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Biomedical subjects

N Nathanson

Publications and source records attributed to N Nathanson.

At least 19 recordsLinked to original sources
PubMed2005

Virus perpetuation in populations: biological variables that determine persistence or eradication.

In this review, I use the term "perpetuation" for persistence of a virus in a population, since this is a different phenomenon from persistence of a virus in an infected host. Important variables that influence perpetuation differ in small (<1000 individuals) and large (>10,000) populations: in small populations, two important variables are persistence in individuals, and turnover of the population, while in large populations important variables are transmissibility, generation time, and seasonality. In small populations, viruses such as poliovirus that cause acute infections cannot readily be perpetuated, in contrast to viruses such as hepatitis B virus, that cause persistent infections. However, small animal populations can turnover significantly each year, permitting the perpetuation of some viruses that cause acute infections. Large populations of humans are necessary for the perpetuation of acute viruses; for instance, measles required a population of 500,000 for perpetuation in the pre-measles vaccine era. Furthermore, if an acute virus, such as poliovirus, exhibits marked seasonality in large populations, then it may disappear during the seasonal trough, even in the presence of a large number of susceptible persons. Eradication is the converse of perpetuation and can be used as a definitive approach to the control of a viral disease, as in the instance of smallpox. Therefore, the requirements for perpetuation have significant implications for practical public health goals.

Animals↗
PubMed2000

Biological considerations in the development of a human immunodeficiency virus vaccine.

Over the last 12 years, many human immunodeficiency virus (HIV) vaccine candidates have been tried in humans, with disappointing results. In particular, recombinant envelope proteins have failed to elicit strong cellular immune responses or neutralizing antibody against many wild-type isolates of HIV-1. Attenuated strains of simian immunodeficiency virus (SIV), although capable of protecting against virulent strains of SIV, often retain residual pathogenicity. These difficulties suggest that it will be necessary to address a number of biological questions that underpin the rational development of an AIDS vaccine: (1) Will natural infection with HIV protect against superinfection? (2) Is partial protection induced by an HIV vaccine adequate to prevent AIDS? (3) What are the immune correlates of protection for an AIDS vaccine? (4) Will a monotypic HIV-1 vaccine confer cross-clade immunity? (5) Is mucosal immunity important for an effective AIDS vaccine? (6) Is there a rationale for therapeutic immunization? Ongoing research that is addressing these questions should lead to the formulation of a safe and effective AIDS vaccine.

AIDS Vaccines↗
PubMed2000

Future directions for NIH-supported pediatric AIDS research.

The Office of AIDS Research (OAR) at the National Institutes of Health (NIH) is responsible for the coordination of AIDS research. In June 1999, the OAR, in conjunction with the NIH Institutes and Centers, initiated a review of NIH-sponsored pediatric AIDS research. This article discusses a number of important priorities for future clinical research in NIH-sponsored pediatric AIDS in both developed and developing countries. These have the potential to significantly prevent perinatal transmission, reduce adolescent infections, and impact treatment of pediatric infections.

Acquired Immunodeficiency Syndrome↗
PubMed1999

The role of nonhuman primates in the development of an AIDS vaccine.

Over the past decade, a substantial research investment has generated a vast body of knowledge relevant to the development of an effective AIDS vaccine. Furthermore, studies in nonhuman primates have demonstrated that a number of candidate immunogens can confer a significant degree of protection against a potentially pathogenic SIV or SHIV. Currently, there exists a robust program that supports discovery of new HIV immunogens and a proven successful program for collaborative human trials of promising vaccine candidates. However, we believe that there is a gap between discovery and clinical trials. An orderly process for screening of candidate immunogens prior to human trials would facilitate the vaccine development program. We suggest that nonhuman primates can fill this strategic gap and could accelerate vaccine development. Recognizing that there is considerable controversy about the potential usefulness of the primate models, we have attempted to set forth the relevant practical and biological issues as a series of questions for discussion. The most important biological problem is the absence of a single immune response correlate that will predict vaccine efficacy. Data from primate models indicate that such a single predictive correlate may not exist. In turn, this argues for a vaccine screening protocol that includes a pathogenic virus challenge, an approach only available in the nonhuman primate model. The further assumption is that nonprimate models can be used to predict the relative protective efficacy of diverse immunization protocols, a hypothesis that can only be tested by comparative studies yet to be conducted. A 'standard' set of virus challenges must be selected for comparison of different immunization protocols, and this effort has been initiated. At the practical level, it appears that the large number of candidate immunogens now being developed requires a screening process of the kind proposed, since it would not be practical to test all new immunogens and protocols in humans. In conclusion, it appears timely to crystallize an orderly process for the discovery, screening, and human testing of candidate AIDS vaccines, understanding that a vaccine development program should not be conducted at the expense of investigator-initiated research in the diverse disciplines that support rational vaccine design and development. The components of a rational process of vaccine development are well established and only remain to be welded into one coherent program.

