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M W Russell

Publications and source records attributed to M W Russell.

At least 37 records · Page 2Linked to original sources
PubMed2000

Generation of female genital tract antibody responses by local or central (common) mucosal immunization.

Genital antibody responses were compared in female mice immunized intravaginally (i.vag.) or intranasally (i.n.) with a bacterial protein antigen (AgI/II of Streptococcus mutans) coupled to the B subunit of cholera toxin. Serum and salivary antibodies were also evaluated as measures of disseminated mucosal and systemic responses. Although i.vag. immunization induced local vaginal immunoglobulin A (IgA) and IgG antibody responses, these were not disseminated to a remote secretion, the saliva, and only modest levels of serum antibodies were generated. In contrast, i.n. immunization was substantially more effective at inducing IgA and IgG antibody responses in the genital tract and in the circulation, as well as at inducing IgA antibodies in the saliva. Moreover, mucosal and systemic antibodies induced by i.n. immunization persisted for at least 12 months. Analysis of the molecular form of genital IgA indicated that the majority of both total IgA and specific IgA antibody was polymeric, and likely derived from the common mucosal immune system.

Administration, Intranasal↗
PubMed2000

Anti-inflammatory therapy reduces total costs of asthma care compared with bronchodilation: the Asthma Outcomes Registry.

BACKGROUND: Current consensus guidelines recommend reliance on anti-inflammatory drugs to treat asthma, reserving theophylline and other long-acting bronchodilators as adjuncts for patients whose symptoms are not well controlled with anti-inflammatory therapy. The effect of such recommendations on total costs of asthma care has not yet been examined, however. OBJECTIVE: To explore the relation between choice of maintenance therapy with anti-inflammatory agents vs long-acting bronchodilators and annual costs of asthma care using data from the Asthma Outcomes Registry. METHODS: Patients 16 years and older were selected from the Asthma Outcomes Registry cohort if they had received either anti-inflammatories (inhaled corticosteroids or cromones) or long-acting bronchodilators (theophylline, salmeterol, oral beta-agonists, or ipratropium bromide), but not both, for at least 1 year before study entry. Oral corticosteroid-dependent patients, those with other chronic lung disease, and those with incomplete cost data during the 365 days before and after their enrollment in the Asthma Outcomes Registry (baseline and follow-up years) were excluded. The effect of anti-inflammatory vs bronchodilator therapy was assessed by comparing the change (follow-up minus baseline) in total costs of asthma care. RESULTS: A total of 314 patients met criteria for study inclusion (237 treated with anti-inflammatories and 77 treated with bronchodilators). Median costs during the baseline year were similar in the anti-inflammatory and bronchodilator groups ($341 and $335, respectively). In the follow-up year, the median change in cost in the anti-inflammatory group was a decline of $93 compared with an increase of $76 in the bronchodilator group (P < .0001). This treatment effect was consistent across subgroups defined by age and amount of medication consumed. CONCLUSIONS: These findings add support to current guidelines recommending reliance on anti-inflammatory therapy to control asthma. The emergence of new therapeutic agents to control inflammation may continue to reduce the costs of treating this important disease.

Adolescent↗
PubMed1999

Mucosal immunity in the genital tract: prospects for vaccines against sexually transmitted diseases--a review.

PROBLEM: Consistent with the absence of protective immunity resulting from previous infection with Neisseria gonorrhoeae, the genital mucosal immune response in human gonorrhea is weak: only low levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies are detectable against gonococci, and inflammatory cytokine responses are poor. METHOD OF STUDY: Mucosal immunization strategies designed to induce persisting genital antibody responses might afford protection against infection, if appropriate conserved antigens can also be identified. RESULTS: Intragastric or intranasal immunization with bacterial antigens expressed as recombinant chimeric proteins with cholera toxin A2/B subunits induced persisting IgA antibodies in genital and other secretions, and circulating IgG antibodies. CONCLUSION: Although gonococci may avoid inducing or even suppress immune responses during natural infection, alternative approaches to vaccine development may be successful. However, inadequate understanding of the origins of antibodies in the genital tract, and their effector mechanisms, will need to be rectified to make this possible.

Bacterial Vaccines↗
PubMed1999

Protective immunity against Streptococcus mutans infection in mice after intranasal immunization with the glucan-binding region of S. mutans glucosyltransferase.

