Showing papers by "National Institutes of Health published in 1989"
TL;DR: A fatigue severity scale was internally consistent, correlated well with visual analogue measures, clearly differentiated controls from patients, and could detect clinically predicted changes in fatigue over time and identify features that distinguish fatigue between two chronic medical disorders.
Abstract: • Fatigue is a prominent disabling symptom in a variety of medical and neurologic disorders. To facilitate research in this area, we developed a fatigue severity scale, subjected it to tests of internal consistency and validity, and used it to compare fatigue in two chronic conditions: systemic lupus erythematosus and multiple sclerosis. Administration of the fatigue severity scale to 25 patients with multiple sclerosis, 29 patients with systemic lupus erythematosus, and 20 healthy adults revealed that the fatigue severity scale was internally consistent, correlated well with visual analogue measures, clearly differentiated controls from patients, and could detect clinically predicted changes in fatigue over time. Fatigue had a greater deleterious impact on daily living in patients with multiple sclerosis and systemic lupus erythematosus compared with controls. The results further showed that fatigue was largely independent of self-reported depressive symptoms and that several characteristics could differentiate fatigue that accompanies multiple sclerosis from fatigue that accompanies systemic lupus erythematosus. This study demonstrates (1) the clinical and research applications of a scale that measures fatigue severity and (2) helps to identify features that distinguish fatigue between two chronic medical disorders.
4,974 citations
TL;DR: Assays of ten blood transfusions in the United States that resulted in chronic NANBH revealed that there was at least one positive blood donor in nine of these cases and that all ten recipients seroconverted during their illnesses.
Abstract: A specific assay has been developed for a blood-borne non-A, non-B hepatitis (NANBH) virus in which a polypeptide synthesized in recombinant yeast clones of the hepatitis C virus (HCV) is used to capture circulating viral antibodies. HCV antibodies were detected in six of seven human sera that were shown previously to transmit NANBH to chimpanzees. Assays of ten blood transfusions in the United States that resulted in chronic NANBH revealed that there was at least one positive blood donor in nine of these cases and that all ten recipients seroconverted during their illnesses. About 80 percent of chronic, post-transfusion NANBH (PT-NANBH) patients from Italy and Japan had circulating HCV antibody; a much lower frequency (15 percent) was observed in acute, resolving infections. In addition, 58 percent of NANBH patients from the United States with no identifiable source of parenteral exposure to the virus were also positive for HCV antibody. These data indicate that HCV is a major cause of NANBH throughout the world.
3,198 citations
TL;DR: A consistent inverse relation of high-density lipoprotein cholesterol levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies.
Abstract: The British Regional Heart Study (BRHS) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol (HDLC) and incidence of coronary heart disease was eliminated by covariance adjustment. Using the proportional hazards model and adjusting for age, blood pressure, smoking, body mass index, and low-density lipoprotein cholesterol, we analyzed this relation separately in the Framingham Heart Study (FHS), Lipid Research Clinics Prevalence Mortality Follow-up Study (LRCF) and Coronary Primary Prevention Trial (CPPT), and Multiple Risk Factor Intervention Trial (MRFIT). In CPPT and MRFIT (both randomized trials in middle-age high-risk men), only the control groups were analyzed. A 1-mg/dl (0.026 mM) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2% in men (FHS, CPPT, and MRFIT) and 3% in women (FHS). In LRCF, where only fatal outcomes were documented, a 1-mg/dl increment in HDLC was associated with significant 3.7% (men) and 4.7% (women) decrements in cardiovascular disease mortality rates. The 95% confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably, and all contained the range 1.9-2.9%. HDLC levels were essentially unrelated to non-cardiovascular disease mortality. When differences in analytic methodology were eliminated, a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies.
3,149 citations
TL;DR: Several transcribed sequences and conserved segments were identified in this cloned region and one corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.
