Showing papers by "National Institutes of Health published in 1993"

Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems

Abstract: An N⋅log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolutions using fast Fourier transforms. Timings and accuracies are presented for three large crystalline ionic systems.

Vascular dementia Diagnostic criteria for research studies: Report of the NINDS‐AIREN International Workshop*

Abstract: Criteria for the diagnosis of vascular dementia (VaD) that are reliable, valid, and readily applicable in a variety of settings are urgently needed for both clinical and research purposes. To address this need, the Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of VaD. Compared with other current criteria, these guidelines emphasize (1) the heterogeneity of vascular dementia syndromes and pathologic subtypes including ischemic and hemorrhagic strokes, cerebral hypoxic-ischemic events, and senile leukoencephalopathic lesions; (2) the variability in clinical course, which may be static, remitting, or progressive; (3) specific clinical findings early in the course (eg, gait disorder, incontinence, or mood and personality changes) that support a vascular rather than a degenerative cause; (4) the need to establish a temporal relationship between stroke and dementia onset for a secure diagnosis; (5) the importance of brain imaging to support clinical findings; (6) the value of neuropsychological testing to document impairments in multiple cognitive domains; and (7) a protocol for neuropathologic evaluations and correlative studies of clinical, radiologic, and neuropsychological features. These criteria are intended as a guide for case definition in neuroepidemiologic studies, stratified by levels of certainty (definite, probable, and possible). They await testing and validation and will be revised as more information becomes available.

The de Facto US Mental and Addictive Disorders Service System: Epidemiologic Catchment Area Prospective 1-Year Prevalence Rates of Disorders and Services

Abstract: • After initial interviews with 20 291 adults in the National Institute of Mental Health Epidemiologic Catchment Area Program, we estimated prospective 1-year prevalence and service use rates of mental and addictive disorders in the US population. An annual prevalence rate of 28.1% was found for these disorders, composed of a 1-month point prevalence of 15.7% (at wave 1) and a 1-year incidence of new or recurrent disorders identified in 12.3% of the population at wave 2. During the 1-year follow-up period, 6.6% of the total sample developed one or more new disorders after being assessed as having no previous lifetime diagnosis at wave 1. An additional 5.7% of the population, with a history of some previous disorder at wave 1, had an acute relapse or suffered from a new disorder in 1 year. Irrespective of diagnosis, 14.7% of the US population in 1 year reported use of services in one or more component sectors of the de facto US mental and ad- dictive service system. With some overlap between sectors, specialists in mental and addictive disorders provided treatment to 5.9% of the US population, 6.4% sought such services from general medical physicians, 3.0% sought these services from other human service professionals, and 4.1% turned to the voluntary support sector for such care. Of those persons with any disorder, only 28.5% (8.0 per 100 population) sought mental health/addictive services. Persons with specific disorders varied in the proportion who used services, from a high of more than 60% for somatization, schizophrenia, and bipolar disorders to a low of less than 25% for addictive disorders and severe cognitive impairment. Applications of these descriptive data to US health care system reform options are considered in the context of other variables that will determine national health policy.

Detecting Subtle Sequence Signals: A Gibbs Sampling Strategy for Multiple Alignment

Abstract: A wealth of protein and DNA sequence data is being generated by genome projects and other sequencing efforts. A crucial barrier to deciphering these sequences and understanding the relations among them is the difficulty of detecting subtle local residue patterns common to multiple sequences. Such patterns frequently reflect similar molecular structures and biological properties. A mathematical definition of this "local multiple alignment" problem suitable for full computer automation has been used to develop a new and sensitive algorithm, based on the statistical method of iterative sampling. This algorithm finds an optimized local alignment model for N sequences in N-linear time, requiring only seconds on current workstations, and allows the simultaneous detection and optimization of multiple patterns and pattern repeats. The method is illustrated as applied to helix-turn-helix proteins, lipocalins, and prenyltransferases.

The role of secondary brain injury in determining outcome from severe head injury.