Here we present the construction and characterization of a chimeric vaccine protein combining the glucan-binding domain (GLU) of the gtfB-encoded water-insoluble glucan-synthesizing glucosyltransferase enzyme (GTF-I) from Streptococcus mutans and thioredoxin from Escherichia coli, which increases the solubility of coexpressed recombinant proteins and stimulates proliferation of murine T cells. The protective potential of intranasal (i.n.) immunization with this chimeric immunogen was compared to that of the GLU polypeptide alone in a mouse infection model. Both immunogens were able to induce statistically significant mucosal (salivary and vaginal) and serum responses (P < 0.01) which were sustained to the end of the study (experimental day 100). Following infection with S. mutans, sham-immunized mice maintained high levels of this cariogenic organism ( approximately 60% of the total oral streptococci) for at least 5 weeks. In contrast, animals immunized with the thioredoxin-GLU chimeric protein (Thio-GLU) showed significant reduction (>85%) in S. mutans colonization after 3 weeks (P < 0.05). The animals immunized with GLU alone required 5 weeks to demonstrate significant reduction (>50%) of S. mutans infection (P < 0.05). Evaluation of dental caries activity at the end of the study showed that mice immunized with either Thio-GLU or GLU had significantly fewer carious lesions in the buccal enamel or dentinal surfaces than the sham-immunized animals (P < 0.01). The protective effects against S. mutans colonization and caries activity following i.n. immunization with GLU or Thio-GLU are attributed to the induced salivary immunoglobulin A (IgA) anti-GLU responses. Although in general Thio-GLU was not significantly better than GLU alone in stimulating salivary IgA responses and in protection against dental caries, the finding that the GLU polypeptide alone, in the absence of any immunoenhancing agents, is protective against disease offers a promising and safe strategy for the development of a vaccine against caries.

Administration, Intranasal↗
PubMed1999

A controlled clinical study of the effect of nasal immunization with a Streptococcus mutans antigen alone or incorporated into liposomes on induction of immune responses.

Recent attention to mucosal immunization strategies has been focused on the nasal route for vaccine delivery. This study was designed to determine the effectiveness of a liposome-protein vaccine compared to that of a protein-only vaccine in inducing immune responses in humans. Healthy subjects were randomly assigned to two groups and immunized intranasally with a crude antigen preparation rich in glucosyltransferase (C-GTF) from Streptococcus mutans, alone or in liposomes. Parotid saliva, nasal wash, and serum were collected prior to and at weekly intervals following immunization and were analyzed for anti-C-GTF activity by enzyme-linked immunosorbent assay. The levels of immunoglobulin A (IgA) anti-C-GTF activity in the nasal wash from both groups after immunization increased to a mean peak of fivefold over the baseline level on day 28. Salivary IgA anti-C-GTF responses were induced to a lesser extent. IgG and IgA anti-C-GTF responses in serum were detected on day 14. The IgA responses were predominantly of the IgA1 subclass. These results show that C-GTF vaccines were more effective in inducing a local secretory IgA antibody response than a salivary or serum response when they were given intranasally. The IgA1 anti-C-GTF response in nasal wash samples for liposomal antigen versus antigen only was the only response which was significantly different (P < 0.04). This suggests that the form of the antigen affects the magnitude of the local mucosal response but not that of a disseminated response. These results provide evidence for the effective use of a nasal protein vaccine in humans for the induction of mucosal and systemic responses.

Administration, Intranasal↗
PubMed1999

Functional and immunogenic characterization of two cloned regions of Streptococcus mutans glucosyltransferase I.

