Showing papers by "National Institutes of Health published in 1986"
TL;DR: Two metabolites of the steroid hormones progesterone and deoxycorticosterone are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons, which may explain the ability of certain steroid hormones to rapidly alter neuronal excitability.
Abstract: Two metabolites of the steroid hormones progesterone and deoxycorticosterone, 3 alpha-hydroxy-5 alpha-dihydroprogesterone and 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone, are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex. At concentrations between 10(-7) and 10(-5)M both steroids inhibited binding of the convulsant t-butylbicyclophosphorothionate to the GABA-receptor complex and increased the binding of the benzodiazepine flunitrazepam; they also stimulated chloride uptake (as measured by uptake of 36Cl-) into isolated brain vesicles, and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons. These data may explain the ability of certain steroid hormones to rapidly alter neuronal excitability and may provide a mechanism for the anesthetic and hypnotic actions of naturally occurring and synthetic anesthetic steroids.
2,175 citations
TL;DR: Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.
Abstract: • To evaluate dorsolateral prefrontal cortex (DLPFC) physiology and function simultaneously, 20 medication-free patients with chronic schizophrenia and 25 normal controls underwent three separate xenon Xe 133 inhalation procedures for determination of regional cerebral blood flow (rCBF): first at rest, then while performing an automated version of the Wisconsin Card Sort (WCS), a DLPFC-specific cognitive test, and while peforming a simple number-matching (NM) test. During rest, patients had significantly reduced relative, but not absolute, rCBF to DLPFC. During NM, no specific region differentiated patients from controls. During WCS, however, both absolute and relative rCBF to DLPFC significantly distinguished patients from controls. While controls showed a clear increase in DLPFC rCBF, patients did not. The changes were regionally specific, involving only DLPFC. Furthermore, in patients, DLPFC rCBF correlated positively with WCS cognitive performance, suggesting that the better DLPFC was able to function, the better patients could perform. Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.
2,066 citations
TL;DR: The adoptive transfer of tumor-infiltrating lymphocytes (TIL) expanded in interleukin-2 (IL-2) to mice bearing micrometastases from various types of tumors showed that TIL are 50 to 100 times more effective in their therapeutic potency than are lymphokine-activated killer cells.
Abstract: The adoptive transfer of tumor-infiltrating lymphocytes (TIL) expanded in interleukin-2 (IL-2) to mice bearing micrometastases from various types of tumors showed that TIL are 50 to 100 times more effective in their therapeutic potency than are lymphokine-activated killer (LAK) cells. Therefore the use of TIL was explored for the treatment of mice with large pulmonary and hepatic metastatic tumors that do not respond to LAK cell therapy. Although treatment of animals with TIL alone or cyclophosphamide alone had little impact, these two modalities together mediated the elimination of large metastatic cancer deposits in the liver and lung. The combination of TIL and cyclophosphamide was further potentiated by the simultaneous administration of IL-2. With the combination of cyclophosphamide, TIL, and IL-2, 100% of mice (n = 12) bearing the MC-38 colon adenocarcinoma were cured of advanced hepatic metastases, and up to 50% of mice were cured of advanced pulmonary metastases. Techniques have been developed to isolate TIL from human tumors. These experiments provide a rationale for the use of TIL in the treatment of humans with advanced cancer.
1,775 citations
TL;DR: It is suggested that mononuclear phagocytes may serve as primary targets for infection and agents for virus dissemination and that these virus-infected cells may play a role in the pathogenesis of the disease.
Abstract: Cells with properties characteristic of mononuclear phagocytes were evaluated for infectivity with five different isolates of the AIDS virus, HTLV-III/LAV. Mononuclear phagocytes cultured from brain and lung tissues of AIDS patients harbored the virus. In vitro-infected macrophages from the peripheral blood, bone marrow, or cord blood of healthy donors produced large quantities of virus. Virus production persisted for at least 40 days and was not dependent on host cell proliferation. Giant multinucleated cells were frequently observed in the macrophage cultures and numerous virus particles, often located within vacuole-like structures, were present in infected cells. The different virus isolates were compared for their ability to infect macrophages and T cells. Isolates from lung- and brain-derived macrophages had a significantly higher ability to infect macrophages than T cells. In contrast, the prototype HTLV-III beta showed a 10,000-fold lower ability to infect macrophages than T cells and virus production was one-tenth that in macrophage cultures infected with other isolates, indicating that a particular variant of HTLV-III/LAV may have a preferential tropism for macrophages or T cells. These results suggest that mononuclear phagocytes may serve as primary targets for infection and agents for virus dissemination and that these virus-infected cells may play a role in the pathogenesis of the disease.