Abstract: An understanding of the basic defect in the inherited disorder cystic fibrosis requires cloning of the cystic fibrosis gene and definition of its protein product. In the absence of direct functional information, chromosomal map position is a guide for locating the gene. Chromosome walking and jumping and complementary DNA hybridization were used to isolate DNA sequences, encompassing more than 500,000 base pairs, from the cystic fibrosis region on the long arm of human chromosome 7. Several transcribed sequences and conserved segments were identified in this cloned region. One of these corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.
3,050 citations
TL;DR: As part of the National Institute of Mental Health Epidemiologic Catchment Area study, 7954 respondents were questioned at baseline and 1 year later about sleep complaints and psychiatric symptoms using the Diagnostic Interview Schedule.
Abstract: As part of the National Institute of Mental Health Epidemiologic Catchment Area study, 7954 respondents were questioned at baseline and 1 year later about sleep complaints and psychiatric symptoms using the Diagnostic Interview Schedule. Of this community sample, 10.2% and 3.2% noted insomnia and hypersomnia, respectively, at the first interview. Forty percent of those with insomnia and 46.5% of those with hypersomnia had a psychiatric disorder compared with 16.4% of those with no sleep complaints. The risk of developing new major depression was much higher in those who had insomnia at both interviews compared with those without insomnia (odds ratio, 39.8; 95% confidence interval, 19.8 to 80.0). The risk of developing new major depression was much less for those who had insomnia that had resolved by the second visit (odds ratio, 1.6; 95% confidence interval, 0.5 to 5.3). Further research is needed to determine if early recognition and treatment of sleep disturbances can prevent future psychiatric disorders.
2,658 citations
TL;DR: There was limited evidence of the specific effectiveness of interpersonal psychotherapy and none for cognitive behavior therapy, but Superior recovery rates were found for both interpersonal Psychotherapy and imipramine plusclinical management, as compared with placebo plus clinical management.
Abstract: • We investigated the effectiveness of two brief psychotherapies, interpersonal psychotherapy and cognitive behavior therapy, for the treatment of outpatients with major depressive disorder diagnosed by Research Diagnostic Criteria. Two hundred fifty patients were randomly assigned to one of four 16-week treatment conditions: interpersonal psychotherapy, cognitive behavior therapy, imipramine hydrochloride plus clinical management (as a standard reference treatment), and placebo plus clinical management. Patients in all treatments showed signifi-cant reduction in depressive symptoms and improvement in functioning over the course of treatment. There was a consistent ordering of treatments at termination, with imipramine plus clinical management generally doing best, placebo plus clinical management worst, and the two psychotherapies in between but generally closer to imipramine plus clinical management. In analyses carried out on the total samples without regard to initial severity of illness (the primary analyses), there was no evidence of greater effectiveness of one of the psychotherapies as compared with the other and no evidence that either of the psychotherapies was significantly less effective than the standard reference treatment, imipramine plus clinical management. Comparing each of the psychotherapies with the placebo plus clinical management condition, there was limited evidence of the specific effectiveness of interpersonal psychotherapy and none for cognitive behavior therapy. Superior recovery rates were found for both interpersonal psychotherapy and imipramine plus clinical management, as compared with placebo plus clinical management. On mean scores, however, there were few significant differences in effectiveness among the four treatments in the primary analyses. Secondary analyses, in which patients were dichotomized on intial level of severity of depressive symptoms and impairment of functioning, helped to explain the relative lack of significant findings in the primary analyses. Significant differences among treatments were present only for the subgroup of patients who were more severely depressed and functionally impaired; here, there was some evidence of the effectiveness of interpersonal psychotherapy with these patients and strong evidence of the effectiveness of imipramine plus clinical management. In contrast, there were no significant differences among treatments, including placebo plus clinical management, for the less severely depressed and functionally impaired patients.
2,171 citations
TL;DR: The use of novel two-dimensional nuclear magnetic resonance (NMR) pulse sequences to provide insight into protein dynamics is described, suggesting that there is no correlation between these rapid small amplitude motions and secondary structure for S. Nase.
