilation and other environmental characteristics, as well as individual differences in sensitivity to and/or concern about adverse effects of ETS. The optimal assessment of exposure to tobacco smoke would be by analysis of the concentrations of a component of smoke in the body fluids of an exposed individual— i.e., a biologic marker or biomarker. There are two broad questions that need to be considered in assessing the validity of a biomarker of tobacco smoke exposure. The first is how well does the concentration of a marker chemical in the air reflect exposure to toxic constituents of smoke that are of concern? The second is how well does a concentration of a particular chemical in a biologic fluid reflect an individual's intake of that chemical (or a related chemical) from tobacco smoke? The National Research Council (3) has proposed criteria for a valid marker of ETS in the air as follows: The marker 1) should be unique or nearly unique for ETS so that other sources are minor in comparison; 2) should be easily detectable; 3) should be emitted at similar rates for a variety of tobacco products; and 4)