1,762 citations
TL;DR: It is directly demonstrated that excitatory amino acids acting at NMDA receptors on spinal cord neurones increase the intracellular Ca2+ activity, measured using the indicator dye arsenazo III, and that this is the result of Ca2- influx through NMDA receptor channels.
Abstract: Excitatory amino acids act via receptor subtypes in the mammalian central nervous system (CNS). The receptor selectively activated by N-methyl-D-aspartic acid (NMDA) has been best characterized using voltage-clamp and single-channel recording; the results suggest that NMDA receptors gate channels that are permeable to Na+, K+ and other monovalent cations. Various experiments suggest that Ca2+ flux is also associated with the activation of excitatory amino-acid receptors on vertebrate neurones. Whether Ca2+ enters through voltage-dependent Ca2+ channels or through excitatory amino-acid-activated channels of one or more subtype is unclear. Mg2+ can be used to distinguish NMDA-receptor-activated channels from voltage-dependent Ca2+ channels, because at micromolar concentrations Mg2+ has little effect on voltage-dependent Ca2+ channels while it enters and blocks NMDA receptor channels. Marked differences in the potency of other divalent cations acting as Ca2+ channel blockers compared with their action as NMDA antagonists also distinguish the NMDA channel from voltage-sensitive Ca2+ channels. However, we now directly demonstrate that excitatory amino acids acting at NMDA receptors on spinal cord neurones increase the intracellular Ca2+ activity, measured using the indicator dye arsenazo III, and that this is the result of Ca2+ influx through NMDA receptor channels. Kainic acid (KA), which acts at another subtype of excitatory amino-acid receptor, was much less effective in triggering increases in intracellular free Ca2+.
1,712 citations
TL;DR: The identity of an important cell type that supports replication of the AIDS retrovirus in brain tissue was determined in two affected individuals and these cells were mononucleated and multinucleated macrophages that actively synthesized viral RNA and produced progeny virions in the brains of the patients.
Abstract: One of the common neurological complications in patients with the acquired immune deficiency syndrome (AIDS) is a subacute encephalopathy with progressive dementia. By using the techniques of cocultivation for virus isolation, in situ hybridization, immunocytochemistry, and transmission electron microscopy, the identity of an important cell type that supports replication of the AIDS retrovirus in brain tissue was determined in two affected individuals. These cells were mononucleated and multinucleated macrophages that actively synthesized viral RNA and produced progeny virions in the brains of the patients. Infected brain macrophages may serve as a reservoir for virus and as a vehicle for viral dissemination in the infected host.
1,675 citations
TL;DR: In this paper, a simple method that alleviates the dynamic range problem and that facilitates the suppression of signals from protons that are not coupled to the lowy nucleus is described, where the low-y nucleus was assumed to be 13C.
1,316 citations
TL;DR: The biochemical characteristics, gene cloning, cell sources, biological properties and actions of IL-1 are discussed, and reasons why this pleitotropic, nonspecific hormone-like cytokine is of considerable concern to immunologists are given.
1,259 citations
TL;DR: Two studies of coping among community-dwelling adults (N= 255,151) were used to examine the influence of personality on coping responses, the perceived effectiveness of coping mechanisms, and the effects of coping and personality on well-being as mentioned in this paper.
Abstract: Two studies of coping among community-dwelling adults (N= 255,151) were used to examine the influence of personality on coping responses, the perceived effectiveness of coping mechanisms, and the effects of coping and personality on well-being In both studies a wide range of potential stressors was examined, categorized as losses, threats, or challenges The personality dimensions of neuroticism, extraversion, and openness to experience, as measured by both self-reports and spouse- and peer-ratings, were systematically related to coping mechanisms in both studies There was general agreement across types of stressors on the use and perceived effectiveness of the 27 coping mechanisms, and individuals who used more effective ways of coping generally reported higher subsequent happiness and life satisfaction However, personality variables are also known to be determinants of well-being, and the associations between coping and well-being were reduced when personality measures were partialled out Some implications for the design and interpretation of coping effectiveness studies are discussed
1,176 citations
TL;DR: It is concluded that, as compared with high-dose oral prednisone alone, treatment of lupus glomerulonephritis with intravenous cyclophosphamide reduces the risk of end-stage renal failure with few serious complications.
