Showing papers by "University of Zurich published in 1993"
TL;DR: These experiments show that PrPC, possibly at close to normal levels, is required for the usual susceptibility to scrapie and that lack of homology between incoming prions and the host's PrP genes retards disease.
2,075 citations
TL;DR: Mutant mice offer the possibility for the further elucidation of IFN-gamma-mediated functions by transgenic cell- or tissue-specific reconstitution of a functional receptor.
Abstract: Interferon-gamma (IFN-gamma) exerts pleiotropic effects, including antiviral activity, stimulation of macrophages and natural killer cells, and increased expression of major histocompatibility complex antigens. Mice without the IFN-gamma receptor had no overt anomalies, and their immune system appeared to develop normally. However, mutant mice had a defective natural resistance, they had increased susceptibility to infection by Listeria monocytogenes and vaccinia virus despite normal cytotoxic and T helper cell responses. Immunoglobulin isotype analysis revealed that IFN-gamma is necessary for a normal antigen-specific immunoglobulin G2a response. These mutant mice offer the possibility for the further elucidation of IFN-gamma-mediated functions by transgenic cell- or tissue-specific reconstitution of a functional receptor.
1,583 citations
TL;DR: The new edition of the World Health Organization (WHO) book on ‘Histological Typing of Tumours of the Central Nervous System’ reflects the progress in brain tumour classification which has been achieved since publication of the first edition in 1979.
Abstract: The new edition of the World Health Organization (WHO) book on 'Histological Typing of Tumours of the Central Nervous System' reflects the progress in brain tumour classification which has been achieved since publication of the first edition in 1979. Several new tumour entities have been added, including the pleomorphic xanthoastrocytoma, central neurocytoma, the infantile desmoplastic astrocytoma/ganglioglioma, and the dysembryoplastic neuroepithelial tumour. The list of histological variants has also been expanded. In line with recent morphological and molecular data on glioma progression, the glioblastoma is now grouped together with astrocytic tumours. The classification of childhood tumours has been largely retained, the diagnosis primitive neuroectodermal tumour (PNET) only being recommended as a generic term for cerebellar medulloblastomas and neoplasms that are histologically indistinguishable from medulloblastoma but located in the CNS at sites other than the cerebellum. The WHO grading scheme was revised and adapted to new entities but its use, as before, remains optional.
1,532 citations
TL;DR: A multicenter historical cohort study of 2015 subjects with chronic pancreatitis who were recruited from clinical centers in six countries finds that pancreatitis may be a risk factor for pancreatic cancer, but the magnitude of the relation between these two diseases is unclear.
Abstract: Background The results of case-control studies and anecdotal reports suggest that pancreatitis may be a risk factor for pancreatic cancer, but there have been no studies of sufficient size and power to assess the magnitude of the relation between these two diseases. Methods and Results We undertook a multicenter historical cohort study of 2015 subjects with chronic pancreatitis who were recruited from clinical centers in six countries. A total of 56 cancers were identified among these patients during a mean (±SD) follow-up of 7.4 ±6.2 years. The expected number of cases of cancer calculated from country-specific incidence data and adjusted for age and sex was 2.13, yielding a standardized incidence ratio (the ratio of observed to expected cases) of 26.3 (95 percent confidence interval, 19.9 to 34.2). For subjects with a minimum of two or five years of follow-up, the respective standardized incidence ratios were 16.5 (95 percent confidence interval, 11.1 to 23.7) and 14.4 (95 percent confidence interval, 8...
1,528 citations
TL;DR: It is reported here that mice homozygous for a disrupted Tnfr l allele (Tnfr1 0) are resistant to the lethal effect of low doses of lipopolysaccharide after sensitization with D-galactosamine, but remain sensitive to high doses oflipopoly Saccharide.