Abstract: As triage and resuscitation protocols evolve, it is critical to determine the major extracranial variables influencing outcome in the setting of severe head injury. We prospectively studied the outcome from severe head injury (GCS score < or = 8) in 717 cases in the Traumatic Coma Data Bank. We investigated the impact on outcome of hypotension (SBP < 90 mm Hg) and hypoxia (Pao2 < or = 60 mm Hg or apnea or cyanosis in the field) as secondary brain insults, occurring from injury through resuscitation. Hypoxia and hypotension were independently associated with significant increases in morbidity and mortality from severe head injury. Hypotension was profoundly detrimental, occurring in 34.6% of these patients and associated with a 150% increase in mortality. The increased morbidity and mortality related to severe trauma to an extracranial organ system appeared primarily attributable to associated hypotension. Improvements in trauma care delivery over the past decade have not markedly altered the adverse influence of hypotension. Hypoxia and hypotension are common and detrimental secondary brain insults. Hypotension, particularly, is a major determinant of outcome from severe head injury. Resuscitation protocols for brain injured patients should assiduously avoid hypovolemic shock on an absolute basis.

Two Shorter Forms of the CES-D Depression Symptoms Index:

Abstract: Brief measurement devices can alleviate respondent burden and lower refusal rates in surveys. This article reports on a field test of two shorter forms of the Center for Epidemiological Studies Depression (CES-D) symptoms index in a multisite survey of persons 65 and older. Factor analyses demonstrate that the briefer forms tap the same symptoms dimensions as does the original CES-D, and reliability statistics indicate that they sacrifice little precision. Simple transformations are presented to how scores from the briefer forms can be compared to those of the original.

Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death.

Abstract: To delineate specific developmental roles of transforming growth factor beta 1 (TGF-beta 1) we have disrupted its cognate gene in mouse embryonic stem cells by homologous recombination to generate TGF-beta 1 null mice. These mice do not produce detectable amounts of either TGF-beta 1 RNA or protein. After normal growth for the first 2 weeks they develop a rapid wasting syndrome and die by 3-4 weeks of age. Pathological examination revealed an excessive inflammatory response with massive infiltration of lymphocytes and macrophages in many organs, but primarily in heart and lungs. Many lesions resembled those found in autoimmune disorders, graft-vs.-host disease, or certain viral diseases. This phenotype suggests a prominent role for TGF-beta 1 in homeostatic regulation of immune cell proliferation and extravasation into tissues.

Proteins regulating Ras and its relatives.

Abstract: GTPases of the Ras superfamily regulate many aspects of cell growth, differentiation and action. Their functions depend on their ability to alternate between inactive and active forms, and on their cellular localization. Numerous proteins affecting the GTPase activity, nucleotide exchange rates and membrane localization of Ras superfamily members have now been identified. Many of these proteins are much larger and more complex than their targets, containing multiple domains capable of interacting with an intricate network of cellular enzymes and structures.

Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene

Abstract: Estrogen receptor and its ligand, estradiol, have long been thought to be essential for survival, fertility, and female sexual differentiation and development. Consistent with this proposed crucial role, no human estrogen receptor gene mutations are known, unlike the androgen receptor, where many loss of function mutations have been found. We have generated mutant mice lacking responsiveness to estradiol by disrupting the estrogen receptor gene by gene targeting. Both male and female animals survive to adulthood with normal gross external phenotypes. Females are infertile; males have a decreased fertility. Females have hypoplastic uteri and hyperemic ovaries with no detectable corpora lutea. In adult wild-type and heterozygous females, 3-day estradiol treatment at 40 micrograms/kg stimulates a 3- to 4-fold increase in uterine wet weight and alters vaginal cornification, but the uteri and vagina do not respond in the animals with the estrogen receptor gene disruption. Prenatal male and female reproductive tract development can therefore occur in the absence of estradiol receptor-mediated responsiveness.

Identification of protein coding regions by database similarity search.