Abstract: We evaluated renal function in 107 patients with active lupus nephritis who participated in long-term randomized therapeutic trials (median follow-up, seven years). For patients taking oral prednisone alone, the probability of renal failure began to increase substantially after five years of observation. Renal function was better preserved in patients who received various cytotoxic-drug therapies, but the difference was statistically significant only for intravenous cyclophosphamide plus low-dose prednisone as compared with high-dose prednisone alone (P = 0.027). The advantage of treatment with intravenous cyclophosphamide over oral prednisone alone was particularly apparent in the high-risk subgroup of patients who had chronic histologic changes on renal biopsy at study entry. Patients treated with intravenous cyclophosphamide have not experienced hemorrhagic cystitis, cancer, or a disproportionate number of major infections. We conclude that, as compared with high-dose oral prednisone alone, treatment of lupus glomerulonephritis with intravenous cyclophosphamide reduces the risk of end-stage renal failure with few serious complications.
1,100 citations
TL;DR: The volume of ELF determined by urea must be considered an overestimate, or "apparent" volume, since urea diffuses readily through the body, plasma and in situ ELF urea concentrations are identical; thus ELF volume can be calculated using simple dilution principles.
Abstract: Bronchoalveolar lavage is a powerful technique for sampling the epithelial lining fluid (ELF) of the lower respiratory tract but also results in a significant dilution of that fluid. To quantify th...
TL;DR: In this paper, the capacity of purine and pyrimidine nucleoside derivatives to inhibit the infectivity and cytopathic effect of human T-lymphotropic virus type III in vitro was tested.
Abstract: Human T-lymphotropic virus type III (HTLV-III)/lymphadenopathy-associated virus (LAV) is a a newly discovered lymphotropic retrovirus that is cytopathic for helper/inducer T cells in vitro. This virus is the etiologic agent of the acquired immunodeficiency syndrome and related diseases. In the current study, we tested the capacity of purine and pyrimidine nucleoside derivatives to inhibit the infectivity and cytopathic effect of human T-lymphotropic virus type III in vitro. With the ribose moiety of the molecule in a 2',3'-dideoxy configuration, every purine (adenosine, guanosine, and inosine) and pyrimidine (cytidine and thymidine) nucleoside tested suppressed the virus, although the thymidine derivative seemed to have substantially less activity in our system than the others. In general, we observed essentially complete suppression of the virus at doses that were lower by a factor of 10 to 20 than those needed to inhibit the proliferation of the target T cells and the immune reactivity of normal T cells in vitro. An analysis of five adenosine congeners, which differed only in the sugar moiety, revealed that reduction (an absence of hydroxyl determinants) at both the 2' and 3' carbons of the ribose was necessary for an anti-viral effect, and an additional reduction at the 5' carbon nullified the anti-viral activity. These observations may be of value in developing a new class of experimental drugs for the therapy of human T-lymphotropic virus type III infections.
TL;DR: It is suggested that long-term, low-dose alpha interferon therapy may be effective in controlling the disease activity in some patients with chronic non-A,non-B hepatitis.
Abstract: We treated 10 patients who had chronic non-A,non-B hepatitis with recombinant human alpha interferon in varying doses (0.5 to 5 million units) daily, every other day, or three times weekly for up to 12 months. In 8 of the 10 patients, elevated serum aminotransferase levels decreased rapidly during therapy and eventually fell into the normal or nearly normal range. In two of these patients, the interferon therapy was stopped after four months, and in both cases, a prompt return of aminotransferase activities to pretreatment values occurred. Prolonged treatment was associated with a sustained improvement in aminotransferase levels; in three cases, biopsy specimens obtained after one year of therapy showed marked improvement in hepatic histology, even though low doses of alpha interferon had been used. These preliminary findings, although not adequately controlled, suggest that long-term, low-dose alpha interferon therapy may be effective in controlling the disease activity in some patients with chronic non-A,non-B hepatitis. A prospective controlled trial is now needed to assess the role of interferon therapy in this disease.
