Showing papers by "Johns Hopkins University published in 1991"
TL;DR: The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues as mentioned in this paper.
Abstract: Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.
8,063 citations
Journal Article•
TL;DR: A role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage is suggested and a new mechanism for how the loss of wild- type p53 might contribute to tumorigenesis is suggested.
Abstract: The inhibition of replicative DNA synthesis that follows DNA damage may be critical for avoiding genetic lesions that could contribute to cellular transformation. Exposure of ML-1 myeloblastic leukemia cells to nonlethal doses of the DNA damaging agents, gamma-irradiation or actinomycin D, causes a transient inhibition of replicative DNA synthesis via both G1 and G2 arrests. Levels of p53 protein in ML-1 cells and in proliferating normal bone marrow myeloid progenitor cells increase and decrease in temporal association with the G1 arrest. In contrast, the S-phase arrest of ML-1 cells caused by exposure to the anti-metabolite, cytosine arabinoside, which does not directly damage DNA, is not associated with a significant change in p53 protein levels. Caffeine treatment blocks both the G1 arrest and the induction of p53 protein after gamma-irradiation, thus suggesting that blocking the induction of p53 protein may contribute to the previously observed effects of caffeine on cell cycle changes after DNA damage. Unlike ML-1 cells and normal bone marrow myeloid progenitor cells, hematopoietic cells that either lack p53 gene expression or overexpress a mutant form of the p53 gene do not exhibit a G1 arrest after gamma-irradiation; however, the G2 arrest is unaffected by the status of the p53 gene. These results suggest a role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage and thus suggest a new mechanism for how the loss of wild-type p53 might contribute to tumorigenesis.
3,878 citations
TL;DR: The overall predictive accuracy of the first-day APACHE III equation was such that, within 24 h ofICU admission, 95 percent of ICU admissions could be given a risk estimate for hospital death that was within 3 percent of that actually observed.
3,693 citations
TL;DR: These examinations in CHS permit evaluation of CVD risk factors in older adults, particularly in groups previously under-represented in epidemiologic studies, such as women and the very old.
3,631 citations
TL;DR: The APC gene was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein, and these two closely spaced genes encode proteins predicted to contain coiled-coil regions, which were also expressed in a wide variety of tissues.
Abstract: Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers, particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this locus, a portion of the region that is tightly linked to FAP was cloned. Six contiguous stretches of sequence (contigs) containing approximately 5.5 Mb of DNA were isolated. Subclones from these contigs were used to identify and position six genes, all of which were expressed in normal colonic mucosa. Two of these genes (APC and MCC) are likely to contribute to colorectal tumorigenesis. The MCC gene had previously been identified by virtue of its mutation in human colorectal tumors. The APC gene was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein. These two closely spaced genes encode proteins predicted to contain coiled-coil regions. Both genes were also expressed in a wide variety of tissues. Further studies of MCC and APC and their potential interaction should prove useful for understanding colorectal neoplasia.
2,364 citations
TL;DR: Cloning of a complementary DNA for brain nitric oxide synthase reveals recognition sites for NADPH, FAD, flavin mononucleotide and calmodulin as well as phosphorylation sites, indicating that the synthase is regulated by many different factors.
Abstract: Nitric oxide is a messenger molecule, mediating the effect of endothelium-derived relaxing factor in blood vessels and the cytotoxic actions of macrophages, and playing a part in neuronal communication in the brain. Cloning of a complementary DNA for brain nitric oxide synthase reveals recognition sites for NADPH, FAD, flavin mononucleotide and calmodulin as well as phosphorylation sites, indicating that the synthase is regulated by many different factors. The only known mammalian enzyme with close homology is cytochrome P-450 reductase.
2,302 citations
TL;DR: It is established that NO mediates the neurotoxicity of glutamate and Hemoglobin, which complexes NO, prevents neurotoxic effects of both N-methyl-D-aspartate and sodium nitroprusside.