Abstract: Tumour necrosis factor (TNF), jointly referring to TNF alpha and TNF beta, is a central mediator of immune and inflammatory responses; its activities are mediated by two distinct receptors, TNFR1 (p55) and TNFR2 (p75) (reviewed in refs 1-3). The cytoplasmic domains of the TNFRs are unrelated, suggesting that they link to different intracellular signalling pathways. Although most TNF responses have been assigned to one or the other of the TNF receptors (mostly TNFR1), there is no generally accepted model for the physiological role of the two receptor types. To investigate the role of TNFR1 in beneficial and detrimental activities of TNF, we generated TNFR1-deficient mice by gene targeting. We report here that mice homozygous for a disrupted Tnfr1 allele (Tnfr1(0)) are resistant to the lethal effect of low doses of lipopolysaccharide after sensitization with D-galactosamine, but remain sensitive to high doses of lipopolysaccharide. The increased susceptibility of Tnfr1(0)/Tnfr1(0) mutant mice to infection with the facultative intracellular bacterium Listeria monocytogenes indicates an essential role of TNF in nonspecific immunity.
1,283 citations
TL;DR: It is concluded that IL-4 is required for the generation of the Th2-derived cytokines and that immune responses dependent on these cytokines are impaired.
Abstract: Murine T-helper clones are classified into two distinct subsets (Th1 and Th2) on the basis of their patterns of lymphokine secretion. Th1 clones secrete interleukin-2 (IL-2), tumour necrosis factor-beta (TNF-beta) and interferon-gamma (IFN-gamma), whereas Th2 clones secrete IL-4, IL-5 and IL-10 (ref. 1). These subsets are reciprocally regulated by IL-4, IL-10 and IFN-gamma and differentially promote antibody or delayed-type hypersensitivity responses. To evaluate whether IL-4 is required for mounting Th2 responses, we generated IL-4-mutant mice (IL-4-/-) and assessed the cytokine secretion pattern of T cells both from naive and Nippostrongylus brasiliensis infected mice. CD4+ T cells from naive IL-4-/- mice failed to produce Th2-derived cytokines after in vitro stimulation. The levels of Th2 cytokines IL-5, IL-9 and IL-10 from CD4+ T cells obtained after nematode infection were significantly reduced. The reduced IL-5 production in IL-4-/- mice correlated with reduced helminth-induced eosinophilia, which has been shown to be dependent on IL-5 in vivo. We conclude that IL-4 is required for the generation of the Th2-derived cytokines and that immune responses dependent on these cytokines are impaired.
1,222 citations
TL;DR: A simple non-radioactive in situ hybridization procedure for tissue sections and cultured cells using digoxigenin-labelled cRNA probes for the detection of various transcripts present at a wide range of expression levels in the central nervous system is developed.
Abstract: We have developed a simple non-radioactive in situ hybridization procedure for tissue sections and cultured cells using digoxigenin-labelled cRNA probes. This protocol can be applied for the detection of various transcripts present at a wide range of expression levels in the central nervous system. Cerebellar hybridization signals for transcripts estimated to be expressed at high (MBP, myelin basic protein), moderate (GluR1, subunit of AMPA/kainate sensitive glutamate receptors) and low (inositol polyphosphate-5-phosphatase) levels of abundance are demonstrated as examples. The sensitivity and cellular resolution were significantly improved by avoiding any ethanol treatment commonly used in other procedures. The localization of a labelled cell with respect to its environment is shown to be more easily assessed by counterstaining of the tissue with the nuclear dye Hoechst 33258. The present protocol can be combined with immunocytochemistry as demonstrated for glial fibrillary acidic protein (GFAP). All steps of the procedure, including preparation and labelling of the cRNA probes, pretreatment of tissue, hybridization and visualization of the labelled transcripts, are described in detail.
1,175 citations
TL;DR: The results illustrate that partially and sequen-tially induced (protective) immunity or complete exhaustion of T-cell immunity (high zone tolerance) are quantitatively different points on the scale of immunity; some viruses exploit the latter possibility to persist in an immunocompetent host.
Abstract: Viruses that are non- or poorly cytopathic have developed various strategies to avoid elimination by the immune system and to persist in the host. Acute infection of adult mice with the noncytopathic lymphocytic choriomeningitis virus (LCMV) normally induces a protective cytotoxic T-cell response that also causes immunopathology. But some LCMV strains (such as DOCILE (LCMV-D) or Cl-13 Armstrong (Cl-13)) derived from virus carrier mice tend to persist after acute infection of adult mice without causing lethal immunopathological disease. Tendency to persist correlates with tropism, rapidity of virus spread and virus mutations. We report here that these LCMV isolates may persist because they induce most of the specific antiviral CD8+ cytotoxic T cells so completely that they all disappear within a few days and therefore neither eliminate the virus nor cause lethal immunopathology. The results illustrate that partially and sequentially induced (protective) immunity or complete exhaustion of T-cell immunity (high zone tolerance) are quantitatively different points on the scale of immunity; some viruses exploit the latter possibility to persist in an immunocompetent host.