TL;DR: In this article, the authors proposed diagnostic criteria and measures of clinical change for age-associated memory impairment and developed a set of diagnostic criteria based on the report of a national institute of mental health work group.
Abstract: (1986). Age‐associated memory impairment: Proposed diagnostic criteria and measures of clinical change — report of a national institute of mental health work group. Developmental Neuropsychology: Vol. 2, No. 4, pp. 261-276.
TL;DR: In this article, a model of P300 amplitude is proposed that reduces the many hypothetical constructs invoked to explain variations in P3 amplitude to three dimensions: Subjective Probability, Stimulus Meaning, and Information Transmission.
Abstract: A model of P300 amplitude is proposed that reduces the many hypothetical constructs invoked to explain variations in P300 amplitude to three dimensions: 1) Subjective Probahility, 2) Stimulus Meaning, and 3) Information Transmission. Evidence is presented to support the assertion that variables on the subjective prwbability and stimulus meaning dimensions have independent and additive contributions to overall P300 amplitude. The amplitude contributions of both of these dimensions, however, are modulated by a multiplicative relation with the proportion of transmitted stimulus information. Within each dimension, the fundamental experimental variables and their interrelations are specified. An example is presented to show how, by using an additive factors method, the respective amplitude effects of the probability and stimulus meaning dimensions can be separated. Supporting data are presented to show that the proposed model provides a reasonable and testable framework in which to conceptualize P300 results. DESCRIPTORS: Event-related potentials, P300. The prospect of having an electrophysio logical index of cognitive operations has led many researchers to explore the nature of the P300 component of the event-related brain potential (ERP). Since its discovery by Sutton and his colleagues (Sutton, Braren, Zubin, & John, 1965; Sutton, Tueting, Zubin, & John, 1967), studies have demonstrated that P300 amplitude and latency can be used as indices of the nature and timing of a subject's cognitive response to a stimulus.' As a result of
TL;DR: Schizophrenia itself is associated with an increase in brain D2 dopamine receptor density, and the densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers.
Abstract: In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.
TL;DR: In this paper, the initiation, rate of progress of periodontal disease and consequent tooth loss in a population never exposed to any programs or incidents relative to prevention and treatment of dental diseases was described.
Abstract: This paper describes the initiation, rate of progress of periodontal disease and consequent tooth loss in a population never exposed to any programs or incidents relative to prevention and treatment of dental diseases. The group consisted of 480 male laborers at two tea plantations in Sri Lanka. The study design and baseline data have been published. At the initial examination in 1970, the age of the participants ranged between 14 and 31 years. Subsequent examinations occurred in 1971, 1973, 1977, 1982 and 1985. Thus, the study covers the age range 14-46 years. Throughout the study, the clinical indices were scored by the same two examiners, both well-trained and experienced periodontitis. Intra-examiner reproducibility for each index was tested at baseline and repeated periodically during the study. The data for each examination were computerized and updated on an ongoing basis. At the last examination in 1985, there were 161 individuals who had participated in the first survey. This population did not perform any conventional oral hygiene measures and consequently displayed quite uniformly large aggregates of plaque, calculus and stain on their teeth. Virtually all gingival units exhibited inflammation. Based on interproximal loss of attachment and tooth mortality rates, three subpopulations were identified: (1) individuals (approximately 8%) with rapid progression of periodontal disease (RP), those (approximately 81%) with moderate progression (MP), and a group (approximately 11%) who exhibited no progression (NP) of periodontal disease beyond gingivitis. At 35 years of age, the mean loss of attachment in the RP group was approximately 9 mm, the MP group had approximately 4 mm and the NP group had less than 1 mm loss of attachment. At the age of 45 years, the mean loss of attachment in the RP group was approximately 13 mm and the MP group approximately 7 mm. The annual rate of destruction in the RP group varied between 0.1 and 1.0 mm, in the MP group between 0.05 and 0.5 mm, and in the NP group between 0.05 and 0.09 mm. Since this population was virtually caries free, essentially all missing teeth were lost due to periodontal disease. In the RP group, tooth loss already occurred at 20 years of age and increased throughout the next 25 years. At 35 years of age, 12 teeth had been lost, at 40 years of age 20 teeth were missing and at 45 all teeth were lost. In the MP groups, tooth mortality started after 30 years of age and increased throughout the decade.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: It is concluded that Lp(a) is an important attribute that should often be considered when coronary heart disease risk is assessed and was not explained by differences in total cholesterol levels, high-density lipoprotein or low-density lipid levels, subscapular skin fold, systolic blood pressure, history of smoking, alcohol consumption, or age.