Glucosyltransferase (GTF) enzymes of mutans streptococci are considered virulence factors due to their ability to synthesize adhesive glucans, which facilitate cell-to-cell adherence and accumulation. In this study we report the cloning, expression, and characterization of the catalytic (CAT) and glucan-binding (GLU) domains of S. mutans GTF-I encoded by gtfB. The CAT and GLU polypeptides represent amino acid residues 253 to 628 and 1183 to 1473, respectively, of S. mutans GTF-I. Antibodies to recombinant CAT and GLU were generated in rabbits and purified by affinity chromatography. Purified anti-CAT antibodies significantly inhibited water-insoluble glucan synthesis by S. mutans and S. sobrinus GTFs (P < 0.0001 and P < 0.05, respectively). The purified anti-GLU antibodies significantly inhibited both water-insoluble and water-soluble glucan synthesis by S. mutans GTFs (P < 0.0001 and P < 0.05, respectively). These results demonstrate that anti-CAT and anti-GLU antibodies are capable of inhibiting a variety of GTF activities. Since antibodies to S. mutans in saliva are implicated in protection against disease, we next assessed the ability of CAT and GLU polypeptides to induce mucosal antibody responses in mice. Intranasal (i.n.) immunization of mice with CAT showed significantly (P < 0.005) elevated levels of specific immunoglobulin G (IgG) antibody activity in serum and specific IgA antibody activity in serum, saliva, vaginal washes, and fecal samples. GLU immunized animals showed significantly (P < 0.005) elevated levels of specific IgA antibody activity in serum and vaginal secretions. Taken together, these results demonstrate that the recombinant CAT and GLU polypeptides are effective in inducing both mucosal and systemic immune responses. The ability of these polypeptides to induce a mucosal IgA immune response in mice after i.n. immunization supports their use as subunit vaccine candidates in the development of an anticaries vaccine.

Animals↗
PubMed1999

Limited local and systemic antibody responses to Neisseria gonorrhoeae during uncomplicated genital infections.

Repeated infections with Neisseria gonorrhoeae are common among patients attending sexually transmitted disease clinics. We examined whether previous infections or site of infection altered the local and systemic antigonococcal antibody levels in males and females. Antibodies against N. gonorrhoeae MS11 and the patients' homologous infecting isolates were measured by enzyme-linked immunosorbent assay. In general, the local and systemic immune responses to gonococci were extremely modest. There was a slight increase in serum immunoglobulin G (IgG) against the MS11 strain and the homologous isolates in infected males. Levels of serum IgA1 antibodies against MS11 were slightly higher in infected than in uninfected females. A history of previous infections with N. gonorrhoeae did not alter the antibody levels in patients with a current infection, suggesting that immunological memory is not induced by uncomplicated gonococcal infections. Antibody responses to infected subjects' homologous isolates were observed in cervical mucus; IgA1 levels increased while IgG levels decreased. The decline in mucosal IgG against the homologous isolates was less common in subjects having both rectal and cervical infections; otherwise, no effect of rectal involvement was observed. The absence of substantially higher antibody levels to gonococci where there is infection at a site known to contain organized lymphoid tissue suggests that the low levels of responses to uncomplicated infections may not be due simply to an absence of inductive sites in the genital tract. We propose that in addition to its potential ability to avoid the effects of an immune response, N. gonorrhoeae does not elicit strong humoral immune responses during uncomplicated genital infections.

Antibodies, Bacterial↗
PubMed1999

Secretory immunity in defense against cariogenic mutans streptococci.

Specific immune defense against cariogenic mutans streptococci is provided largely by salivary secretory IgA antibodies, which are generated by the common mucosal immune system. This system is functional in newborn infants, who develop salivary IgA antibodies as they become colonized by oral microorganisms. The mechanisms of action of salivary IgA antibodies include interference with sucrose-independent and sucrose- dependent attachment of mutans streptococci to tooth surfaces, as well as possible inhibition of metabolic activities. The goal of protecting infants against colonization by mutans streptococci might be accomplished by applying new strategies of mucosal immunization that would induce salivary IgA antibodies without the complications of parenteral immunization. Strategies of mucosal immunization against mutans streptococci currently under development include the use of surface adhesins and glucosyltransferase as key antigens, which are being incorporated into novel mucosal vaccine delivery systems and adjuvants. The oral application of preformed, genetically engineered antibodies to mutans streptococcal antigens also offers new prospects for passive immunization against dental caries.

Adhesins, Bacterial↗
PubMed1998

Molecular cloning of the human HAND2 gene.

We have cloned and characterized the coding sequence of the human HAND2 basic helix-loop-helix transcription factor. The amino acid sequence includes an amino-terminal polyalanine repeat which is precisely conserved in the rat HAND2 gene. Northern analysis indicates that the HAND2 transcript is 2.3 kb in length and strongly expressed in the human heart.

Amino Acid Sequence↗
PubMed1998

Cost-effectiveness of statins.