1,140 citations
TL;DR: It is demonstrated that mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), two inherited conditions characterized by altered calcium homeostasis.
997 citations
01 Jan 1993
TL;DR: In this article, the authors describe some of the recent developments in the mathematical theory of linear and quasilinear elliptic and parabolic systems with nonhomogeneous boundary conditions.
Abstract: It is the purpose of this paper to describe some of the recent developments in the mathematical theory of linear and quasilinear elliptic and parabolic systems with nonhomogeneous boundary conditions. For illustration we use the relatively simple set-up of reaction-diffusion systems which are — on the one h and — typical for the whole class of systems to which the general theory applies and — on the other h and — still simple enough to be easily described without too many technicalities. In addition, quasilinear reaction-diffusion equations are of great importance in applications and of actual mathematical and physical interest, as is witnessed by the examples we include.
704 citations
TL;DR: In VSV-G (IND) transgenic mice, B cells were unresponsive to the poorly organized VSV -G (ind) present as self antigen but responded promptly to the same antigen presented in the highly organized form.
Abstract: The influence of antigen epitope density and order on B cell induction and antibody production was assessed with the glycoprotein of vesicular stomatitis virus serotype Indiana [VSV-G (IND)]. VSV-G (IND) can be found in a highly repetitive form the envelope of VSV-IND and in a poorly organized form on the surface of infected cells. In VSV-G (IND) transgenic mice, B cells were unresponsive to the poorly organized VSV-G (IND) present as self antigen but responded promptly to the same antigen presented in the highly organized form. Thus, antigen organization influences B cell tolerance.
TL;DR: Results suggest that drk binds autophosphorylated receptor tyrosine kinases with its SH2 domain and the Sos GNRP through its SH3 domains, thereby coupling receptor tyrose kinases to Ras activation.
TL;DR: Normal in vivo immune responses in IL-2-deficient mice question the importance of IL-1 as defined by in vitro studies.
Abstract: The role of costimulatory signals in T cell induction was evaluated in mice lacking the interleukin-2 (IL-2) gene. In vitro secondary antiviral T cell responses were absent unless IL-2 was added, confirming the crucial role of IL-2 in vitro. In vivo, primary and secondary cytotoxic T cell responses against vaccinia and lymphocytic choriomeningitis virus were within normal ranges. B cell reactivity to vesicular stomatitis virus was not impaired. T helper cell responses were delayed but biologically functional. Natural killer cell activity was markedly reduced but inducible. These normal in vivo immune responses in IL-2-deficient mice question the importance of IL-2 as defined by in vitro studies.
TL;DR: The simulations demonstrate that the concept of sleep homeostasis as proposed in the two-process model of sleep regulation can be refined to account in quantitative terms for empirical data and to predict the changes induced by the prolongation of waking or sleep.
TL;DR: On the basis of the comprehensive alignment, a new numbering of amino acid residues applicable to aminotransferases (AT) in general is proposed, and in the multiply aligned sequences, only four out of a total of about 400 amino acids residues proved invariant in all 51 sequences.
Abstract: A total of 150 amino acid sequences of vitamin B6-dependent enzymes are known to date, the largest contingent being furnished by the aminotransferases with 51 sequences of 14 different enzymes. All aminotransferase sequences were aligned by using algorithms for sequence comparison, hydropathy patterns and secondary structure predictions. The aminotransferases could be divided into four subgroups on the basis of their mutual structural relatedness. Subgroup I comprises aspartate, alanine, tyrosine, histidinol-phosphate, and phenylalanine aminotransferases; subgroup II acetylornithine, ornithine, omega-amino acid, 4-aminobutyrate and diaminopelargonate aminotransferases; subgroup III D-alanine and branched-chain amino acid aminotransferases, and subgroup IV serine and phosphoserine aminotransferases. (N-1) Profile analysis, a more stringent application of profile analysis [Gribskov, M., McLachlan, A. D. and Eisenberg, D. (1987) Proc. Natl Acad. Sci. USA 84, 4355-4358], established the homology among the enzymes of each subgroup as well as among all subgroups except subgroup III. However, similarity of active-site segments and the hydropathy patterns around invariant residues suggest that subgroup III, though most distantly related, might also be homologous with the other aminotransferases. On the basis of the comprehensive alignment, a new numbering of amino acid residues applicable to aminotransferases (AT) in general is proposed. In the multiply aligned sequences, only four out of a total of about 400 amino acid residues proved invariant in all 51 sequences, i.e. Gly(314AT)197, Asp/Glu(340AT)222, Lys(385AT)258 and Arg(562AT)386, the number not in parentheses corresponding to the structure of porcine cytosolic aspartate aminotransferase. Apparently, the aminotransferases constitute a group of homologous proteins which diverged into subgroups and, with some exceptions, into substrate-specific individual enzymes already in the universal ancestor cell.
