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Showing papers by "National Institutes of Health published in 1999"


Journal ArticleDOI
TL;DR: This large-scale longitudinal pediatric neuroimaging study confirmed linear increases in white matter, but demonstrated nonlinear changes in cortical gray matter, with a preadolescent increase followed by a postadolescent decrease.
Abstract: Pediatric neuroimaging studies1,2,3,4,5, up to now exclusively cross sectional, identify linear decreases in cortical gray matter and increases in white matter across ages 4 to 20. In this large-scale longitudinal pediatric neuroimaging study, we confirmed linear increases in white matter, but demonstrated nonlinear changes in cortical gray matter, with a preadolescent increase followed by a postadolescent decrease. These changes in cortical gray matter were regionally specific, with developmental curves for the frontal and parietal lobe peaking at about age 12 and for the temporal lobe at about age 16, whereas cortical gray matter continued to increase in the occipital lobe through age 20.

5,140 citations


Journal ArticleDOI
TL;DR: TALOS yields the 10 triplets which have the closest similarity in secondary chemical shift and amino acid sequence to those of the query sequence, and these averages can reliably be used as angular restraints for the protein whose structure is being studied.
Abstract: Chemical shifts of backbone atoms in proteins are exquisitely sensitive to local conformation, and homologous proteins show quite similar patterns of secondary chemical shifts. The inverse of this relation is used to search a database for triplets of adjacent residues with secondary chemical shifts and sequence similarity which provide the best match to the query triplet of interest. The database contains 13Cα, 13Cβ, 13C′, 1Hα and 15N chemical shifts for 20 proteins for which a high resolution X-ray structure is available. The computer program TALOS was developed to search this database for strings of residues with chemical shift and residue type homology. The relative importance of the weighting factors attached to the secondary chemical shifts of the five types of resonances relative to that of sequence similarity was optimized empirically. TALOS yields the 10 triplets which have the closest similarity in secondary chemical shift and amino acid sequence to those of the query sequence. If the central residues in these 10 triplets exhibit similar φ and Ψ backbone angles, their averages can reliably be used as angular restraints for the protein whose structure is being studied. Tests carried out for proteins of known structure indicate that the root-mean-square difference (rmsd) between the output of TALOS and the X-ray derived backbone angles is about 15°. Approximately 3% of the predictions made by TALOS are found to be in error.

3,080 citations


Journal ArticleDOI
TL;DR: A clinical diagnostic classification based on a comprehensive review of the literature regarding the sensitivity and specificity of the characteristic clinical features of PD is proposed: Definite, Probable, and Possible.
Abstract: The clinical diagnosis of Parkinson disease (PD) is based on the identification of some combination of the cardinal motor signs of bradykinesia, rigidity, tremor, and postural instability, but few attempts have been made to develop explicit diagnostic criteria. We propose a clinical diagnostic classification based on a comprehensive review of the literature regarding the sensitivity and specificity of the characteristic clinical features of PD. Three levels of diagnostic confidence are differentiated: Definite, Probable, and Possible. The diagnoses of Possible and Probable PD are based on clinical criteria alone. Neuropathologic confirmation is required for the diagnosis of Definite PD in patients with the clinical diagnosis of Possible or Probable PD. Criteria for histopathologic confirmation of PD are also presented.

2,747 citations


Journal ArticleDOI
TL;DR: The results offer direct visual confirmation that γ-H2AX forms en masse at chromosomal sites of DNA double-strand breaks and suggest the possible existence of units of higher order chromatin structure involved in monitoring DNA integrity.
Abstract: The loss of chromosomal integrity from DNA double-strand breaks introduced into mammalian cells by ionizing radiation results in the specific phosphorylation of histone H2AX on serine residue 139, yielding a specific modified form named γ-H2AX. An antibody prepared to the unique region of human γ-H2AX shows that H2AX homologues are phosphorylated not only in irradiated mammalian cells but also in irradiated cells from other species, including Xenopus laevis, Drosophila melanogaster, and Saccharomyces cerevisiae. The antibody reveals that γ-H2AX appears as discrete nuclear foci within 1 min after exposure of cells to ionizing radiation. The numbers of these foci are comparable to the numbers of induced DNA double-strand breaks. When DNA double-strand breaks are introduced into specific partial nuclear volumes of cells by means of a pulsed microbeam laser, γ-H2AX foci form at these sites. In mitotic cells from cultures exposed to nonlethal amounts of ionizing radiation, γ-H2AX foci form band-like structures on chromosome arms and on the end of broken arms. These results offer direct visual confirmation that γ-H2AX forms en masse at chromosomal sites of DNA double-strand breaks. The results further suggest the possible existence of units of higher order chromatin structure involved in monitoring DNA integrity.