Abstract: The Lp(a) lipoprotein is structurally related to low-density lipoprotein but is found in lower plasma concentration. It has been associated with coronary disease in several white populations. To test the generalizability of this association, we measured serum Lp(a) by quantitative immunoelectrophoresis in 303 Hawaiian men of Japanese ancestry with a prior myocardial infarction (MI) and in 408 population-based controls. Mean values were 17.1 and 13.7 mg/dL (0.171 and 0.137 g/L) respectively. Increased risk for MI was shown mainly for men in the upper quartile of the Lp(a) lipoprotein distribution (≥20.1 mg/dL [≥0.201 g/L]). Odds ratios at younger than 60, 60 to 69, and 70 years of age or older were 2.5, 1.6, and 1.2 times those for men in the lower three quartiles, respectively. In a multiple logistic model the association with MI remained significant and was not explained by differences in total cholesterol levels, high-density lipoprotein or low-density lipoprotein cholesterol levels, subscapular skin fold, systolic blood pressure, history of smoking, alcohol consumption, or age. We conclude that Lp(a) is an important attribute that should often be considered when coronary heart disease risk is assessed. (JAMA1986;256:2540-2544)
TL;DR: The pathophysiologic features of hypercortisolism in depression and Cushing's disease are distinct in each of the disorders and that the ovine corticotropin-releasing hormone stimulation test can be helpful in their differential diagnosis.
Abstract: Primary depression can be associated with substantial hypercortisolism, thus prompting some researchers to suggest that depression shares pathophysiologic features with Cushing's disease. Clinically, depression can be difficult or impossible to distinguish from mild or early Cushing's disease that is associated with depressive features. The purpose of this study was to evaluate whether the pituitary-adrenal responses to ovine corticotropin-releasing hormone could help to clarify the mechanism of hypercortisolism in depression and in Cushing's disease and to assist in the differential diagnosis of these disorders. As compared with controls (n = 34), depressed patients (n = 30) had basal hypercortisolism (P less than 0.001) that was associated with attenuated plasma ACTH responses to ovine corticotropin-releasing hormone (P less than 0.001). This indicates that in patients with depression, the corticotroph cell in the pituitary responds appropriately to the negative feedback of high cortisol levels. In contrast, patients with Cushing's disease (n = 29) had plasma ACTH hyperresponsiveness to ovine corticotropin-releasing hormone (P less than 0.001), despite basal hypercortisolism (P less than 0.001), which indicates a gross impairment of the mechanism by which cortisol exerts negative feedback on the pituitary. Less than 25 percent of the patients with depression or Cushing's disease had peak ACTH responses that overlapped. We conclude that the pathophysiologic features of hypercortisolism in depression and Cushing's disease are distinct in each of the disorders and that the ovine corticotropin-releasing hormone stimulation test can be helpful in their differential diagnosis.
Journal Article•
TL;DR: The existence of a clinical syndrome characterized by a core of depressive and dissociative symptoms and a childhood history of significant trauma, primarily child abuse is documents.
Abstract: The clinical syndrome of multiple personality disorder (MPD) is an unusual dissociative condition that has been poorly characterized. In an attempt to better delineate the clinical phenomenology of MPD, 100 recent cases were collected on a 386-item questionnaire completed by clinicians involved in the treatment of MPD patients. This study documents the existence of a clinical syndrome characterized by a core of depressive and dissociative symptoms and a childhood history of significant trauma, primarily child abuse.
TL;DR: The preincubation modification of the Salmonella/mammalian microsome assay was used to test chemicals in up to fiveSalmonella strains in the presence and absence of rat and hamster liver S-9.
Abstract: This publication includes data of Salmonella mutagenicity results on 270 coded chemicals, encompassing 329 tests performed by three laboratories under contract to the National Toxicology Program (NTP). The preincubation modification of the Salmonella/mammalian microsome assay was used to test chemicals in up to five Salmonella strains in the presence and absence of rat and hamster liver S-9. With a few exceptions, inter- and intralaboratory reproducibility was good.