TL;DR: The amounts of MTF‐1‐DNA complexes are elevated several‐fold in zinc‐treated cells, as measured by bandshift assay, and the presence of an MRE‐binding factor is found in HeLa cell nuclear extracts.
Abstract: Metallothioneins (MTs) are small cysteine-rich proteins whose structure is conserved from fungi to man. MTs strongly bind heavy metals, notably zinc, copper and cadmium. Upon exposure of cells to heavy metal and other adverse treatments, MT gene transcription is strongly enhanced. Metal induction is mediated by several copies of a 15 bp consensus sequence (metal-responsive element, MRE) present in the promoter region of MT genes. We and others have demonstrated the presence of an MRE-binding factor in HeLa cell nuclear extracts. We found that this factor, termed MTF-1 (MRE-binding transcription factor) is inactivated/reactivated in vitro by zinc withdrawal/addition. Here we report that the amounts of MTF-1-DNA complexes are elevated several-fold in zinc-treated cells, as measured by bandshift assay. We have also cloned the cDNA of mouse MTF-1, a 72.5 kDa protein. MTF-1 contains six zinc fingers and separate transcriptional activation domains with high contents of acidic and proline residues. Ectopic expression of MTF-1 in primate or rodent cells strongly enhances transcription of a reporter gene that is driven by four consensus MREd sites, or by the complete mouse MT-I promoter, even at normal zinc levels.
TL;DR: It is concluded that the structurally identified two closely related proteins most likely involved in human and rat renal brush border Na/Pi cotransport.
Abstract: We have isolated two cDNA clones, NaPi-2 and NaPi-3, by screening rat kidney cortex and human kidney cortex cDNA libraries, respectively, for expression of sodium-dependent phosphate transport in Xenopus laevis oocytes. Substrate specificity and a detailed kinetic analysis (Na, Pi, H+ concentrations) suggested that expressed uptake activities relate to proximal tubular brush border membrane Na/Pi cotransport. NaPi-2 cDNA contains 2464 bp encoding a protein of 637 aa; NaPi-3 cDNA contains 2573 bp encoding a protein of 639 aa. NaPi-2- and NaPi-3-deduced protein sequences show high homology to each other but are different from the protein sequence deduced from the previously cloned NaPi-1 cDNA (from rabbit proximal tubules). Hydropathy profile predictions suggest at least eight membrane-spanning regions in NaPi-2/3-related proteins. In vitro translation results in proteins of the expected size and suggests glycosylation. Northern blot analysis shows corresponding mRNA species (approximately 2.7 kb) in kidney cortex of various species but no hybridization with RNAs isolated from a variety of other tissues (including intestinal segments); a hybridization signal (approximately 4.8 kb) was observed only in the lung (human). We conclude that we have structurally identified two closely related proteins most likely involved in human and rat renal brush border Na/Pi cotransport.
TL;DR: Pax genes encode a class of highly conserved transcription factors containing a paired-domain that play important roles in Drosophila and vertebrate development, for example, in segmentation and neurogenesis.
TL;DR: Examining 74 glioblastomas from 67 patients for loss of heterozygosity on chromosomes 10 and 17, and for amplification of the epidermal growth factor receptor gene, suggests the division of gliOBlastoma into genetic subsets.