AIDS Vaccines↗
PubMed1998

Emergence of new viral infections: implications for the blood supply.

New viral infections of humans appear to be emerging at an increasing tempo, probably due to technological developments and societal changes that have enhanced the ability of viruses to invade and spread within the human population. Emergence can be due to several discrete phenomena. Existing viruses of humans continue to be isolated, identified, followed by the description of new nosological entities. An increase in the ratio of cases:infections for ubiquitous viruses may lead to the emergence of new epidemics, associated either with the altered host susceptibility or increased viral virulence. Finally, viruses may invade populations from which they have disappeared or may cross the species barrier to invade new species. When a virus invades a new species it usually fails to spread from individual to individual. However, on rare occasions a virus adapts to a new species, usually involving mutations in the viral genome that alter the cellular host range. In such instances, if circumstances favor transmission, a pandemic may occur. For a new virus to endanger blood products, several criteria must be met. First the virus must be able to spread widely in the human population; second, it must cause a persistent plasma viraemia of moderate to high titre (although there are exceptions); and third, virus carriers must be asymptomatic. This set of conditions has only occurred once in the recorded history of human virology, with human immunodeficiency virus. It would probably be difficult to predict another invasion of the human population with a new virus, at least from studies in comparative virology. Probably the best deterrent strategy to facilitate the early recognition of any such hypothetical rare occurrence is the identification and control of all viruses that presently endanger the blood supply, supplemented by an active surveillance system to identify post-transfusion illnesses of any kind.

Animals↗
PubMed1997

Bovine spongiform encephalopathy (BSE): causes and consequences of a common source epidemic.

Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) or prion disease of cattle first recognized in 1986 in the United Kingdom, where it produced a common source epidemic that peaked in January 1993 and has subsided markedly since that time. The epidemic began simultaneously at many geographic locations and was traced to contamination of meat and bone meal (MBM), a dietary supplement prepared from rendering of slaughterhouse offal. It appears that the epidemic was initiated by the presence of the agent of scrapie (a long-standing TSE of sheep) that was first transmitted to cattle, beginning in the early 1980s, when most rendering plants abandoned the use of organic solvents in the preparation of MBM. The epidemic was probably accelerated by the recycling of infected bovine tissues prior to the recognition of BSE. To terminate the epidemic, a prohibition on the feeding of ruminant-derived protein to ruminants was introduced in the United Kingdom in July 1988. The ruminant feed ban accounts for the decline of the epidemic after an interval of about 5 years, approximately equivalent to the average incubation period of BSE. Relatively few cases of BSE have occurred in cattle born after 1993, and it is predicted that the epidemic will terminate about the year 2000 based on an extrapolation of the present declining curve. A comparison of data from the United Kingdom with data from relatively low incidence countries, such as Switzerland, indicates that this epidemic has been mainly confined to the United Kingdom because of a unique concatenation of risk factors, including: 1) a high ratio of sheep to cattle; 2) a relatively high rate of endemic scrapie; 3) the heavy feeding of MBM to dairy cattle; and 4) changes in the rendering process used to prepare MBM. Recently, cases of a variant form of Creutzfeldt-Jakob disease (a TSE of humans) have been reported in the United Kingdom. These cases, at least 10 of which had onset in 1994-1995, are distinguished by their occurrence in subjects under age 40 years, by their clinical presentation, and by their neurohistopathologic picture. The appearance of this novel disease and its concentration in the United Kingdom have raised the question that it might represent the transmission of BSE to humans. However, the cases gave no history indicating an unusual exposure to live cattle, to the preparation of beef products, or of dietary exposure to bovine tissues, and it remains to be determined whether they are associated with BSE.

Animal Feed↗
PubMed1996

The effect of soft cervical collars on persistent neck pain in patients with whiplash injury.