TL;DR: A model of emotional control based on interactive inhibition between a right negatively biased and left positively biased hemisphere is suggested, however, the details of such a model, including the precise conditions under which emotion-related functions are lateralized, have yet to be elucidated.
TL;DR: The results show that transformation by three growth factor receptor-like oncogenes depends on c-ras proteins, while transformation by two cytoplasmic onCogenes appears to be independent ofc-ras protein.
Abstract: Many retroviral oncogenes have been classified into one of several categories based on structure, enzymology and cellular localization. These genes originated from host cells and are probably derived from genes normally involved in the control of cell proliferation. The cellular counterparts of three oncogenes have been identified as a growth factor or growth factor receptor; related oncogenes include receptor-like membrane proteins which often express tyrosine kinase activity. These growth factor-related oncogenes are structurally and biochemically distinct from the membrane-associated ras gene family, which bind and hydrolyse GTP. Oncogenes localized primarily in the cytoplasm which probably have serine kinase activity, have also been identified. Although the structure and biochemistry of many oncogenes have been extensively studied, relatively little is known about the functional relationships of oncogene proteins within the cell. An opportunity to study such interaction is provided by the identification of a monoclonal antibody that neutralizes cellular ras proteins when microinjected into cells. It has been shown previously that the injected antibody inhibits the initiation of S-phase in NIH 3T3 cells. In the present study we injected this monoclonal antibody into NIH 3T3 cells transformed by a variety of oncogenes. The results show that transformation by three growth factor receptor-like oncogenes depends on c-ras proteins, while transformation by two cytoplasmic oncogenes appears to be independent of c-ras protein.
TL;DR: It is demonstrated that cell-surface expression of this protein, in the absence of other HTLV-III/LAV structural or regulatory proteins, is sufficient to induce CD4-dependent cell fusion, leading to cell death, one of the characteristic manifestations of AIDS (acquired immune deficiency syndrome) virus cytopathology.
Abstract: Formation of syncytia, with progression to cell death, is a characteristic feature of in vitro cultures of susceptible cells infected with human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV)1–3. Viral antigen-positive multi-nucleated giant cells have also been observed in histological sections from infected individuals4,5. In vitro, formation of these multinucleated giant cells occurs through cell fusion which is dependent on cell-surface expression of the differentiation antigen CD4 (ref. 1). Utilizing a recombinant vaccinia virus containing the gene for the envelope glycoprotein of HTLV-III/LAV6, we demonstrate that cell-surface expression of this protein, in the absence of other HTLV-III/LAV structural or regulatory proteins, is sufficient to induce CD4-dependent cell fusion, leading to cell death, one of the characteristic manifestations of AIDS (acquired immune deficiency syndrome) virus cytopathology. This process may contribute to the loss of CD4+ T cells seen in AIDS.
TL;DR: Unexpectedly, the first AUG codon is required for efficient GCN4 expression under starvation conditions and appears to involve antagonism of the inhibitory effect of the 3' proximal AUGcodons since it is dispensable in the absence of these sequences.
TL;DR: It is concluded that initial single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment.
Abstract: To assess the efficacy of single-agent therapy relative to standard combination antibiotic therapy for the initial management of fever and neutropenia in cancer patients, we conducted a randomized trial comparing ceftazidime alone with a combination of cephalothin, gentamicin, and carbenicillin. Of 550 evaluable episodes of fever and neutropenia, 282 were treated with ceftazidime alone and 268 with the combination. All episodes were evaluated for responses at 72 hours after the start of treatment and at resolution of the neutropenia. Of the patients with unexplained fever who were given ceftazidime alone, 99 percent were alive at 72 hours and 98 percent were alive when the neutropenia resolved, as compared with 100 percent and 98 percent, respectively, of those given combination therapy. Of the patients with documented infection who were given ceftazidime alone, 98 percent were alive at 72 hours and 89 percent when the neutropenia resolved, as compared with 98 percent and 91 percent, respectively, of those given combination therapy. The majority of episodes of documented infection in both treatment groups necessitated additional antimicrobial treatment or other modifications of the initial regimen, as compared with only 22 percent of the episodes of unexplained fever. We conclude that initial single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment.