Abstract: Glioblastoma multiforme is a clinically and histologically heterogeneous lesion; however, to date, it has not been possible to subdivide glioblastomas on a clinical, histopathological or biological basis. Previous studies have demonstrated that loss of portions of chromosomes 10 and 17 and amplification of the epidermal growth factor receptor (EGFR) gene are the most frequent genetic alterations in glioblastoma. We therefore examined 74 glioblastomas from 67 patients for loss of heterozygosity on chromosomes 10 and 17, and for amplification of the epidermal growth factor receptor gene, to determine whether glioblastomas can be subtyped on a genetic basis. Using Southern blot analysis we were able to detect different patterns of genomic alterations. Eighteen of 67 informative patients were characterized by a loss of heterozygosity on the short arm of chromosome 17 in the tumor tissue. Forty-five of 64 informative patients showed a loss of heterozygosity on chromosome 10. Amplification of the epidermal growth factor receptor gene was noted in 25 of 67 patients and was restricted to those glioblastomas that had lost portions of chromosome 10. Epidermal growth factor receptor gene amplification occurred significantly more often in patients without chromosome 17p loss than in patients with chromosome 17p loss (p = 0.01). In addition, those glioblastomas with a loss of chromosome 17p occurred in patients significantly younger than those with glioblastomas characterized by EGFR gene amplification (p = 0.001). These data emphasize the genetic heterogeneity of glioblastoma and suggest the division of glioblastoma into genetic subsets.
TL;DR: In this article, the QCD-corrected effective hamiltonian for the b → se+e− and b → sγ decays is evaluated including the next-to-leading logarithmic effects which considerably weaken the qCD corrections to both decays.
TL;DR: It appears that in humans, the inducible high-output NOS is not conserved as an antimicrobial system of macrophages.
Abstract: Nitric oxide synthase (NOS) has received immense interest as an antimicrobial and antitumoral effector system of mononuclear phagocytes from rodents. Because there is increasing doubt that an analogous system exists in human macrophages, NOS was reexamined in these cells. Under tightly controlled conditions, with murine macrophages as positive controls, human macrophages failed to secrete nitric oxide (< 0.1 mumol/10(6) cells/24 h), even after activation with endotoxin, interferon-gamma, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, bacteria, or proliferating lymphocytes. The discrepancy between murine and human macrophages depended on neither the anatomic source (blood, peritoneum), the agent used for activation, nor the duration of activation. NOS activity was paralleled by metabolization of L-arginine to L-citrulline. Exogenous tetrahydrobiopterin, an essential cofactor of NOS not synthesized by human macrophages, did not support NOS activity in human macrophages. Also, no NOS activity was found in cellular subfractions of human macrophages. It appears that in humans, the inducible high-output NOS is not conserved as an antimicrobial system of macrophages.
TL;DR: Although the origin of the simian primates is obscure, new fossil evidence could push it further back by at least 10 million years, reflecting the low sampling level of the primate fossil record, which can potentially also lead to underestimation of times of origin within thePrimate tree.
Abstract: Recent discoveries of fossil primate specimens have produced several surprises and challenged prevailing views of early primate evolution. Plesiadapiformes, long regarded as 'archaic primates', may perhaps be linked to the peculiar colugos instead. Inferred relationships of the earliest known undoubted primates (adapids and omomyids) are in turmoil. Both groups have been proposed as sources for the simian primates. Although the origin of the simian primates is obscure, new fossil evidence could push it further back by at least 10 million years. Such uncertainties reflect the low sampling level of the primate fossil record, which can potentially also lead to underestimation of times of origin within the primate tree.
TL;DR: Recent studies in the hippocampus provide new insights into the mechanisms by which the activation of these receptors leads to presynaptic inhibition of transmitter release, and characterize the second messengers involved in couplingpresynaptic receptors to their effectors.
TL;DR: In this article, four radiometric correction methods for the reduction of slope-aspect effects in a Landsat TM data set are tested in a mountainous test site with regard to their physical soundness and their influence on forest classification, as well as on the visual appearance of the scene.
Abstract: Four radiometric correction methods for the reduction of slope-aspect effects in a Landsat TM data set are tested in a mountainous test site with regard to their physical soundness and their influence on forest classification, as well as on the visual appearance of the scene. Excellent ground reference information and a fine-resolution DEM allowed precise assessment of the applicability of the methods under investigation. The results of the study presented here demonstrate the weakness of the classical cosine correction method for radiometric correction in rugged terrain. The statistical, Minnaert and C-correction approaches, however, yielded an improvement of the forest classification and an impressive reduction of the visual topography effect.