Currently, 6 hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are marketed in the United States (US). Given the wide variation in the prices and efficacy of statins, formal cost-effectiveness analysis may improve drug selection decisions. To assess the cost-effectiveness of statin therapy in primary and secondary prevention of coronary heart disease, we developed a model of the costs and consequences of lipid-regulating therapy and estimated the incremental cost-effectiveness of 5 statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) at usual starting doses versus no therapy. Drug effects on serum lipids were assessed using data approved by the US Food and Drug Administration for product labeling. Annual risks of coronary event occurrence were estimated using Framingham Heart Study coronary risk equations developed for use in this model. Current estimates of direct medical costs of coronary heart disease were used to assign costs to health states and acute coronary events. Main outcome measurements were net cost (statin therapy minus savings in coronary heart disease treatment), gain in life expectancy, and cost per life-year saved. The maximum gain in life expectancy was achieved with atorvastatin, which also had a lower net cost than lovastatin, pravastatin, and simvastatin. Compared with fluvastatin, atorvastatin's greater effectiveness is attained at a lower cost per life-year saved. The cost-effectiveness of HMG-CoA reductase inhibition in primary and secondary prevention of coronary heart disease has been improved with the introduction of atorvastatin.

Aged↗
PubMed1998

Direct medical costs of coronary artery disease in the United States.

To generate current incidence-based estimates of the direct medical costs of coronary artery disease (CAD) in the United States, a Markov model of the economic costs of CAD-related medical care was developed. Risks of initial and subsequent CAD events (sudden CAD death, fatal/nonfatal acute myocardial infarction [AMI], unstable angina, and stable angina) were estimated using new Framingham Heart Study risk equations and population risk profiles derived from national survey data. Costs were assumed to be those related to treatment of initial and subsequent CAD events ("event-related") and follow-up care ("nonevent-related"), respectively. Cost estimates were derived primarily from national public-use databases. First-year direct medical costs of treating CAD events are estimated to be $17,532 for fatal AMI, $15,540 for nonfatal AMI, $2,569 for stable angina, $12,058 for unstable angina, and $713 for sudden CAD death. Nonevent-related direct costs of CAD treatment are estimated to be $1,051 annually. The annual incidence of CAD in the United States is estimated at 616,900 cases, with first-year costs of treatment totaling $5.54 billion. Five- and 10-year cumulative costs in 1995 dollars for patients who are initially free of CAD are estimated at $9.2 billion and $16.5 billion, respectively; for all patients with CAD, these costs are estimated to be $71.5 billion and $126.6 billion, respectively. The direct medical costs of CAD create a large economic burden for the United States health-care system.

Adult↗
PubMed1998

Heritability of ECG measurements in adult male twins.

To assess the genetic contribution to electrocardiographic (ECG) measurements, heritability analysis was performed on ECG data collected on 251 pairs of adult male twins during the second examination of the National Heart, Lung and Blood Institute twin study, a multicenter study of cardiovascular risk factors. Resting 12-lead ECGs were obtained on each twin, pair and, the R-R, QRS, QT, and JT intervals were measured. Both the R-R and QT intervals demonstrated significant heritable components, accounting for 77% and 36%, respectively, of the variability. No significant heritable component of the QRS complex could be identified. Although the MZ intraclass correlation was higher than the DZ intraclass correlation, the JT interval did not demonstrate significant heritability. Therefore, in adult males both heart rate and the duration of ventricular repolarization have significant heritable components. These heritable components may need to be considered when using ECG measurements to screen for patients at risk for cardiovascular disorders or sudden cardiac death.

Adult↗
PubMed1998

Cytokine and antibody responses in women infected with Neisseria gonorrhoeae: effects of concomitant infections.

The levels of interleukin (IL)-1, IL-6, IL-8, IL-10, and transforming growth factor-beta in sera and genital tract secretions from women with gonococcal cervicitis and other genital infections were examined. Cytokines were not elevated in genital secretions from gonococcus-infected compared with uninfected patients. The level of serum IL-6 was higher in gonococcus-infected than in uninfected patients at recruitment. Serum, but not local, IL-1 and IL-6 levels were elevated in patients concomitantly infected with Trichomonas vaginalis or Chlamydia trachomatis in addition to Neisseria gonorrhoeae compared with levels in patients infected with any single organism. Concomitant infection altered neither the total immunoglobulin concentrations nor the levels of antigonococcal antibodies in serum or local secretions. The results suggest that N. gonorrhoeae induces only a limited cytokine and antibody response during uncomplicated cervical infections; however, the presence of other sexually transmitted disease-causing organisms can alter the systemic cytokine but not the antigonococcal antibody levels.