TL;DR: The partially deleted gene for the common biosynthetic precursor of gonadotropin-releasing hormone and GnRH-associated peptide is transcriptionally active as revealed by in situ hybridization histochemistry of hpg hypothalamic tissue sections, but immunocytochemical analysis failed to show the presence of antigen corresponding to any part of the precursor protein.
Abstract: Hereditary hypogonadism in the hypogonadal (hpg) mouse is caused by a deletional mutation of at least 33.5 kilobases encompassing the distal half of the gene for the common biosynthetic precursor of gonadotropin-releasing hormone (GnRH) and GnRH-associated peptide (GAP). The partially deleted gene is transcriptionally active as revealed by in situ hybridization histochemistry of hpg hypothalamic tissue sections, but immunocytochemical analysis failed to show the presence of antigen corresponding to any part of the precursor protein.
Journal Article•
TL;DR: The administration of IL 2 produces a dose-limiting VLS that may be mediated, directly or indirectly, by host lymphoid elements and was not observed in nude mice receiving IL 2.
Abstract: Adoptive immunotherapy with lymphokine-activated killer cells and recombinant interleukin 2 (IL 2) can produce significant reduction of visceral metastases in tumor-bearing mice and, as shown recently, in humans with disseminated cancer. Because further dose escalations of IL 2 have been prevented by the development of a vascular leak syndrome (VLS) in both mice and humans, we investigated this VLS in mice undergoing the systemic administration of high-dose IL 2. A model for quantitating capillary permeability was used in which 125I-bovine serum albumin was injected i.v., and 2 hr later, tissues were counted in a gamma analyzer. A permeability index (PI) was calculated by dividing the mean counts per minute (cpm) of tissues from IL 2-treated mice by those from control animals. The injection of IL 2 produced increases in vascular permeability that were most pronounced in the thymus, spleen, lungs, liver, and kidneys (PI = 18.0, 10.0, 9.7, 6.7, and 6.3, respectively, on day 6). The development of the VLS was highly dependent on the number of days of IL 2 treatment (for example, the lungs contained 638, 1382, 3350, and 6187 cpm after 0, 1, 3, and 6 days of IL 2, respectively). Moreover, the degree of the VLS was directly related to the dose of IL 2 administered. Measurement of the wet and dry weights of lungs from IL 2-treated mice demonstrated that IL 2 produced a dramatic increase in their water weight (from 0.10 g at base line to 0.22 g after 200,000 U of IL 2 for 6 days). The injection of the IL 2 excipient failed to induce capillary leakage in tissues. Immunosuppression of mice by pretreatment irradiation (500 rad) or by injection of cyclophosphamide or by concurrent use of cortisone acetate markedly reduced or eliminated the development of the VLS. Similarly, the VLS was not observed in nude mice receiving IL 2. Thus, the administration of IL 2 produces a dose-limiting VLS that may be mediated, directly or indirectly, by host lymphoid elements.
TL;DR: The identification of a selective benzodiazepine antagonist of ethanol-stimulated 36Cl- uptake in vitro that blocks the anxiolytic and intoxicating actions ofanol suggests that many of the neuropharmacologic actions of ethanol may be mediated via central GABA receptors.
Abstract: Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates gamma-aminobutyric (GABA) receptor-mediated uptake of 36Cl-labeled chlorine into isolated brain vesicles. One drug that acts at GABA-benzodiazepine receptors, the imidazobenzodiazepine Ro15-4513, has been found to be a potent antagonist of ethanol-stimulated 36Cl- uptake into brain vesicles, but it fails to antagonize either pentobarbital- or muscimol-stimulated 36Cl- uptake. Pretreatment of rats with Ro15-4513 blocks the anticonflict activity of low doses of ethanol (but not pentobarbital) as well as the behavioral intoxication observed with higher doses of ethanol. The effects of Ro15-4513 in antagonizing ethanol-stimulated 36Cl- uptake and behavior are completely blocked by benzodiazepine receptor antagonists. However, other benzodiazepine receptor inverse agonists fail to antagonize the actions of ethanol in vitro or in vivo, suggesting a novel interaction of Ro15-4513 with the GABA receptor-coupled chloride ion channel complex. The identification of a selective benzodiazepine antagonist of ethanol-stimulated 36Cl- uptake in vitro that blocks the anxiolytic and intoxicating actions of ethanol suggests that many of the neuropharmacologic actions of ethanol may be mediated via central GABA receptors.