Abstract: Sequence similarity between a translated nucleotide sequence and a known biological protein can provide strong evidence for the presence of a homologous coding region, even between distantly related genes. The computer program BLASTX performed conceptual translation of a nucleotide query sequence followed by a protein database search in one programmatic step. We characterized the sensitivity of BLASTX recognition to the presence of substitution, insertion and deletion errors in the query sequence and to sequence divergence. Reading frames were reliably identified in the presence of 1% query errors, a rate that is typical for primary sequence data. BLASTX is appropriate for use in moderate and large scale sequencing projects at the earliest opportunity, when the data are most prone to containing errors.

HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease

Abstract: PRIMARY infection with the human immunodeficiency virus (HIV) is generally followed by a burst of viraemia with or without clinical symptoms1–3. This in turn is followed by a prolonged period of clinical latency. During this period there is little, if any, detectable viraemia, the numbers of infected cells in the blood are very low, and it is extremely difficult to demonstrate virus expression in these cells4. We have analysed viral burden and levels of virus replication simultaneously in the blood and lymphoid organs of the same individuals at various stages of HIV disease. Here we report that in early-stage disease there is a dichotomy between the levels of viral burden and virus replication in peripheral blood versus lymphoid organs. HIV disease is active in the lymphoid tissue throughout the period of clinical latency, even at times when minimal viral activity is demonstrated in blood.

Tumor Cell Interactions with the Extracellular Matrix During Invasion and Metastasis

Abstract: Recent findings have produced great strides in developing an understanding of the molecular events involved in processes necessary for tumor cell invasion and subsequent metastasis formation. This information has been useful in developing new targets for therapeutic intervention such as disruption of tumor cell attachment by peptide analogues of cell adhesion molecules and the use of protease inhibitors to limit extracellular matrix proteolysis required for tumor cell invasion. Future efforts must focus on how the events of cell attachment, matrix proteolysis, and cell migration are controlled and integrated. This requires a better understanding of the transcriptional controls and cell signaling mechanisms that are involved in these events. Preliminary findings suggest that cell-matrix interactions influence gene expression and that the protease inhibitor balance can greatly influence cell-matrix interactions. Therefore it appears that all three steps in the invasive process are linked and interdependent. While this complicates the study of these processes, it is our belief that understanding this interdependence is critical for further development of metastasis research.

Insulin Resistance and Insulin Secretory Dysfunction as Precursors of Non-Insulin-Dependent Diabetes Mellitus: Prospective Studies of Pima Indians

Abstract: Background The relative roles of obesity, insulin resistance, insulin secretory dysfunction, and excess hepatic glucose production in the development of non-insulin-dependent diabetes mellitus (NIDDM) are controversial. We conducted a prospective study to determine which of these factors predicted the development of the disease in a group of Pima Indians. Methods A body-composition assessment, oral and intravenous glucose-tolerance tests, and a hyperinsulinemic-euglycemic clamp study were performed in 200 nondiabetic Pima Indians (87 women and 113 men; mean [±SD] age, 26 ±6 years). The subjects were followed yearly thereafter for an average of 5.3 years. Results Diabetes developed in 38 subjects during follow-up. Obesity, insulin resistance (independent of obesity), and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM. The six-year cumulative incidence of NIDDM was 39 percent in persons with values belo...

Macromolecular Crowding: Biochemical, Biophysical, and Physiological Consequences

Abstract: CONTENTS PERSPECTIVES AND OVERVIEW 28 Nomenclature 30 THEORETICAL CONCEPTS 31 The Effect of Macromolecular C owdin9 on Solution Equilibria 31 The Effect of Macromolecular C owdin# on Reaction Rates 36 The Effect of Macromolecular Crowding on Diffusive Transport of Solutes 37 The Effective Specific Volume of a Macromolecule--What Is It? 40

Oxidation of free amino acids and amino acid residues in proteins by radiolysis and by metal-catalyzed reactions