Abstract: This paper describes the use of novel two-dimensional nuclear magnetic resonance (NMR) pulse sequences to provide insight into protein dynamics. The sequences developed permit the measurement of the relaxation properties of individual nuclei in macromolecules, thereby providing a powerful experimental approach to the study of local protein mobility. For isotopically labeled macromolecules, the sequences enable measurements of heteronuclear nuclear Overhauser effects (NOE) and spin-lattice (T1) and spin-spin (T2) 15N or 13C relaxation times with a sensitivity similar to those of many homonuclear 1H experiments. Because T1 values and heteronuclear NOEs are sensitive to high-frequency motions (10(8)-10(12) s-1) while T2 values are also a function of much slower processes, it is possible to explore dynamic events occurring over a large time scale. We have applied these techniques to investigate the backbone dynamics of the protein staphylococcal nuclease (S. Nase) complexed with thymidine 3',5'-bisphosphate (pdTp) and Ca2+ and labeled uniformly with 15N. T1, T2, and NOE values were obtained for over 100 assigned backbone amide nitrogens in the protein. Values of the order parameter (S), characterizing the extent of rapid 1H-15N bond motions, have been determined. These results suggest that there is no correlation between these rapid small amplitude motions and secondary structure for S. Nase. In contrast, 15N line widths suggest a possible correlation between secondary structure and motions on the millisecond time scale. In particular, the loop region between residues 42 and 56 appears to be considerably more flexible on this slow time scale than the rest of the protein.
1,760 citations
TL;DR: A simple, one-step procedure for the preparation of competent Escherichia coli that uses a transformation and storage solution and can be frozen in TSS without addition of other components.
Abstract: We have developed a simple, one-step procedure for the preparation of competent Escherichia coli that uses a transformation and storage solution [TSS; 1 x TSS is LB broth containing 10% (wt/vol) polyethylene glycol, 5% (vol/vol) dimethyl sulfoxide, and 50 mM Mg2+ at pH 6.5]. Cells are mixed with an equal volume of ice-cold 2 x TSS and are immediately ready for use. Genetic transformation is equally simple: plasmid DNA is added and the cells are incubated for 5-60 min at 4 degrees C. A heat pulse is not necessary and the incubation time at 4 degrees C is not crucial, so there are no critical timing steps in the transformation procedure. Transformed bacteria are grown and selected by standard methods. Thus, this procedure eliminates the centrifugation, washing, and long-term incubation steps of current methods. Although cells taken early in the growth cycle (OD600 0.3-0.4) yield the highest transformation efficiencies (10(7)-10(8) transformants per micrograms of plasmid DNA), cells harvested at other stages in the growth cycle (including stationary phase) are capable of undergoing transformation (10(5)-10(7) transformants per micrograms of DNA). For long-term storage of competent cells, bacteria can be frozen in TSS without addition of other components. Our procedure represents a simple and convenient method for the preparation, transformation, and storage of competent bacterial cells.
1,681 citations
TL;DR: It is suggested that BFA disrupts a dynamic membrane-recycling pathway between the ER and cis/medial Golgi, effectively blocking membrane transport out of but not back to the ER.
1,655 citations
TL;DR: There is a small repertoire of main-chain conformations for at least five of the six hypervariable regions of antibodies, and that the particular conformation adopted is determined by a few key conserved residues.
Abstract: On the basis of comparative studies of known antibody structures and sequences it has been argued that there is a small repertoire of main-chain conformations for at least five of the six hypervariable regions of antibodies, and that the particular conformation adopted is determined by a few key conserved residues. These hypotheses are now supported by reasonably successful predictions of the structures of most hypervariable regions of various antibodies, as revealed by comparison with their subsequently determined structures.
1,576 citations
TL;DR: Etude du controle de la proliferation des lymphocytes T par les cellules presentant l'antigene, examen des signaux biologiques and biochimiques impliques dans ce mecanisme.
Abstract: Etude du controle de la proliferation des lymphocytes T par les cellules presentant l'antigene. Examen des signaux biologiques et biochimiques impliques dans ce mecanisme. Proposition d'un modele permettant d'expliquer les phenomenes
TL;DR: The potency for inhibition of the NMDA-activated current by several alcohols is linearly related to their intoxicating potency, suggesting that alcohol-induced inhibition of responses to NMDA receptor activation may contribute to the neural and cognitive impairments associated with intoxication.