2,451 citations


Journal ArticleDOI
TL;DR: In this paper, the chemokine receptors CXCR4 and CCR5, members of the G protein-coupled receptor superfamily, have been identified as the principal coreceptors for T cell line-tropic and macrophagetropic HIV-1 isolates, respectively.
Abstract: In addition to CD4, the human immunodeficiency virus (HIV) requires a coreceptor for entry into target cells. The chemokine receptors CXCR4 and CCR5, members of the G protein-coupled receptor superfamily, have been identified as the principal coreceptors for T cell line-tropic and macrophage-tropic HIV-1 isolates, respectively. The updated coreceptor repertoire includes numerous members, mostly chemokine receptors and related orphans. These discoveries provide a new framework for understanding critical features of the basic biology of HIV-1, including the selective tropism of individual viral variants for different CD4 C target cells and the membrane fusion mechanism governing virus entry. The coreceptors also provide molecular perspectives on central puzzles of HIV-1 disease, including the selective transmission of macrophage-tropic variants, the appearance of T cell line-tropic variants in many infected persons during progression to AIDS, and differing susceptibilities of individuals to infection and disease progression. Genetic findings have yielded major insights into the in vivo roles of individual coreceptors and their ligands; of particular importance is the discovery of an inactivating mutation in the CCR5 gene which, in homozygous form, confers strong resistance to HIV-1 infection. Beyond providing new perspectives on fundamental aspects of HIV-1 transmission and pathogenesis, the coreceptors suggest new avenues for developing novel therapeutic and preventative strategies to combat the AIDS epidemic.

2,245 citations


Journal ArticleDOI
TL;DR: 'BLAST 2 Sequences', a new BLAST-based tool for aligning two protein or nucleotide sequences, is described, utilizing the BLAST algorithm for pairwise DNA-DNA or protein-protein sequence comparison.
Abstract: 'BLAST 2 Sequences', a new BLAST-based tool for aligning two protein or nucleotide sequences, is described. While the standard BLAST program is widely used to search for homologous sequences in nucleotide and protein databases, one often needs to compare only two sequences that are already known to be homologous, coming from related species or, e.g. different isolates of the same virus. In such cases searching the entire database would be unnecessarily time-consuming. 'BLAST 2 Sequences' utilizes the BLAST algorithm for pairwise DNA-DNA or protein-protein sequence comparison. A World Wide Web version of the program can be used interactively at the NCBI WWW site (http://www.ncbi.nlm.nih.gov/gorf/bl2.++ +html). The resulting alignments are presented in both graphical and text form. The variants of the program for PC (Windows), Mac and several UNIX-based platforms can be downloaded from the NCBI FTP site (ftp://ncbi.nlm.nih.gov).

2,244 citations


Journal ArticleDOI
01 Jan 1999-Science
TL;DR: The temporal program of gene expression during a model physiological response of human cells, the response of fibroblasts to serum, was explored with a complementary DNA microarray representing 8600 different human genes.
Abstract: The temporal program of gene expression during a model physiological response of human cells, the response of fibroblasts to serum, was explored with a complementary DNA microarray representing about 8600 different human genes. Genes could be clustered into groups on the basis of their temporal patterns of expression in this program. Many features of the transcriptional program appeared to be related to the physiology of wound repair, suggesting that fibroblasts play a larger and richer role in this complex multicellular response than had previously been appreciated.