Abstract: Nitric oxide (NO) mediates several biological actions, including relaxation of blood vessels, cytotoxicity of activated macrophages, and formation of cGMP by activation of glutamate receptors in cerebellar slices. Nitric oxide synthase (EC 1.14.23.-) immunoreactivity is colocalized with nicotinamide adenine di-nucleotide phosphate diaphorase in neurons that are uniquely resistant to toxic insults. We show that the nitric oxide synthase inhibitors, N omega-nitro-L-arginine (EC50 = 20 microM) and N omega-monomethyl-L-arginine (EC50 = 170 microM), prevent neurotoxicity elicited by N-methyl-D-aspartate and related excitatory amino acids. This effect is competitively reversed by L-arginine. Depletion of the culture medium of arginine by arginase or arginine-free growth medium completely attenuates N-methyl-D-aspartate toxicity. Sodium nitroprusside, which spontaneously releases NO, produces dose-dependent cell death that parallels cGMP formation. Hemoglobin, which complexes NO, prevents neurotoxic effects of both N-methyl-D-aspartate and sodium nitroprusside. These data establish that NO mediates the neurotoxicity of glutamate.
2,229 citations
TL;DR: Fibrillin is implicate as the protein defective in patients with the Marfan syndrome and a de novo missense mutation in the fibrillin gene is described in two patients with sporadic disease.
Abstract: Marfan syndrome is an inherited disorder of connective tissue manifested in the ocular, skeletal and cardiovascular systems. It is inherited as an autosomal dominant with high penetrance, but has great clinical variability. Linkage studies have mapped the Marfan locus to chromosome 15q15-21.3. There have been no reports of genetic heterogeneity in the syndrome. Following the identification of fibrillin (a glycoprotein component of the extracellular microfibril), immunohistopathological quantification of the protein in skin and fibroblast culture, and examination of fibrillin synthesis, extracellular transport, and incorporation into the extracellular matrix (D. M. Milewicz, R.E.P., E. S. Crawford and P. H. Byers, manuscript in preparation) have demonstrated abnormalities of fibrillin metabolism in most patients. A portion of the complementary DNA encoding fibrillin has been cloned and mapped by in situ hybridization to chromosome 15. Here we report that the fibrillin gene is linked to the Marfan phenotype (theta = 0.00; logarithm of the odds (lod) = 3.9) and describe a de novo missense mutation in the fibrillin gene in two patients with sporadic disease. We thus implicate fibrillin as the protein defective in patients with the Marfan syndrome.
1,899 citations
TL;DR: The data suggest that more than one gene on chromosome 5q21 may contribute to colorectal neoplasia, and that mutations of the APC gene can cause both FAP and GS.
Abstract: Previous studies suggested that one or more genes on chromosome 5q21 are responsible for the inheritance of familial adenomatous polyposis (FAP) and Gardner's syndrome (GS), and contribute to tumor development in patients with noninherited forms of colorectal cancer. Two genes on 5q21 that are tightly linked to FAP (MCC and APC) were found to be somatically altered in tumors from sporadic colorectal cancer patients. One of the genes (APC) was also found to be altered by point mutation in the germ line of FAP and GS patients. These data suggest that more than one gene on chromosome 5q21 may contribute to colorectal neoplasia, and that mutations of the APC gene can cause both FAP and GS. The identification of these genes should aid in understanding the pathogenesis of colorectal neoplasia and in the diagnosis and counseling of patients with inherited predispositions to colorectal cancer.
1,882 citations
TL;DR: The identity of neuronal NO synthase and NADPH diaphorase suggests a role for NO in modulating neurotoxicity, and is in line with previous work on neuronal messenger molecules.
Abstract: NADPH diaphorase staining neurons, uniquely resistant to toxic insults and neurodegenerative disorders, have been colocalized with neurons in the brain and peripheral tissue containing nitric oxide synthase (EC 11423-), which generates nitric oxide (NO), a recently identified neuronal messenger molecule In the corpus striatum and cerebral cortex, NO synthase immunoreactivity and NADPH diaphorase staining are colocalized in medium to large aspiny neurons These same neurons colocalize with somatostatin and neuropeptide Y immunoreactivity NO synthase immunoreactivity and NADPH diaphorase staining are colocalized in the pedunculopontine nucleus with choline acetyltransferase-containing cells and are also colocalized in amacrine cells of the inner nuclear layer and ganglion cells of the retina, myenteric plexus neurons of the intestine, and ganglion cells of the adrenal medulla Transfection of human kidney cells with NO synthase cDNA elicits NADPH diaphorase staining The ratio of NO synthase to NADPH diaphorase staining in the transfected cells is the same as in neurons, indicating that NO synthase fully accounts for observed NADPH staining The identity of neuronal NO synthase and NADPH diaphorase suggests a role for NO in modulating neurotoxicity
1,836 citations
TL;DR: This paper examined the relationship between family structure and children's achievement in high school and found that children who live with single parents or stepparents during adolescence received less encouragement and less help with school work than children who lived with both natural parents, and parental involvement has positive effects on children's school achievement.