Abstract: The ion current induced by the glutamate receptor agonist N-methyl-D-aspartate (NMDA) in voltage-clamped hippocampal neurons was inhibited by ethanol (EtOH). Inhibition increased in a concentration-dependent manner over the range 5 to 50 mM, a range that also produces intoxication. The amplitude of the NMDA-activated current was reduced 61 percent by 50 mM EtOH; in contrast, this concentration of EtOH reduced the amplitude of current activated by the glutamate receptor agonists kainate and quisqualate by only 18 and 15 percent, respectively. The potency for inhibition of the NMDA-activated current by several alcohols is linearly related to their intoxicating potency, suggesting that alcohol-induced inhibition of responses to NMDA receptor activation may contribute to the neural and cognitive impairments associated with intoxication.
TL;DR: Treatment with le uprolide and flutamide is superior to treatment with leuprolide alone in patients with advanced prostate cancer, and Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade.
Abstract: To test the hypothesis that maximal androgen blockade improves the effectiveness of the treatment of prostatic cancer, we conducted a randomized, double-blind trial in patients with disseminated, previously untreated prostate cancer (stage D2). All 603 men received leuprolide, an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins, in combination with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. As compared with the 300 patients receiving leuprolide and placebo, the 303 patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival (16.5 vs. 13.9 months; P = 0.039) and an increase in the median length of survival (35.6 vs. 28.3 months; P = 0.035). The differences between the treatments were particularly evident for men with minimal disease and good performance status; however, further studies should be conducted in this subgroup. Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade, when leuprolide alone often produces a painful flare in the disease. We conclude that in patients with advanced prostate cancer, treatment with leuprolide and flutamide is superior to treatment with leuprolide alone.
TL;DR: These results indicate that the HIV-1 rev gene product induces HIV- 1 structural gene expression by activating the sequence-specific nuclear export of incompletely spliced HIV-2 RNA species.
Abstract: HUMAN immunodeficiency virus type 1 (HIV-1) replication requires the expression of two classes of viral mRNA. The early class of HIV-1 transcripts is fully spliced and encodes viral regulatory gene products. The functional expression of one of these nuclear regulatory proteins, termed Rev (formerly Art or Trs), induces the cytoplasmic expression of the incompletely spliced, late class of HIV-1 mRNAs that encode the viral structural proteins, including Gag and Env1–6. Here, we provide evidence that this induction reflects the export from the cell nucleus to the cytoplasm of a pool of unspliced viral RNA constitutively expressed in the nucleus. The hypothesis that Rev acts on RNA transport, rather than splicing, is further supported by the observation that the cytoplasmic expression of a non-spliceable HIV-1 env gene sequence is also subject to Rev regulation. Here we show that this Rev response requires a specific target sequence which coincides with a complex RNA secondary structure present in the env gene. The response to Rev is fully maintained when this sequence is relocated to other exonic or intronic locations within env but is ablated by inversion. These results indicate that the HIV-1 rev gene product induces HIV-1 structural gene expression by activating the sequence-specific nuclear export of incompletely spliced HIV-1 RNA species.
TL;DR: Evaluation of MDR1 gene expression may prove to be a valuable tool in the identification of individuals whose cancers are resistant to specific agents, and the information may be useful in designing or altering chemotherapeutic protocols in these patients.
Abstract: Chemotherapy has proven to be an effective treatment for the cure and palliation of some human cancers (Chabner, 1982). Some tumors, however, appear to be intrinsically resistant to chemotherapy. For cancers that can be treated with chemotherapy, based on the hypothesis that resistance to single agents occurs with high frequency, protocols involving multiple drugs with different intracellular targets have been designed. In many cases, such as acute lymphocytic leukemia and neuroblastoma (Simone et al., 1982), Hodgkin’s disease (De-Vita and Hellman, 1982), and germ cell cancers (Paulson et al., 1982), dramatic results have been achieved with such protocols. However, all too frequently relapse occurs after such therapy and the recurrent tumors are resistant to further chemotherapy. In effect, such tumors develop a multidrug resistance (MDR) phenotype that is very similar to the intrinsic resistance of some primary cancers.