2,062 citations


Journal ArticleDOI
TL;DR: The recent successful generation of double knockout, or alpha beta ERKO mice of both sexes, suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO.
Abstract: All scientific investigations begin with distinct objectives: first is the hypothesis upon which studies are undertaken to disprove, and second is the overall aim of obtaining further information, from which future and more precise hypotheses may be drawn Studies focusing on the generation and use of gene-targeted animal models also apply these goals and may be loosely categorized into sequential phases that become apparent as the use of the model progresses Initial studies of knockout models often focus on the plausibility of the model based on prior knowledge and whether the generation of an animal lacking the particular gene will prove lethal or not Upon the successful generation of a knockout, confirmatory studies are undertaken to corroborate previously established hypotheses of the function of the disrupted gene product As these studies continue, observations of unpredicted phenotypes or, more likely, the lack of a phenotype that was expected based on models put forth from past investigations are noted Often the surprising phenotype is due to the loss of a gene product that is downstream from the functions of the disrupted gene, whereas the lack of an expected phenotype may be due to compensatory roles filled by alternate mechanisms As the descriptive studies of the knockout continue, use of the model is often shifted to the role as a unique research reagent, to be used in studies that 1) were not previously possible in a wild-type model; 2) aimed at finding related proteins or pathways whose existence or functions were previously masked; or 3) the subsequent effects of the gene disruption on related physiological and biochemical systems The alpha ERKO mice continue to satisfy the confirmatory role of a knockout quite well As summarized in Table 4, the phenotypes observed in the alpha ERKO due to estrogen insensitivity have definitively illustrated several roles that were previously believed to be dependent on functional ER alpha, including 1) the proliferative and differentiative actions critical to the function of the adult female reproductive tract and mammary gland; 2) as an obligatory component in growth factor signaling in the uterus and mammary gland; 3) as the principal steroid involved in negative regulation of gonadotropin gene transcription and LH levels in the hypothalamic-pituitary axis; 4) as a positive regulator of PR expression in several tissues; 5) in the positive regulation of PRL synthesis and secretion from the pituitary; 6) as a promotional factor in oncogene-induced mammary neoplasia; and 7) as a crucial component in the differentiation and activation of several behaviors in both the female and male The list of unpredictable phenotypes in the alpha ERKO must begin with the observation that generation of an animal lacking a functional ER alpha gene was successful and produced animals of both sexes that exhibit a life span comparable to wild-type The successful generation of beta ERKO mice suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO In support of this is our recent successful generation of double knockout, or alpha beta ERKO mice of both sexes The precise defects in certain components of male reproduction, including the production of abnormal sperm and the loss of intromission and ejaculatory responses that were observed in the alpha ERKO, were quite surprising In turn, certain estrogen pathways in the alpha ERKO female appear intact or unaffected, such as the ability of the uterus to successfully exhibit a progesterone-induced decidualization response, and the possible maintenance of an LH surge system in the hypothalamus [ABSTRACT TRUNCATED]

2,053 citations


Journal ArticleDOI
TL;DR: This review summarizes current research on the structure-function analysis of P-glycoprotein, its mechanism of action, and facts and speculations about its normal physiological role.
Abstract: Considerable evidence has accumulated indicating that the multidrug transporter or P-glycoprotein plays a role in the development of simultaneous resistance to multiple cytotoxic drugs in cancer cells. In recent years, various approaches such as mutational analyses and biochemical and pharmacological characterization have yielded significant information about the relationship of structure and function of P-glycoprotein. However, there is still considerable controversy about the mechanism of action of this efflux pump and its function in normal cells. This review summarizes current research on the structure-function analysis of P-glycoprotein, its mechanism of action, and facts and speculations about its normal physiological role.

1,980 citations


Journal ArticleDOI
24 Nov 1999-Cell
TL;DR: Although the signals that cause susceptibility or resistance to methylation are still unknown, genetic approaches in plants are leading the way forward and exciting revelations are expected as the knowledge vacuum in this area is filled over the next few years.

1,871 citations


Journal Article
TL;DR: This paper focuses on hot pepper, which is eaten on a daily basis by an estimated one-quarter of the world’s population and has potential to be a biological target for regenerative medicine.
Abstract: Natural products afford a window of opportunity to study important biology. If the natural product is used or abused by human beings, finding its biological target(s) is all the more significant. Hot pepper is eaten on a daily basis by an estimated one-quarter of the world’s population and

Journal ArticleDOI
TL;DR: Technical aspects of cDNA microarrays are reviewed, including the general principles, fabrication of the arrays, target labelling, image analysis and data extraction, management and mining.
Abstract: cDNA microarrays are capable of profiling gene expression patterns of tens of thousands of genes in a single experiment. DNA targets, in the form of 3' expressed sequence tags (ESTs), are arrayed onto glass slides (or membranes) and probed with fluorescent- or radioactively-labelled cDNAs. Here, we review technical aspects of cDNA microarrays, including the general principles, fabrication of the arrays, target labelling, image analysis and data extraction, management and mining.