Adolescent↗
PubMed1998

Evaluation of immunoglobulin A1 (IgA1) protease and IgA1 protease-inhibitory activity in human female genital infection with Neisseria gonorrhoeae.

Immunoglobulin A1 (IgA1) protease, an enzyme that selectively cleaves human IgA1, may be a virulence factor for pathogenic organisms such as Neisseria gonorrhoeae. Host protection from the effects of IgA1 protease includes antibody-mediated inhibition of IgA1 protease activity, and it is believed that the relative balance between IgA1 protease and inhibitory antibodies contributes to the pathogenesis of disease caused by IgA1 protease-producing organisms. We have examined the levels of these two opposing factors in genital tract secretions and sera from women with uncomplicated infection with N. gonorrhoeae. When IgA1 in cervical mucus was examined by Western blotting, no evidence of cleavage fragments characteristic of IgA1 protease activity was seen in gonococcus-infected or control patients. Cleavage fragments typical of IgA1 protease were detected, however, after the addition of exogenous IgA1 protease to cervical mucus. Degraded IgA1 was detected in some vaginal wash samples, but the fragment pattern was not typical of IgA1 protease activity. All N. gonorrhoeae isolates from the infected patients produced IgA1 protease in vitro. All but two serum samples and 16 of 65 cervical mucus samples displayed inhibitory activity against gonococcal IgA1 protease, but there was no significant difference in the level of inhibitory activity between gonococcus-infected and noninfected patients in either cervical mucus or serum. There was no difference in the levels of IgA1 protease-inhibitory activity in serum or cervical mucus collected from patients at recruitment and 2 weeks later. These results suggest that cleavage of IgA1 by gonococcal IgA1 protease within the lumen of the female lower genital tract is unlikely to be a significant factor in the pathogenesis of infections by N. gonorrhoeae.

Adolescent↗
PubMed1998

Comparison of an adherence domain and a structural region of Streptococcus mutans antigen I/II in protective immunity against dental caries in rats after intranasal immunization.

Previous studies have identified an N-terminal saliva-binding region (SBR) on Streptococcus mutans surface antigen I/II (AgI/II) and suggested its importance in the initial adherence of S. mutans to saliva-coated tooth surfaces and subsequent development of dental caries. In this study, we compared the SBR with a C-terminal structural region of AgI/II (AgII) in their abilities to induce protective immunity against caries in rats. When SBR, AgII, or the whole AgI/II molecule was administered intranasally as a conjugate with the B subunit of cholera toxin (CT), in the presence of CT adjuvant, substantial levels of salivary immunoglobulin A anti-AgI/II antibodies were induced. Evaluation of caries activity showed that the SBR, though not as protective as the parent molecule, was superior to AgII and thus can be further considered as a component in a multivalent caries vaccine.

Administration, Intranasal↗
PubMed1998

Passive and active protection against disorders of the gut.

The large surface area of mucosal surfaces, particularly of the gastrointestinal tract, is protected against microorganisms and environmental antigens by various innate factors (e.g., mucins, lactoferrin, and others) and specific antibodies which are of IgA, or in some species, IgG Isotypes. Passive protection provided by effective prenatal transplacental transport of maternal antibodies and/or post-natal consumption of milk antibodies in breastfed newborns, is essential for the survival of neonates. Passive protection of mucosal surfaces by pre-formed antibodies in non-breast juveniles or adults is currently used only on an experimental basis: IgA-enriched preparations of gamma-globulin have been successfully given to children, and antibodies specific for several gastrointestinal pathogens have been isolated from immunized cows' milk, hens' eggs, or transgenic plants. Systemic administration of pre-formed antibodies is effective for protection against intestinal pathogens in species (e.g., mice, rats) endowed with efficient hepatobiliary transport of IgA into the gut lumen. However, this route of antibody administration is of limited efficiency in other species, including humans, in which almost all intestinal antibodies are produced locally by plasma cells in the gut mucosa and are not derived to a significant degree from the circulation. Active immunization is preferable for long-lasting protection. The site of immunization and presence of lymphoid tissues with inductive potential play an essential role in generating humoral immune responses in mucosal secretions. The relative efficiency of immunization routes (e.g., oral, nasal, rectal or genital) in the induction of preferential antibody responses in the intestinal secretion has not been studied extensively. Furthermore, suitable antigen delivery systems for achieving this goal must also be considered.

Animals↗