TL;DR: It is concluded that interferon alfa therapy is beneficial in reducing disease activity in chronic hepatitis C; however, the beneficial responses are often transient.
Abstract: Infection with the hepatitis C virus may result in chronic liver disease for which no effective therapy is now available. We studied the effects of recombinant human interferon alfa in a prospective, randomized, double-blind, placebo-controlled trial in patients with well-documented chronic hepatitis C. Forty-one patients were enrolled in the trial, 37 of whom were later found to have antibody to hepatitis C virus. Twenty-one patients received interferon alfa (2 million units) subcutaneously three times weekly for six months, and 20 received placebo. The mean serum aminotransferase levels and the histologic features of the liver improved significantly in the patients treated with interferon but not in the patients given placebo. Ten patients treated with interferon (48 percent) had a complete response, defined as a decline in mean serum aminotransferase levels to the normal range during therapy; three others had a decrease in mean aminotransferase levels of more than 50 percent. After treatment e...
TL;DR: These findings, coupled with the previous demonstration of 17p allele loss in lung cancer, strongly implicate p53 as an anti-oncogene whose disruption is involved in the pathogenesis of human lung cancer.
Abstract: Allele loss is a hallmark of chromosome regions harboring recessive oncogenes. Lung cancer frequently demonstrates loss of heterozygosity on 17p. Recent evidence suggests that the p53 gene located on 17p13 has many features of such an antioncogene. The p53 gene was frequently mutated or inactivated in all types of human lung cancer. The genetic abnormalities of p53 include gross changes such as homozygous deletions and abnormally sized messenger RNAs along with a variety of point or small mutations, which map to the p53 open reading frame and change amino acid sequence in a region highly conserved between mouse and man. In addition, very low or absent expression of p53 messenger RNA in lung cancer cell lines compared to normal lung was seen. These findings, coupled with the previous demonstration of 17p allele loss in lung cancer, strongly implicate p53 as an anti-oncogene whose disruption is involved in the pathogenesis of human lung cancer.
TL;DR: It is shown that cross-linkage of FcεRI on a series of non-transformed murine mast cell lines, or treatment of these cells with calcium ionophores, stimulates increased messenger RNA levels and secretion of a group of lymphokines classically produced by a subset of murine T cell lines (TH2cells).
Abstract: The cross-linkage of high affinity Fc epsilon receptors (Fc epsilon RI) on mast cells and basophils is central to the induction of allergic inflammatory responses. As a result of such cross-linkage, mast cells secrete a variety of preformed biologically active substances, such as histamine, and newly synthesized arachidonic acid metabolites. Here we show that cross-linkage of Fc epsilon RI on a series of nontransformed murine mast cell lines, or treatment of these cells with calcium ionophores, stimulates increased messenger RNA levels and secretion of a group of lymphokines classically produced by a subset of murine T cell lines (TH2 cells). These factors include interleukin-3 (a mast cell growth factor)s interleukin-4 (an IgE 'switch factor'), interleukin-5 (an eosinophil differentiation factor) and interleukin-6 (a factor controlling immunoglobulin secretion). The production of these polypeptide factors by mast cells may have great importance in the induction of allergic and anti-parasite inflammatory responses.
TL;DR: A stochastic, finite population model is developed that describes the steady state effect of hitchhiking on the distribution of the number of selectively neutral polymorphic sites in a random sample.
Abstract: The number of selectively neutral polymorphic sites in a random sample of genes can be affected by ancestral selectively favored substitutions at linked loci. The degree to which this happens depends on when in the history of the sample the selected substitutions happen, the strength of selection and the amount of crossing over between the sampled locus and the loci at which the selected substitutions occur. This phenomenon is commonly called hitchhiking. Using the coalescent process for a random sample of genes from a selectively neutral locus that is linked to a locus at which selection is taking place, a stochastic, finite population model is developed that describes the steady state effect of hitchhiking on the distribution of the number of selectively neutral polymorphic sites in a random sample. A prediction of the model is that, in regions of low crossing over, strongly selected substitutions in the history of the sample can substantially reduce the number of polymorphic sites in a random sample of genes from that expected under a neutral model.