Journal ArticleDOI
TL;DR: Defects in insulin secretion and insulin action occur early in the pathogenesis of diabetes, and intervention to prevent diabetes should target both abnormalities.
Abstract: The pathogenesis of type 2 diabetes involves abnormalities in insulin action, insulin secretion, and endogenous glucose output (EGO). However, the sequence with which these abnormalities develop and their relative contributions to the deterioration in glucose tolerance remain unclear in the absence of a detailed longitudinal study. We measured insulin action, insulin secretion, and EGO longitudinally in 17 Pima Indians, in whom glucose tolerance deteriorated from normal (NGT) to impaired (IGT) to diabetic over 5.1 ± 1.4 years. Transition from NGT to IGT was associated with an increase in body weight, a decline in insulin-stimulated glucose disposal, and a decline in the acute insulin secretory response (AIR) to intravenous glucose, but no change in EGO. Progression from IGT to diabetes was accompanied by a further increase in body weight, further decreases in insulin-stimulated glucose disposal and AIR, and an increase in basal EGO. Thirty-one subjects who retained NGT over a similar period also gained weight, but their AIR increased with decreasing insulin-stimulated glucose disposal. Thus, defects in insulin secretion and insulin action occur early in the pathogenesis of diabetes. Intervention to prevent diabetes should target both abnormalities.

Journal ArticleDOI
TL;DR: It is suggested that aggressive melanoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis, providing a biomechanical explanation for the generation of microvessels in vitro.
Abstract: Tissue sections from aggressive human intraocular (uveal) and metastatic cutaneous melanomas generally lack evidence of significant necrosis and contain patterned networks of interconnected loops of extracellular matrix. The matrix that forms these loops or networks may be solid or hollow. Red blood cells have been detected within the hollow channel components of this patterned matrix histologically, and these vascular channel networks have been detected in human tumors angiographically. Endothelial cells were not identified within these matrix-embedded channels by light microscopy, by transmission electron microscopy, or by using an immunohistochemical panel of endothelial cell markers (Factor VIII-related antigen, Ulex, CD31, CD34, and KDR[Flk-1]). Highly invasive primary and metastatic human melanoma cells formed patterned solid and hollow matrix channels (seen in tissue sections of aggressive primary and metastatic human melanomas) in three-dimensional cultures containing Matrigel or dilute Type I collagen, without endothelial cells or fibroblasts. These tumor cell-generated patterned channels conducted dye, highlighting looping patterns visualized angiographically in human tumors. Neither normal melanocytes nor poorly invasive melanoma cells generated these patterned channels in vitro under identical culture conditions, even after the addition of conditioned medium from metastatic pattern-forming melanoma cells, soluble growth factors, or regimes of hypoxia. Highly invasive and metastatic human melanoma cells, but not poorly invasive melanoma cells, contracted and remodeled floating hydrated gels, providing a biomechanical explanation for the generation of microvessels in vitro. cDNA microarray analysis of highly invasive versus poorly invasive melanoma tumor cells confirmed a genetic reversion to a pluripotent embryonic-like genotype in the highly aggressive melanoma cells. These observations strongly suggest that aggressive melanoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis.


Journal ArticleDOI
TL;DR: It is reported here that, in the absence of any foreign substances, dendritic cells can be activated by endogenous signals received from cells that are stressed, virally infected or killed necrotically, but not by healthy cells or those dying apoptotically.
Abstract: Dendritic cells, the most potent antigen-presenting cells, need to be activated before they can function to initiate an immune response. We report here that, in the absence of any foreign substances, dendritic cells can be activated by endogenous signals received from cells that are stressed, virally infected or killed necrotically, but not by healthy cells or those dying apoptotically. Injected in vivo with an antigen, the endogenous activating substances can function as natural adjuvants to stimulate a primary immune response, and they may represent the natural initiators of transplant rejection, spontaneous tumor rejection, and some forms of autoimmunity.

Journal ArticleDOI
01 Apr 1999-Neuron
TL;DR: The increased activity in visual cortex in the absence of visual stimulation may reflect a top-down bias of neural signals in favor of the attended location, which derives from a fronto-parietal network.

Journal ArticleDOI
TL;DR: It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPAR α mRNA is induced during fasting in wildtype mice, indicating that PPARα plays a pivotal role in the management of energy stores during fasting.
Abstract: Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.