Abstract: Integrating ideas from child development with sociological models of educational attainment, the AA. examine the relationship between family structure―whether both parents are present in the household―and children's achievement in high school. Using data from the High School and Beyond study, sophomore cohort, 1986, they ask whether differences in achievement are accounted for by differences in parents' educational aspirations and parenting styles. Children who live with single parents or stepparents during adolescence receive less encouragement and less help with school work than children who live with both natural parents, and parental involvement has positive effects on children's school achievement. Differences in parental behavior, however, account for little of the difference in educational attainment between children from intact and nonintact families
TL;DR: Black Americans are at higher risk of primary open-angle glaucoma than their white neighbors, which may reflect an underlying genetic susceptibility to this disease and indicates that additional efforts are needed to identify and treat this sight-threatening disorder in high-risk communities.
Abstract: Objective. —To compare the prevalence of primary open-angle glaucoma between black and white Americans. Design, Setting, and Participants. —The design was a population-based prevalence survey of a noninstitutionalized black and white population aged 40 years or older from the eastern and southeastern health districts of Baltimore, Md. A multistage random sampling strategy was used to identify 7104 eligible participants, of whom 5308 (2395 blacks, 2913 whites) received an ophthalmologic screening examination. Those with abnormalities were referred for definitive diagnostic evaluation. Main Outcome Measure. —Primary open-angle glaucoma was defined based on evidence of glaucomatous optic nerve damage, including abnormal visual fields and/or severe optic disc cupping, and was independent of intraocular pressure. Main Results. —Age-adjusted prevalence rates for primary open-angle glaucoma were four to five times higher in blacks as compared with whites. Rates among blacks ranged from 1.23% in those aged 40 through 49 years to 11.26% in those 80 years or older, whereas rates for whites ranged from 0.92% to 2.16%, respectively. There was no difference in rates of primary open-angle glaucoma between men and women for either blacks or whites in this population. Based on these data, an estimated 1.6 million persons aged 40 years or older in the United States have primary open-angle glaucoma. Conclusions. —Black Americans are at higher risk of primary open-angle glaucoma than their white neighbors. This may reflect an underlying genetic susceptibility to this disease and indicates that additional efforts are needed to identify and treat this sight-threatening disorder in high-risk communities. ( JAMA . 1991;266:369-374)
Duke University1, University of North Carolina at Chapel Hill2, University of Pittsburgh3, Vanderbilt University4, University of South Florida5, University of Virginia6, Memorial Sloan Kettering Cancer Center7, St. Elizabeth's Medical Center8, Virginia Mason Medical Center9, Johns Hopkins University10, Medical College of Wisconsin11, University of Chicago12, Stanford University13, Amgen14, University of California, Los Angeles15
TL;DR: A randomized clinical trial to test the hypothesis that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer and the clinical implications.
Abstract: Background. Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. Methods. Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, <1.0×l09 per liter, with a temperature ≥38.2°C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. The patients were randomly assigned to receive either placebo or G-CSF, with treatment beginning on day 4 and continuing through day 17 of a 21 -day cycle. Results. The safety of the study treatment could be evaluated in 207 of the 211 pa...
TL;DR: Data seem to implicate malignant cytology as a serious adverse finding, especially with respect to the risk for regional/distant and abdominal failure, in patients with negative surgical-pathological risk factors.
TL;DR: In this article, the authors identified mutant strains of S. cerevisiae that fail to properly arrest their cell cycles at mitosis in response to the loss of microtubule function.
TL;DR: Results confirmed that IOP is an important factor in glaucoma, but did not support the traditional distinction between "normal" and "elevated" pressure, nor its corollaries, "low-tension" glau coma and "high-tensions" glAUcoma.