Abstract: Basic mechanisms that underlie the oxygen free radical-promoted oxidation of free amino acids and amino acid residues of proteins are derived from radiolysis studies. Results of these studies indicate that the most common pathway for the oxidation of simple aliphatic amino acids involves the hydroxyl radical-mediated abstraction of a hydrogen atom to form a carbon-centered radical at the alpha-position of the amino acid or amino acid residue in the polypeptide chain. Addition of O2 to the carbon-centered radicals leads to formation of peroxy radical derivatives, which upon decomposition lead to production of NH3 and alpha-ketoacids, or to production of NH3, CO2, and aldehydes or carboxylic acids containing one less carbon atom. As the number of carbon atoms in the amino acid is increased, hydrogen abstraction at other positions in the carbon chain becomes more important and leads either to the formation of hydroxy derivatives, or to amino acid cross-linked products as a consequence of carbon-centered radical recombination processes. alpha-Hydrogen abstraction plays a minor role in the oxidation of aromatic amino acids by radiolysis. Instead, the aromatic ring is the primary site of attack leading to hydroxy derivatives, to ring scission, and in the case of tyrosine to the formation of Tyr-Tyr cross-linked dimers. The basic pattern for the oxidation of amino acids by metal ion-catalyzed reactions (Fenton chemistry) is similar to the alpha-hydrogen abstraction pathway. But unlike the case of oxidation by radiolysis, this Fenton pathway is the major mechanism for the oxidation of all aliphatic amino acids, regardless of chain length, as well as for the oxidation of aromatic amino acids. Curiously, the Fe(III)-catalyzed oxidation of free amino acids is almost completely dependent upon the presence of bicarbonate ion, and is greatly stimulated by iron chelators at chelator/Fe(III) ratios less than 1.0, and is inhibited at chelator/Fe(III) ratios greater than 1.0. It is deduced that the most active catalytic complex is composed of two equivalents of HCO3-, an amino acid, and at least one equivalent of iron; however, two forms of iron, an iron-chelate and another form, must somehow be involved. In contrast to the situation with radiolysis, the aromatic rings of aromatic amino acids are only minor targets for metal-catalyzed reactions. All amino acid residues in proteins are subject to attack by hydroxyl radicals generated by ionizing radiation; however, the aromatic amino acids and sulfur-containing amino acids are most sensitive to oxidation.(ABSTRACT TRUNCATED AT 400 WORDS)

Periodontal Disease: The sixth complication of diabetes mellitus

Abstract: Periodontal disease is a chronic inflammatory condition characterized by destruction of the periodontal tissues and resulting in loss of connective tissue attachment, loss of alveolar bone, and the formation of pathological pockets around the diseased teeth. Some level of periodontal disease has been found in most populations studied and is responsible for a substantial portion of the tooth loss in adulthood.

The Unified Medical Language System.

Abstract: In 1986, the National Library of Medicine began a long-term research and development project to build the Unified Medical Language System (UMLS). The purpose of the UMLS is to improve the ability of computer programs to "understand" the biomedical meaning in user inquiries and to use this understanding to retrieve and integrate relevant machine-readable information for users. Underlying the UMLS effort is the assumption that timely access to accurate and up-to-date information will improve decision making and ultimately the quality of patient care and research. The development of the UMLS is a distributed national experiment with a strong element of international collaboration. The general strategy is to develop UMLS components through a series of successive approximations of the capabilities ultimately desired. Three experimental Knowledge Sources, the Metathesaurus, the Semantic Network, and the Information Sources Map have been developed and are distributed annually to interested researchers, many of whom have tested and evaluated them in a range of applications. The UMLS project and current developments in high-speed, high-capacity international networks are converging in ways that have great potential for enhancing access to biomedical information.