Journal ArticleDOI
05 May 1999-JAMA
TL;DR: Increasing detection of presymptomatic tumors by imaging procedures, such as ultrasonography, computed tomography, and magnetic resonance imaging, does not fully explain the upward incidence trends of renal cell carcinoma.
Abstract: ContextClinical surveys have revealed that incidental detection of renal cell carcinoma is rising because of increased use of imaging procedures.ObjectiveTo examine incidence, mortality, and survival trends of renal cell and renal pelvis cancers by age, sex, race, and tumor stage at diagnosis.DesignCalculation of age-adjusted incidence and mortality rates, along with 5-year relative survival rates, using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program.Setting and ParticipantsPatients diagnosed as having kidney cancer from 1975 through 1995 in the 9 geographic areas covered by tumor registries in the SEER program, which represent about 10% of the US population.Main Outcome MeasuresIncidence, mortality, and 5-year relative survival rates by time periods.ResultsThe age-adjusted incidence rates for renal cell carcinoma between 1975 and 1995 for white men, white women, black men, and black women were 9.6, 4.4, 11.1, and 4.9 per 100,000 person-years, respectively. The corresponding rates for renal pelvis cancer were 1.5, 0.7, 0.8, and 0.5 per 100,000 person-years. Renal cell cancer incidence rates increased steadily between 1975 and 1995, by 2.3% annually among white men, 3.1% among white women, 3.9% among black men, and 4.3% among black women. Increases were greatest for localized tumors but were also seen for more advanced and unstaged tumors. In contrast, the incidence rates for renal pelvis cancer declined among white men and remained stable among white women and blacks. Although 5-year relative survival rates for patients with renal cell cancer improved among whites but not among blacks, kidney cancer mortality rates increased in all race and sex groups.ConclusionsIncreasing detection of presymptomatic tumors by imaging procedures, such as ultrasonography, computed tomography, and magnetic resonance imaging, does not fully explain the upward incidence trends of renal cell carcinoma. Other factors may be contributing to the rapidly increasing incidence of renal cell cancer in the United States, particularly among blacks.

Journal ArticleDOI
TL;DR: The modular nature of the IL-4 receptor and the specialization of different receptor regions for distinct functions, most notably the independent regulation of cell growth and gene activation are emphasized.
Abstract: ▪ Abstract Interleukin-4 is a multifunctional cytokine that plays a critical role in the regulation of immune responses. Its effects depend upon binding to and signaling through a receptor complex consisting of the IL-4Rα chain and the common gamma chain (γc), resulting in a series of phosphorylation events mediated by receptor-associated kinases. In turn, these cause the recruitment of mediators of cell growth, of resistance to apoptosis, and of gene activation and differentiation. Here we describe our current understanding of the organization of the IL-4 receptor, of the signaling pathways that are induced as a result of receptor occupancy, and of the various mechanisms through which receptor function is modulated. We particularly emphasize the modular nature of the receptor and the specialization of different receptor regions for distinct functions, most notably the independent regulation of cell growth and gene activation.

Journal ArticleDOI
TL;DR: In this article, the authors investigated whether interleukin-6 and C-reactive protein levels predict all-cause and cause-specific mortality in a population-based sample of nondisabled older people.

Journal ArticleDOI
TL;DR: The World Health Organization classification of hematologic malignancies, including lymphoid, myeloid, histiocytic, and mast cell neoplasms, has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment ofhematologicmalignancies.

Journal ArticleDOI
TL;DR: Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD).
Abstract: Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD) In heterozygotes, HDL-C levels are about one-half those of normal individuals Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families We report here refining of our previous linkage of the TD gene to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1) We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype An in-frame insertion-deletion in exon 12 was found in the second family Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD

Journal ArticleDOI
TL;DR: The somatomedin hypothesis that insulin-like growth factor I (IGF-I) was a hepatically derived circulating mediator of growth hormone and is a crucial factor for postnatal growth and development is reassessed.
Abstract: The somatomedin hypothesis proposed that insulin-like growth factor I (IGF-I) was a hepatically derived circulating mediator of growth hormone and is a crucial factor for postnatal growth and development To reassess this hypothesis, we have used the Cre/loxP recombination system to delete the igf1 gene exclusively in the liver igf1 gene deletion in the liver abrogated expression of igf1 mRNA and caused a dramatic reduction in circulating IGF-I levels However, growth as determined by body weight, body length, and femoral length did not differ from wild-type littermates Although our model proves that hepatic IGF-I is indeed the major contributor to circulating IGF-I levels in mice it challenges the concept that circulating IGF-I is crucial for normal postnatal growth Rather, our model provides direct evidence for the importance of the autocrine/paracrine role of IGF-I