Abstract: A detailed ocular examination, including perimetry, was conducted on 5308 black and white subjects aged 40 years and older in a population-based prevalence survey in east Baltimore, Md. Repeated, detailed examinations were carried out on selected subjects. Roughly half of all subjects with optic nerve damage from primary open angle glaucoma, regardless of race, were unaware that they had the condition. The average intraocular pressure (IOP) among black patients with glaucoma who were receiving treatment was virtually identical to that in those black patients who were not receiving treatment (median IOP, 20 mm Hg); treated eyes of white patients had a lower IOP than those eyes of white patients who were not receiving treatment (mean [+/- SD] IOP, 18.69 +/- 3.23 mm Hg vs 24.15 +/- 5.23 mm Hg; P less than .001). The risk of glaucomatous optic nerve damage increased with the height of the screening IOP, particularly at levels of 22 to 29 and 30 mm Hg and above (relative rate compared with IOP of 15 mm Hg or lower, 12.8 and 40.1 mm Hg, respectively). More than half of all glaucomatous eyes had a screening IOP below 21 mm Hg, whether these eyes were receiving treatment or not. The IOP in glaucomatous eyes tended to rise on follow-up, in contrast with nonglaucomatous eyes in which the IOP was as likely to rise as to fall. Results confirmed that IOP is an important factor in glaucoma, but did not support the traditional distinction between "normal" and "elevated" pressure, nor its corollaries, "low-tension" glaucoma and "high-tension" glaucoma.
TL;DR: Nerve fiber layer defects expanded with time, often by the development and coalescence of adjacent areas of damage, and field defects closely corresponded, but nerve fiber layer loss was generally more widespread.
Abstract: • Standardized perimetry and nerve fiber layer and color fundus photography were performed annually on 1344 eyes with elevated intraocular pressures. In 83 eyes, glaucomatous field defects developed that met rigid criteria on manual kinetic and suprathreshold static perimetry. Individual nerve fiber layer photographs were read by two masked observers. The more sensitive of the two identified nerve fiber layer defects in 88% of readable photographs at the time field loss first occurred; 60% (6/10) of eyes already had nerve fiber layer defects 6 years before field loss. In contrast, the nerve fiber layer was considered abnormal in only 11% (3/27) of normal eyes and 26% (84/327) of hypertensive eyes. The location of nerve fiber layer and field defects closely corresponded, but nerve fiber layer loss was generally more widespread. Examiner experience and severity of optic nerve damage influenced results. Mild focal defects were more readily recognized than more severe diffuse atrophy. Nerve fiber layer defects expanded with time, often by the development and coalescence of adjacent areas of damage.
TL;DR: Evidence is presented for the validity of the Contemplation Ladder, a measure of readiness to consider smoking cessation, and its ability to distinguish between groups known a priori to differ in readiness.
Abstract: Presents evidence for the validity of the Contemplation Ladder, a measure of readiness to consider smoking cessation. Analyses of data collected from more than 400 smokers at two worksites before and during a 10-month intervention indicate that Ladder scores were significantly associated with reported intention to quit, number of previous quit attempts, perceived co-worker encouragement to quit, and socioeconomic status. Ladder scores predicted subsequent participation in programs designed to educate workers about their smoking habit and its contingent risks. The Ladder did not predict biochemically validated abstinence of 24 hr or more. To assess its ability to distinguish between groups known a priori to differ in readiness, we administered the Ladder to 36 participants in a clinic-based smoking cessation program. As predicted, clinic patients scored significantly higher than the workers on the Ladder. The importance of distinguishing between smokers at the lowest stages of readiness to quit is discussed.
TL;DR: This paper examined the connections between school programs of parent involvement, teachers' attitudes, and the practices that teachers use to involve parents of their own students in inner-city elementary and middle schools.
Abstract: This study uses data from 171 teachers in 8 inner-city elementary and middle schools to examine the connections between school programs of parent involvement, teachers' attitudes, and the practices that teachers use to involve parents of their own students. Patterns are examined at 2 levels of schooling (elementary and middle), in different academic subjects, under various classroom organizations (self-contained, semi-departmentalized, departmentalized), and under different levels of shared support for parent involvement by the teachers and significant other groups. Each of these variables has important implications for the types and strengths of school programs and teachers' practices of parent involvement. The results add to the validation of Epstein's typology of 5 types of school and family connections. The data used in this study were collected as the first step in a 3-year action research process in which the sampled schools are engaged. The process is outlined in terms that any school can follow to...