Epidemiologic Evidence Showing That Human Papillomavirus Infection Causes Most Cervical Intraepithelial Neoplasia

Abstract: Given improvements in human papillomavirus (HPV) testing that have revealed a strong link between sexual activity history and cervical HPV infection the authors conducted a large case-control study of HPV and cervical intraepithelial neoplasia (CIN) to evaluate whether sexual behavior and the other established risk factors for CIN influence risk primarily via HPV infection. The authors studied 500 women with CIN and 500 control subjects receiving cytologic screening at Kaiser Permanente a large prepaid health plan in Portland Oregon. The established epidemiologic risk factors for CIN were assessed by telephone interview. The authors performed HPV testing of cervicovaginal lavage specimens by gene amplification using polymerase chain reaction with a consensus primer to target the L1 gene region of HPV. Unconditional logistic regression analysis was used to estimate relative risk of CIN and to adjust the epidemiologic associations for HPV test results to demonstrate whether the associations were mediated by HPV. The case subjects demonstrated the typical epidemiologic profile of CIN: they had more sex partners more cigarette smoking earlier ages at first sexual intercourse and lower socioeconomic status. Statistical adjustment for HPV infection substantially reduced the size of each of these case-control differences. 76% of cases could be attributed to HPV infection; the results of cytologic review suggested that the true percentage was even higher. Once HPV infection was taken into account an association of parity with risk of CIN was observed in both HPV-negative and HPV-positive women. The data show that the great majority of all grades of CIN can be attributed to HPV infection particularly with the cancer-associated types of HPV. In light of this conclusion the investigation of the natural history of HPV has preventive as well as etiologic importance. (authors)

The "bystander effect": tumor regression when a fraction of the tumor mass is genetically modified.

Abstract: Tumor cells expressing the herpes simplex virus thymidine kinase (HSV-TK) gene are sensitive to the drug ganciclovir (GCV). We demonstrate here that HSV-TK-positive cells exposed to GCV were lethal to HSV-TK-negative cells as a result of a "bystander effect." HSV-TK-negative cells were killed in vitro when the population of cultured cells contained only 10% HSV-TK-positive cells. The mechanism of this "bystander effect" on HSV-TK-negative cells appeared to be related to the process of apoptotic cell death when HSV-TK-positive cells were exposed to GCV. Flow cytometric and electron microscopic analyses suggested that apoptotic vesicles generated from the dying gene-modified cells were phagocytized by nearby, unmodified tumor cells. Prevention of apoptotic vesicle transfer prevented the bystander effect. The toxic effect of HSV-TK-positive cells on HSV-TK-negative cells was reproduced in an in vivo model. A mixed population of tumor cells consisting of HSV-TK-positive and HSV-TK-negative cells was inoculated s.c. into mice. Regression of the tumor mass occurred when the inoculum consisted of as few as 10% HSV-TK-expressing tumor cells. The bystander effect was also demonstrated in i.p. tumor studies. Initial experiments demonstrated that prolonged survival (> 70 days) occurred when a mixture containing 50% HSV-TK-positive and 50% HSV-TK-negative cells was injected i.p. followed by GCV treatment. Further, survival was prolonged for mice with a preexisting HSV-TK-negative i.p. tumor burden by injecting HSV-TK-positive cells and GCV. These results suggest that genetic modification of tumor cells may be useful for developing cancer therapies.

Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor

Abstract: The interleukin-2 receptor gamma chain (IL-2R gamma) is a necessary component of functional IL-2 receptors. IL-2R gamma mutations result in X-linked severe combined immunodeficiency (XSCID) in humans, a disease characterized by the presence of few or no T cells. In contrast, SCID patients with IL-2 deficiency and IL-2-deficient mice have normal numbers of T cells, suggesting that IL-2R gamma is part of more than one cytokine receptor. By using chemical cross-linking, IL-2R gamma was shown to be physically associated with the IL-7 receptor. The presence of IL-2R gamma augmented both IL-7 binding affinity and the efficiency of internalization of IL-7. These findings may help explain the defects of XSCID. Given its role in more than one cytokine receptor system, the common gamma chain (gamma c) is proposed as the designation for IL-2R gamma.