Journal ArticleDOI
10 Feb 1999-JAMA
TL;DR: Among healthy 45- to 68-year-old men, hand grip strength was highly predictive of functional limitations and disability 25 years later, suggesting good muscle strength in midlife may protect people from old age disability by providing a greater safety margin above the threshold of disability.
Abstract: ContextPoor muscle strength, functional limitations, and disability often coexist, but whether muscle strength during midlife predicts old age functional ability is not known.ObjectiveTo determine whether hand grip strength measured during midlife predicts old age functional limitations and disability in initially healthy men.Design and SettingA 25-year prospective cohort study, the Honolulu Heart Program, which began in 1965 among Japanese-American men living on Oahu, Hawaii.ParticipantsA total of 6089 45- to 68-year-old men who were healthy at baseline and whose maximal hand grip strength was measured from 1965 through 1970. Altogether, 2259 men died over the follow-up period and 3218 survivors participated in the disability assessment in 1991 through 1993.Main Outcome MeasuresFunctional limitations including slow customary walking speed (≤0.4 m/s) and inability to rise from a seated position without using the arms, and multiple self-reported upper extremity, mobility, and self-care disability outcomes.ResultsAfter adjustment for multiple potential confounders, risk of functional limitations and disability 25 years later increased as baseline hand grip strength, divided into tertiles, declined. The odds ratio (OR) of walking speed of 0.4 m/s or slower was 2.87 (95% confidence interval [CI], 1.76-4.67) in those in the lowest third and 1.79 (95% CI, 1.14-2.81) in the middle third of grip strength vs those in the highest third. The risk of self-care disability was more than 2 times greater in the lowest vs the highest grip strength tertile. Adding chronic conditions identified at follow-up to the models predicting disability reduced the ORs related to grip strength only minimally.ConclusionsAmong healthy 45- to 68-year-old men, hand grip strength was highly predictive of functional limitations and disability 25 years later. Good muscle strength in midlife may protect people from old age disability by providing a greater safety margin above the threshold of disability.

Journal ArticleDOI
TL;DR: The present data demonstrate the existence of six phenotypic variants of sCJD, and the physicochemical properties of PrPSc in conjunction with the PRNP codon 129 genotype largely determine this phenotypesic variability, and allow a molecular classification of the disease variants.
Abstract: Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.

Journal ArticleDOI
11 Jun 1999-Science
TL;DR: Tetanic synaptic stimulation induced a rapid delivery of tagged receptors into dendritic spines as well as clusters in dendrites and may contribute to the enhanced AMPA receptor-mediated transmission observed during long-term potentiation and activity-dependent synaptic maturation.
Abstract: To monitor changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor distribution in living neurons, the AMPA receptor subunit GluR1 was tagged with green fluorescent protein (GFP). This protein (GluR1-GFP) was functional and was transiently expressed in hippocampal CA1 neurons. In dendrites visualized with two-photon laser scanning microscopy or electron microscopy, most of the GluR1-GFP was intracellular, mimicking endogenous GluR1 distribution. Tetanic synaptic stimulation induced a rapid delivery of tagged receptors into dendritic spines as well as clusters in dendrites. These postsynaptic trafficking events required synaptic N-methyl-D-aspartate (NMDA) receptor activation and may contribute to the enhanced AMPA receptor-mediatedtransmission observed during long-term potentiation and activity-dependent synaptic maturation.

Journal ArticleDOI
TL;DR: In this paper, the authors provided varying estimates of the risk of progression in chronic hepatitis C. The combined population data indicated that the disease progresses slowly over approximately 30 years, on average.

Journal ArticleDOI
19 Mar 1999-Science
TL;DR: Findings provide evidence for a gradual maturation, during late childhood and adolescence, of fiber pathways presumably supporting motor and speech functions.
Abstract: Structural maturation of fiber tracts in the human brain, including an increase in the diameter and myelination of axons, may play a role in cognitive development during childhood and adolescence. A computational analysis of structural magnetic resonance images obtained in 111 children and adolescents revealed age-related increases in white matter density in fiber tracts constituting putative corticospinal and frontotemporal pathways. The maturation of the corticospinal tract was bilateral, whereas that of the frontotemporal pathway was found predominantly in the left (speech-dominant) hemisphere. These findings provide evidence for a gradual maturation, during late childhood and adolescence, of fiber pathways presumably supporting motor and speech functions.

Journal ArticleDOI
01 Oct 1999-Cell
TL;DR: The findings demonstrate the pivotal function of MT1-MMP in connective tissue metabolism, and illustrate that modeling of the soft connective tissues matrix by resident cells is essential for the development and maintenance of the hard tissues of the skeleton.