OBJECTIVE: To assess the efficacy of soft cervical collars in the early management of whiplash-injury-related pain. METHODS: A controlled, clinical trial was conducted in an urban ED. Adults with neck pain following automobile crashes indicated their initial degrees of pain on a visual analog scale. Patients with cervical spine fractures or subluxation, focal neurologic deficits, or other major distracting injuries were excluded. Patients were assigned to receive a soft cervical collar or no collar based on their medical record numbers. Pain at > or = 6 weeks postinjury was coded as none, better, same, or worse, and analyzed as 3 dichotomous outcomes: recovered (pain = none); improved (pain = none or better); and deteriorated (pain = worse). RESULTS: Of 250 patients enrolled, 196 (78%) were available for follow-up. Of these patients, 104 (53%) were assigned to the soft cervical collar group, and 92 (47%) to the control group. These groups were similar in age, gender, seat position in the car, seat belt use, and initial pain score. Pain persisted at > or = 6 weeks in 122 (62%) patients. The groups showed no difference in follow-up pain category (p = 0.59). There was no significant difference between the 2 groups in complete recovery (p = 0.34), improvement (p = 0.34), or deterioration (p = 0.60). The study had a power of 80% to detect an absolute difference of at least 20% in recovery, 17% in improvement, and 7% in deterioration (2-tailed, alpha = 0.05). CONCLUSIONS: Most patients with whiplash injuries have persistent pain for at least 6 weeks. Soft cervical collars do not influence the duration or degree of persistent pain.

Adult↗
PubMed1995

Tropism of bunyaviruses: evidence for a G1 glycoprotein-mediated entry pathway common to the California serogroup.

The California serogroup is composed of antigenically and biologically related viruses within the Bunyavirus genus of the Bunyaviridae. We used a large panel of murine cells to study their tissue tropisms and found virtually identical patterns of viral replication among all of the members of this serogroup, in contrast to other members of the family (Bunyamwera, Cache Valley, and Punta Toro viruses). By analyzing the nonpermissive infections with both an RNA dot-blot and a virus binding assay, we determined that tropism for cultured cells was determined at the level of entry. A truncated soluble form of the La Crosse G1 glycoprotein (sG1) was expressed in a baculovirus system and, despite slight differences in glycosylation, was shown to resemble native G1 by immunoprecipitation with six monoclonal antibodies. sG1 bound to permissive but not to nonpermissive cell lines, as demonstrated by flow cytometry. The sG1 effectively blocked infection of permissive cell lines with all of the California serogroup viruses, but did not block infection of two other bunyaviruses. These results indicate that the California serogroup bunyaviruses share a common receptor on vertebrate cells which may differ from the receptor used by other Bunyaviridae and demonstrate that the G1 glycoprotein is the virus attachment protein. sG1 will be a useful reagent in the search for a putative receptor molecule.

3T3 Cells↗
PubMed1995

Completion of the La Crosse virus genome sequence and genetic comparisons of the L proteins of the Bunyaviridae.

La Crosse virus is a member of the Bunyavirus genus in the family Bunyaviridae, viruses with trisegmented RNA genomes of mostly negative polarity composed of large (L), medium (M), and small (S) segments. The sequences of the La Crosse/original M and S RNA segments have been previously characterized. Using reverse transcriptase in conjunction with PCR amplification, we have obtained the nucleotide sequence of the L RNA segment, which encodes the viral polymerase in a single large open reading frame. Comparison of the amino acid sequence of the LAC L protein with the sequence of other polymerases from members of the Bunyaviridae, demonstrated the presence of several conserved motifs, some of which are characteristic of many polymerase proteins. A genetic tree comparing the available polymerase proteins of the Bunyaviridae provides insights into the phylogenetic relationships within this large family. Members of the genus Bunyavirus, which are mosquito-borne and infect mammals, have a closer relationship to the plant viruses represented by tomato spotted wilt virus (Tospovirus genus) than to viruses of other genera in the family Bunyaviridae.

Amino Acid Sequence↗
PubMed1995

Protection from La Crosse virus encephalitis with recombinant glycoproteins: role of neutralizing anti-G1 antibodies.

La Crosse virus, a member of the California serogroup of bunyaviruses, is an important cause of pediatric encephalitis in the midwestern United States. Like all bunyaviruses, La Crosse virus contains two glycoproteins, G1 and G2, the larger of which, G1, is the target of neutralizing antibodies. To develop an understanding of the role of each of the glycoproteins in the generation of a protective immune response, we immunized 1-week-old mice with three different preparations: a vaccinia virus recombinant (VV.ORF) that expresses both G1 and G2, a vaccinia virus recombinant (VV.G1) that expresses G1 only, and a truncated soluble G1 (sG1) protein prepared in a baculovirus system. Whereas VV.ORF generated a protective response that was mostly directed against G1, VV.G1 was only partially effective at inducing a neutralizing response and at protecting mice from a potentially lethal challenge with La Crosse virus. Nevertheless, a single immunization with the sG1 preparation resulted in a robust immune response and protection against La Crosse virus. These results indicate that (i) the G1 protein by itself can induce an immune response sufficient for protection from a lethal challenge with La Crosse virus, (ii) a neutralizing humoral response correlates with protection, and (iii) the context in which G1 is presented affects its immunogenicity. The key step in the defense against central nervous system infection appeared to be interruption of a transient viremia that occurred just after La Crosse virus inoculation.

Aging↗