TL;DR: The results clarify the roles of these genetically defined receptor proteins in cholinergic transmission in brain and suggest that m2 was also present in noncholinergic cortical and subcortical structures, providing evidence that this subtype may presynaptically modulate release of other neurotransmitters and/or function postsynaptically.
Abstract: mRNAs encoding five genetically distinct muscarinic ACh receptors are present in the CNS. Because of their pharmacological similarities, it has not been possible to detect the individual encoded proteins; thus, their physiological functions are not well defined. To characterize the family of proteins, a panel of subtype-selective antibodies was generated against recombinant muscarinic receptor proteins and shown to bind specifically to each of the cloned receptors. Using immunoprecipitation, three receptor proteins (m1, m2, and m4) accounted for the vast majority of the total solubilized muscarinic binding sites in rat brain. These receptor subtypes had marked differences in regional and cellular localization as shown by immunocytochemistry. The m1-protein was present in cortex and striatum and was localized to cell bodies and neurites, consistent with its role as a major postsynaptic muscarinic receptor. The m2-receptor protein was abundant in basal forebrain, scattered striatal neurons, mesopontine tegmentum, and cranial motor nuclei; this distribution is similar to that of cholinergic neurons and suggests that m2 is an autoreceptor. However, m2 was also present in noncholinergic cortical and subcortical structures, providing evidence that this subtype may presynaptically modulate release of other neurotransmitters and/or function postsynaptically. The m4-receptor was enriched in neostriatum, olfactory tubercle, and islands of Calleja, indicating an important role in extrapyramidal function. These results clarify the roles of these genetically defined receptor proteins in cholinergic transmission in brain.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: This is the second in a series of three papers that empirically examine the competitiveness of simulated annealing in certain well-studied domains of combinatorial optimization.
Abstract: This is the second in a series of three papers that empirically examine the competitiveness of simulated annealing in certain well-studied domains of combinatorial optimization. Simulated annealing is a randomized technique proposed by S. Kirkpatrick, C. D. Gelatt and M. P. Vecchi for improving local optimization algorithms. Here we report on experiments at adapting simulated annealing to graph coloring and number partitioning, two problems for which local optimization had not previously been thought suitable. For graph coloring, we report on three simulated annealing schemes, all of which can dominate traditional techniques for certain types of graphs, at least when large amounts of computing time are available. For number partitioning, simulated annealing is not competitive with the differencing algorithm of N. Karmarkar and R. M. Karp, except on relatively small instances. Moreover, if running time is taken into account, natural annealing schemes cannot even outperform multiple random runs of the local optimization algorithms on which they are based, in sharp contrast to the observed performance of annealing on other problems.
TL;DR: Several adaptive filter structures are proposed for noise cancellation and arrhythmia detection and an adaptive recurrent filter structure is proposed for acquiring the impulse response of the normal QRS complex.
Abstract: Several adaptive filter structures are proposed for noise cancellation and arrhythmia detection. The adaptive filter essentially minimizes the mean-squared error between a primary input, which is the noisy electrocardiogram (ECG), and a reference input, which is either noise that is correlated in some way with the noise in the primary input or a signal that is correlated only with ECG in the primary input. Different filter structures are presented to eliminate the diverse forms of noise: baseline wander, 60 Hz power line interference, muscle noise, and motion artifact. An adaptive recurrent filter structure is proposed for acquiring the impulse response of the normal QRS complex. The primary input of the filter is the ECG signal to be analyzed, while the reference input is an impulse train coincident with the QRS complexes. This method is applied to several arrhythmia detection problems: detection of P-waves, premature ventricular complexes, and recognition of conduction block, atrial fibrillation, and paced rhythm. >
TL;DR: The p53 mutations are the first genetic alterations demonstrated to occur in a high proportion of primary invasive bladder cancers, and Detection of such mutations ex vivo has clinical implications for monitoring individuals whose tumor cells are shed extracorporeally.