TL;DR: It is concluded that the administration of endotoxin to normal subjects causes a depression ofleft ventricular function that is independent of changes in left ventricular volume or vascular resistance, and suggests that endotoxin is a major mediator of the cardiovascular dysfunction in this condition.
Abstract: Marked abnormalities in cardiovascular function accompany septic shock, and bacterial endotoxin is believed to be one of the principal mediators of these abnormalities. To evaluate the cardiovascular effects of endotoxemia in humans, we measured hemodynamic variables in nine normal subjects given an intravenous bolus dose of endotoxin (Escherichia coli, 4 ng per kilogram of body weight) and in six normal subjects given a bolus dose of saline, before and three hours after administration. All the subjects then underwent volume loading with normal saline (mean, 2217 ml) during the fourth and fifth hours after administration of the bolus, and the measurements were repeated. Three hours after the administration of endotoxin and before volume loading, the cardiac index had increased by 53 percent and the heart rate by 36 percent (both changes were significant; P less than or equal to 0.008), and the systemic vascular-resistance index had decreased by 46 percent (P = 0.004). After volume loading (five hours after the administration of endotoxin), the left ventricular ejection fraction decreased by 1 percent of the base-line value in the subjects given endotoxin, but increased by 14 percent in the controls (P = 0.008). The left ventricular end-diastolic and end-systolic volume indexes increased by 18 percent (P = 0.07) and 24 percent (P = 0.042), respectively. Left ventricular performance, as measured by the ratio of the peak systolic pressure to the end-systolic volume index, was depressed (a decrease of 0.90 in the subjects given endotoxin vs. an increase of 0.76 in the controls; P = 0.024). We conclude that the administration of endotoxin to normal subjects causes a depression of left ventricular function that is independent of changes in left ventricular volume or vascular resistance. The changes in function are similar to those observed in septic shock and suggest that endotoxin is a major mediator of the cardiovascular dysfunction in this condition.
TL;DR: In this paper, the comportement energetique des bicouches lipidiques avec description des methodes permettant de mesurer les forces entre molecules lipidiques.
TL;DR: T lymphocyte chemotactic factor was purified to homogeneity from the conditioned media of phytohemagglutinin-stimulated human blood mononuclear leukocytes and the amino-terminal amino acid sequence of the purified TCF showed identity with neutrophil-activating protein (NAP-1).
Abstract: T lymphocyte chemotactic factor (TCF) was purified to homogeneity from the conditioned media of phytohemagglutinin-stimulated human blood mononuclear leukocytes by a sequence of chromatography procedures. The amino-terminal amino acid sequence of the purified TCF showed identity with neutrophil-activating protein (NAP-1). Both TCF and recombinant NAP-1 (rNAP-1) were chemotactic for neutrophils and T lymphocytes in vitro supporting the identity of TCF with NAP-1. Injection of rNAP-1 into lymphatic drainage areas of lymph nodes in Fisher rats caused accelerated emigration of only lymphocytes in high endothelial venules. Intradermal injection of rNAP-1 caused dose-dependent accumulation of neutrophils and lymphocytes.
TL;DR: The light and electron microscopic structure of lobar bronchial biopsies taken at fiberoptic bronchoscopy from 11 atopic asthmatics, four of which were symptomatic and seven of whom were asymptomatic, was studied to study the structural changes in mild asthma.