TL;DR: Between July 1989 and June 1991, 312 patients with blunt thoracic or abdominal injuries were examined prospectively and pathologic findings were demonstrated sonographically in 113 cases, with positive clinical findings and negative sonographic examination results.
Abstract: Between July 1989 and June 1991, 312 patients with blunt thoracic or abdominal injuries were examined prospectively. Sonographic examination was performed by surgeons in the emergency room using a mobile ultrasound unit. In 113 (36.2%) cases pathologic findings were demonstrated sonographically. These included 47 cases of hemothorax, 11 pericardial effusions, 52 cases of intra-abdominal fluid, 24 lesions of intra-abdominal organs, and 10 cases of retroperitoneal hematoma. Physical examination findings were positive in 96 (30.8%), negative in 63 (20.2%), and equivocal in 153 (49.0%). Two hundred thirty-nine patients had between one and eight injuries in addition to the blunt abdominal or thoracic trauma. These patients had an average Injury Severity Score (ISS) of 19.9 (range, 1 to 75). The 73 patients with isolated blunt trauma of the thorax or abdomen had an ISS of 4.9 (range, 0-25). None of the 66 patients (21.2%) with positive clinical findings and negative sonographic examination results had to be operated on later in the course of treatment, while 5 (36%) of 14 patients (4.5%) with negative physical examination findings and positive sonographic findings had to undergo surgery. The sensitivity for the demonstration of intra-abdominal fluid and organ lesions was 98.1% and 41.4%, respectively. The overall sensitivity and specificity of the ultrasonic examination were 90.0% and 99.5%, respectively.
01 Apr 1993
TL;DR: This paper investigates the definition, detection, and management of events in the active object-oriented database system SAMOS, and presents various event specification facilities based on simple but nevertheless powerful constructs which support the modelling of time aspects.
Abstract: In this paper we investigate the definition, detection, and management of events in the active object-oriented database system SAMOS. First, we present various event specification facilities based on simple but nevertheless powerful constructs which support the modelling of time aspects as well. Second we show how events can be detected in an efficient way. Finally, we deal with the internal representation of events using the benefits of the underlying data model.
TL;DR: In this paper, the SINDRUM II spectrometer has been used to perform a search for μ → e conversion in muonic atoms with the assumption of a giant resonance excitation of the Ca nucleaus.
TL;DR: The results are consistent with recent electrophysiological studies indicating that the establishment of NREMS is associated with a progressive hyperpolarization of thalamocortical neurons during which the membrane potential exhibits oscillations first in the spindle frequency range and then in the range of SWA.
Abstract: The dynamics of the sleep EEG were investigated by all-night spectral analysis of 51 sleep records. Power density was calculated for 1-Hz bins in the 0.25-25.0 Hz range. Values in non-rapid-eye-movement sleep (NREMS) were higher than in REMS in the 0.25-16.0 Hz range, and lower in the 18.25-22.0 Hz range. Power density in the 0.25-12.0 Hz range showed a declining trend over the first four NREMS episodes, which, depending on the frequency bin, could be approximated by non-linear or linear decay functions. In the frequency range of sleep spindles (12.25-15.0 Hz), power density in the 13.25-15.0 Hz band showed an increasing trend between NREMS episode 2 and NREMS episode 4. A correlation matrix of 25 1-Hz bins revealed for NREMS a negative correlation between slow-wave activity (SWA; 0.25-4.0 Hz) and activity in the spindle frequency range. This negative correlation was highest in the first NREMS episode and diminished progressively over the subsequent NREMS episodes. Within NREMS episodes, the values in the spindle frequency range showed a U-shaped time course, the trough coinciding with a high level of SWA. By contrast, in both the early and late part of the episode the two types of activity changed in the same direction. The results are consistent with recent electrophysiological studies indicating that the establishment of NREMS is associated with a progressive hyperpolarization of thalamocortical neurons during which the membrane potential exhibits oscillations first in the spindle frequency range and then in the range of SWA.
TL;DR: The hypothesis that high beta-carotene concentrations within the normal range reduce the risk of a first myocardial infarction is supported and is compatible with previous observations of reduced risk among vitamin E supplement users only.