Abstract: Although bladder cancers are very common, little is known about their molecular pathogenesis. In this study, invasive bladder cancers were evaluated for the presence of gene mutations in the p53 suppressor gene. Of 18 tumors evaluated, 11 (61 percent) were found to have genetic alterations of p53. The alterations included ten point mutations resulting in single amino acid substitutions, and one 24-base pair deletion. In all but one case, the mutations were associated with chromosome 17p allelic deletions, leaving the cells with only mutant forms of the p53 gene products. Through the use of the polymerase chain reaction and oligomer-specific hybridization, p53 mutations were identified in 1 to 7 percent of the cells within the urine sediment of each of three patients tested. The p53 mutations are the first genetic alterations demonstrated to occur in a high proportion of primary invasive bladder cancers. Detection of such mutations ex vivo has clinical implications for monitoring individuals whose tumor cells are shed extracorporeally.
TL;DR: Multivariable-adjusted odds ratios point to differences of considerable magnitude in the risk of carotid atherosclerosis between groups defined by clinical and public health-oriented risk factor cut-points.
Abstract: To assess whether carotid atherosclerosis measured by B-mode ultrasound is related to cardiovascular risk factors, 386 cases with carotid artery wall thickening and an equal number of controls free of arterial intima-media thickening were drawn from the cohort of the Atherosclerosis Risk in Communities (ARIC) Study examined in four communities in the United States between 1988 and 1990. Cases and controls were individually matched on sex, race, age group, study center, and date of examination. The mean values of total cholesterol, low density lipoprotein (LDL) cholesterol, total triglyceride, blood pressure, and pack-years of cigarette smoking were higher in cases than controls. Mean high density lipoprotein (HDL) cholesterol was lower in cases than controls. Case-control differences were all statistically significant. Multivariable-adjusted odds ratios point to differences of considerable magnitude in the risk of carotid atherosclerosis between groups defined by clinical and public health-oriented risk factor cut-points.
TL;DR: This article cast the generalized linear random effects model in a Bayesian framework and use a Monte Carlo method, the Gibbs sampler, to overcome the current computational limitations, which is flexible to easily accommodate changes in the number of observations.
Abstract: Generalized linear models have unified the approach to regression for a wide variety of discrete, continuous, and censored response variables that can be assumed to be independent across experimental units. In applications such as longitudinal studies, genetic studies of families, and survey sampling, observations may be obtained in clusters. Responses from the same cluster cannot be assumed to be independent. With linear models, correlation has been effectively modeled by assuming there are cluster-specific random effects that derive from an underlying mixing distribution. Extensions of generalized linear models to include random effects has, thus far, been hampered by the need for numerical integration to evaluate likelihoods. In this article, we cast the generalized linear random effects model in a Bayesian framework and use a Monte Carlo method, the Gibbs sampler, to overcome the current computational limitations. The resulting algorithm is flexible to easily accommodate changes in the number...
TL;DR: This work presents a heuristic for clinical research in which the measurement of attention is essential, and substitutes for the diffuse and global concept of “attention” a group of four processes and links them to a putative system of cerebral structures.
Abstract: A model for conceptualizing the components or elements of attention is presented. The model substitutes for the diffuse and global concept of “attention” a group of four processes and links them to a putative system of cerebral structures. Data in support of the model are presented; they are derived from neuropsychological test scores obtained from two samples, the first consisting of 203 adult neuropsychiatric patients and normal control subjects, and the second, an epidemiologically-based sample of 435 elementary school children. Principal components analyses of test scores from these two populations yielded similar results: a set of independent elements of attention that are assayed by different tests. This work presents a heuristic for clinical research in which the measurement of attention is essential.
TL;DR: Effective treatment with 91 percent survival is available for patients with TTP-HUS, and treatment with aspirin and dipyridamole was effective in those with a poor response to plasma exchange.
Abstract: Background and Methods. Thrombotic thrombocytopenic purpura—hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, central nervous system abnormalities, and renal dysfunction. In early reports the mortality approached 100 percent. A treatment protocol was introduced in 1979 for patients admitted to Johns Hopkins Hospital with the diagnosis of TTP-HUS. Treatment regimens included 200 mg of prednisone a day, for patients with minimal symptoms and no central nervous system symptoms, and prednisone plus plasma exchange, for patients with rapid clinical deterioration who did not improve after 48 hours of prednisone alone and for patients presenting with central nervous system symptoms and rapidly declining hematocrit values and platelet counts. Results. A total of 108 patients were treated, and 91 percent survived. Prednisone alone was judged to be effective in 30 patients with mild TTP-HUS (2 relapses and 2 deaths). Plasma exchange plus pre...