Abstract: Little is known of the structural changes in mild asthma We have studied the light and electron microscopic structure of lobar bronchial biopsies taken at fiberoptic bronchoscopy from 11 atopic asthmatics, four of whom were symptomatic and seven of whom were asymptomatic The former and three of the latter had bronchial hyperresponsiveness to methacholine (PC20 < 4 mg/ml) Quantitative comparisons were made with biopsies from ten control subjects with normal airway reactivity; five had hay fever and five were nonatopic healthy volunteers Complete absence of surface epithelium was found in three cases of symptomatic asthma, and stratified squamous epithelium was present in the fourth A biopsy from one of the healthy control subjects had also lost its surface epithelium The degree of epithelial loss in all subjects correlated with the degree of airway reactivity (rs = 067, p < 0001) The reticular lamina of the epithelial basement membrane showed a trend toward thickening in the seven hyperreactive as
TL;DR: The isolation, sequence and expression of a complementary DNA clone encoding the membrane form of guanylate cyclase from rat brain are reported, which represents a new class of mammalian cell-surface receptors which contain an extracellular ligand-binding domain and an intracellular guanyl cyclase catalytic domain.
Abstract: ATRIAL natriuretic peptide (ANP) is a polypeptide hormone whose effects include the induction of diuresis, natriuresis and vasorelaxation1. One of the earliest events following binding of ANP to receptors on target cells is an increase in cyclic GMP concentration, indicating that this nucleotide might act as a mediator of the physiological effects of the hormone2,3. Guanylate cyclase exists in at least two different molecular forms: a soluble haem-containing enzyme consisting of two summits4,5 and a non-haem-containing transmembrane protein having a single subunit6. It is the membrane form of guanylate cyclase that is activated following binding of ANP to target cells3,7,8. We report here the isolation, sequence and expression of a complementary DNA clone encoding the membrane form of guanylate cyclase from rat brain. Transfec-tion of this cDNA into cultured mammalian cells results in expression of guanylate cyclase activity and ANP-binding activity. The ANP receptor/guanylate cyclase represents a new class of mammalian cell-surface receptors which contain an extracellular ligand-binding domain and an intracellular guanylate cyclase catalytic domain.
TL;DR: It is demonstrated that a purely immunologic manipulation can mediate the regression of advanced cancers in selected patients and may provide a base for the development of practical, effective biologic treatments for some cancer patients.
Abstract: We have administered 1039 courses of high-dose interleukin-2 (IL-2) to 652 cancer patients. Five hundred ninety-six patients had metastatic cancer that either had failed standard effective therapies or had disease for which no standard effective therapy existed, and 56 patients were treated in the absence of evaluable disease in the adjuvant setting. IL-2 was administered either alone (155 patients) or in conjunction with activated immune cells such as lymphokine activated killer (LAK) cells (214 patients) or tumor infiltrating lymphocytes (TIL) (66 patients), with other cytokines such as alpha interferon (a-IFN)(128 patients) or tumor necrosis factor (TNF)(38 patients), with monoclonal antibodies (32 patients), or with the chemotherapeutic agent cyclophosphamide (19 patients). Initial results with the treatment of high-dose IL-2 alone or in conjunction with LAK cells have indicated that objective regressions of cancer can be achieved in 20% to 35% of patients with selected advanced metastatic cancers. Although most responses have been seen in patients with metastatic renal cell cancer, melanoma, colorectal cancer, and non-Hodgkin's lymphoma, many histologic types of cancer have not been treated in significant numbers. These regressions can be durable; of 18 patients achieving a complete response, ten have not experienced recurrence at intervals from 18 to 52 months. Although combinations of IL-2 with TNF do not appear to result in increased responses, there is a suggestion in our initial phase I studies that the combination of a-IFN and IL-2 is more effective than the administration of cytokine alone and this combination deserves further study. Similarly the adoptive transfer of TIL in conjunction with IL-2 also appears to be more effective than the use of IL-2 alone. The toxic side effects in patients treated with high-dose IL-2 are presented and include malaise, nausea and vomiting, hypotension, fluid retention, and organ dysfunction. Treatment-related deaths were seen in 1% of all treatment courses and in 1.5% of patients. These studies demonstrate that a purely immunologic manipulation can mediate the regression of advanced cancers in selected patients and may provide a base for the development of practical, effective biologic treatments for some cancer patients.