TL;DR: Established parental tumors could be cured by the systemic immune response generated by injection of the genetically engineered tumors by providing a rationale for the use of lymphokine gene-transfected tumor cells as a modality for cancer therapy.
Abstract: The generation of antigen-specific antitumor immunity is the ultimate goal in cancer immunotherapy. When cells from a spontaneously arising murine renal cell tumor were engineered to secrete large doses of interleukin-4 (IL-4) locally, they were rejected in a predominantly T cell-independent manner. However, animals that rejected the IL-4-transfected tumors developed T cell-dependent systemic immunity to the parental tumor. This systemic immunity was tumor-specific and primarily mediated by CD8+ T cells. Established parental tumors could be cured by the systemic immune response generated by injection of the genetically engineered tumors. These results provide a rationale for the use of lymphokine gene-transfected tumor cells as a modality for cancer therapy.
Centers for Disease Control and Prevention1, Johns Hopkins University2, University of Rochester3, Georgetown University4, University of Minnesota5, University of Pennsylvania6, Harvard University7, University of California, Los Angeles8, National Institutes of Health9, University of Pittsburgh10, Northwestern University11, University of California, San Diego12, World Health Organization13, University College London14, Columbia University15, Max Planck Society16
TL;DR: These definitions have been developed in conjunction with the International Classification of Diseases-10 (ICD-10, unpublished draft of the World Health Organization) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, unpublishedDraft of the American Psychiatric Association) and are not identical.
Abstract: Infection with human immunodeficiency virus-type 1 (HIV-1) has been associated with avariety of neurologic disorders thought to be caused, directly or indirectly, by HIV-1.1-6 Although these disorders have been described clinically, there is no consensus terminology or criteria for diagnosis. To develop consensus nomenclature and case definitions for HIV-1-associated neurologic conditions for research purposes, the American Academy of Neurology AIDS Task Force convened a working group of neurologists, neuropsychologists, psychiatrists, and sociologists that included representatives of the American Neurological Association, the World Federation of Neurology, the International Neuropsychological Society, the National Academy of Neuropsychology, the American Psychological Association, the American Psychiatric Association, the World Health Organization, and the Centers for Disease Control (CDC). These definitions have been developed in conjunction with the International Classification of Diseases-10 (ICD-10, unpublished draft of the World Health Organization) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, unpublished draft of the American Psychiatric Association). Although consistent with the ICD-10, the definitions are not identical. HIV-2 may cause similar disorders, but the neurologic manifestations of HIV-2 are unknown and are not addressed in this article.
TL;DR: Analysis of the deduced amino acid sequence suggests that CHIP28 protein contains six bilayer-spanning domains, two exofacial potential N-glycosylation sites, and intracellular N and C termini.
Abstract: CHIP28 is a 28-kDa integral membrane protein with similarities to membrane channels and is found in erythrocytes and renal tubules. A cDNA for CHIP28 was isolated from human fetal liver cDNA template by a three-step polymerase chain reaction (PCR) cloning strategy, starting with degenerate oligonucleotide primers corresponding to the N-terminal amino acid sequence determined from purified CHIP28 protein. Using the third-step PCR product as a probe, we isolated a recombinant from a human bone marrow cDNA library. The combined sequence of the PCR products and bone marrow cDNA contains 38 base pairs of 5' untranslated nucleotide sequence, an 807-bp open reading frame, and approximately 2 kilobases of 3' untranslated sequence containing a polyadenylation signal. This corresponds to the 3.1-kilobase transcript identified by RNA blot-hybridization analysis. Authenticity of the deduced amino acid sequence of the CHIP28 protein C terminus was confirmed by expression and immunoblotting. Analysis of the deduced amino acid sequence suggests that CHIP28 protein contains six bilayer-spanning domains, two exofacial potential N-glycosylation sites, and intracellular N and C termini. Search of the DNA sequence data base revealed a strong homology with the major intrinsic protein of bovine lens, which is the prototype of an ancient but recently recognized family of membrane channels. These proteins are believed to form channels permeable to water and possibly other small molecules. CHIP28 shares homology with all known members of this channel family, and it is speculated that CHIP28 has a similar function.