TL;DR: This study developed a key methodological tool, the mean graph, which allowed the transformation of the numerical cell line response data into graphic patterns that were particularly expressive of differential cell growth inhibition.
Abstract: The objective of this study was to develop and investigate an approach to optimally detect, rank, display, and analyze patterns of differential growth inhibition among cultured cell lines. Such patterns of cellular responsiveness are produced by substances tested in vitro against disease-oriented panels of human tumor cell lines in a new anticancer screening model under development by the National Cancer Institute. In the first phase of the study, we developed a key methodological tool, the mean graph, which allowed the transformation of the numerical cell line response data into graphic patterns. These patterns were particularly expressive of differential cell growth inhibition and were conveniently amenable to further analyses by an algorithm we devised and implemented in the COMPARE computer program.
TL;DR: A newly-constructed antibody-like molecule containing the gp!20-binding domain of the receptor for human immunodeficiency virus blocks HIV-1 infection of T cells and monocytes, making it a good candidate for therapeutic use.
Abstract: A newly-constructed antibody-like molecule containing the gp120-binding domain of the receptor for human immunodeficiency virus blocks HIV-1 infection of T cells and monocytes. Its long plasma half-life, other antibody-like properties, and potential to block all HIV isolates, make it a good candidate for therapeutic use.
TL;DR: The data suggest that Jung's theory is either incorrect or inadequately operationalized by the MBTI and cannot provide a sound basis for interpreting it, but correlational analyses showed that the four MBTI indices did measure aspects of four of the five major dimensions of normal personality.
Abstract: The Myers-Briggs Type Indicator (MBTI, Myers & McCaulley, 1985) was evaluated from the perspectives of Jung's theory of psychological types and the five-factor model of personality as measured by self-reports and peer ratings on the NEO Personality Inventory (NEO-PI, Costa & McCrae, 1985b) Data were provided by 267 men and 201 women ages 19 to 93 Consistent with earlier research and evaluations, there was no support for the view that the MBTI measures truly dichotomous preferences or qualitatively distinct types, instead, the instrument measures four relatively independent dimensions The interpretation of the Judging-Perceiving index was also called into question The data suggest that Jung's theory is either incorrect or inadequately operationalized by the MBTI and cannot provide a sound basis for interpreting it However, correlational analyses showed that the four MBTI indices did measure aspects of four of the five major dimensions of normal personality The five-factor model provides an alternative basis for interpreting MBTI findings within a broader, more commonly shared conceptual framework
TL;DR: It is concluded that HPV16 E6 and E7 cooperative to immortalize human keratinocytes in vitro with an efficiency similar to that of the entire early region of the viral DNA.
Abstract: The human papillomavirus types (HPVs) most often associated with cancer of the cervix, such as HPV16, have been reported previously to immortalize normal human foreskin keratinocytes in vitro, while the types that are primarily associated with benign cervical lesions failed to do so. In this study we have determined the HPV16 genes that are responsible for the immortalizing activity of the viral genome. Transfection with a plasmid in which E6 and E7 were the only intact open reading frames (ORFs) induced an indefinite life-span in the keratinocytes with an efficiency similar to that of the entire early region of the viral DNA. Mutants in the E6E7 clone with inactivating lesions in E6 or E7 failed to induce immortalization. When transfected alone, E7 could induce hyperproliferation, but these cells eventually senesced. By itself, E6 exhibited no activity, Co-transfection of a plasmid with an intact E6 ORF and a second plasmid with an intact E7 ORF generated keratinocyte lines with indefinite growth potential. The E6 and E7 proteins were detected in the lines induced by the E6E7 DNA and by co-transfection of the E6 and E7 plasmids. Therefore, we conclude that HPV16 E6 and E7 cooperative to immortalize human keratinocytes in vitro. Changes in cellular gene expression are probably also required for immortalization since all of the keratinocyte lines examined were aneuploid. Serum and calcium resistant sublines were isolated from the E6E7 induced lines, indicating that other HPV genes do not play an obligatory role in the generation of resistance to differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)