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Study Objective: Mucociliary clearance is an important host defense function of the upper respiratory tract that requires the coordinated beating of cilia and results in the transport of mucus to the oropharynx. Guaifenesin is a commonly prescribed drug that is reported to improve the clearance of respiratory secretions. We hypothesized that guaifenesin increases nasal mucociliary clearance related to increases in ciliary beat frequency (CBF) and that a direct relationship exists between nasal CBF and nasal mucociliary clearance., Design: Double-blind placebo-controlled crossover study., Participants: Ten healthy volunteers with a previous history of sinus disease., Interventions: Subjects received guaifenesin or placebo on days 1 to 7 or days 14 to 21., Measurements and Results: In vivo saccharine transit time (STT) was measured by noting the time in minutes required for the subject to taste a saccharin particle placed on the inferior turbinate of the naris. The CBF was determined by video microscopy on ten separate groups of beating ciliated nasal mucosal cells obtained by brushing immediately after each STT determination. We found that there was no significant change between the guaifenesin-or placebo-treated groups from baseline values of STT (p = 0.94) or CBF (p = 0.46). Regression analysis demonstrated no relationship between STT and CBF for repeated measures within subjects (mean r2 = 0.18; mean p = 0.66) and between STT and CBF when all paired measurements were combined across subjects (r2 = 0.47; p = 0.46)., Conclusion: We conclude that guaifenesin exerts no measurable effect on in vivo nasal mucociliary clearance or ex vivo nasal ciliary motility in healthy volunteers with previous sinus disease. In addition, there appears to be no relationship between nasal STT measured in vivo and CBF measured ex vivo. The lack of correlation is most likely due to variations in CBF related to sampling artifacts introduced by the nasal brushing process.

The in vitro anti-viral activity of garlic extract (GE) on human cytomegalovirus (HCMV) was evaluated by tissue culture, plaque reduction and early antigen assay. A dose dependent inhibitory effect of GE was evident when GE was applied simultaneously with HCMV. But the effect was stronger when the monolayers were pretreated with GE. In addition, the anti-viral effect of GE persisted long in infected cells after its being removed from the culture medium. The strongest anti-viral effect of GE was demonstrated when it was applied continuously. It is therefore recommended that clinical use of GE against HCMV infection should be persistent and the prophylactic use of GE is preferable in immunocompromised patients.

IgA antibodies produced by plasma cells in secretory tissues associated with mucosal surfaces represent a major host defense against infectious agents. Precursors of these IgA-producing cells originate in gut-associated lymphoid tissue and, to a lesser extent, in bronchial-associated lymphoid tissue and migrate via the blood not only to gut but also to other mucosal tissues, forming a common mucosal immune system. Oral administration of antigen leads to priming of precursor cells in the gut and subsequent occurrence of specific secretory IgA (S-IgA) antibody in saliva, milk, tears, and the respiratory and genital tracts. On the basis of a review of the world literature, it has been concluded that oral live vaccines elicit higher antibody titers in remote-site secretions and in serum than do oral killed vaccines, which usually stimulate only relatively low levels of local secretory antibody. Oral immunization induces S-IgA in children and adults (including the elderly) without detectable adverse effects. Despite a number of remaining questions, oral immunization against extraintestinal infections is a promising area for future clinical studies.

Secretory IgA antibody may be important in protection against respiratory viral infections, and the concept of a common mucosal immune system offers the theoretical basis for the convenient stimulation of this antibody. Therefore, the oral route was compared with intramuscular injection in a double-blind, placebo-controlled study in young healthy volunteers. A killed influenza vaccine, given in enteric-coated capsules (total of 98 ug hemagglutinin of A/Bangkok) led to significant salivary and nasal IgA antibody rises in a 4-week period. The preimmunization titers in secretions were inversely correlated with the antibody rise after immunization. The orally administered vaccine was associated with no more side effects than placebo, in contradistinction to reactions following the intramuscular route. The latter route also was without significant effect in regard to a stimulation of secretory antibodies. The observed simultaneous induction of antibodies in saliva and nasal secretions following oral administration of killed vaccine gives further evidence of a common mucosal immune system and its possible clinical use.

Cell mediated immunity in the respiratory tract, operating somewhat independently of systemic cell mediated immunity CMI, has been recognized only rather recently. Local CMI has been shown to be more consistently and more potently stimulated following local administration of immunogen. In addition, in the few studies that have been done relative to protection, local immunization has resulted in greater resistance to organisms usually considered protected against by CMI. Thus, like the humoral immune system, CMI appears to operate locally in the respiratory tract, at least partially independent of systemic CMI. This paper deals with the evidence relative to local CMI, as well as a discussion of the role of the pulmonary macrophage, the mechanisms whereby local CMI may operate in protection, and the evidence for the presence of T-cell memory in the respiratory tract.

In the elderly, respiratory infections are frequent and constitute the leading cause of death. Presumably this is the consequence of reduced local immunity in the respiratory tract. The present knowledge based on investigations in man and laboratory animals, including results of own research, is reviewed. Further research is needed to give a definite answer and to improve immunoprophylaxis in the elderly.

Publications produced by faculty over a three-year period are used in analyzing the relative research productivity of basic and clinical science departments in a college of medicine. The citation ratings of the journals, the number of authors, and the byline position of the faculty member are used in various publication evaluation schemes. The departments vary almost tenfold in research productivity per faculty member. Results of the analysis demonstrate that the number of authors and the byline position influence departmental productivity rankings very little. Rankings are substantially affected, however, when the journals are weighted based heavily on citation ratings.

Bacille Calmette-Guérin (BCG) has been used effectively to protect nonspecifically against bacterial infections and neoplasms, probably by enhancement of cell-mediated immunity. It has been suggested that cell-mediated immunity plays a role in the host defense against certain viral infections. In recent in vitro studies, macrophages from animals sensitized by BCG were more effective in lowering the titer of influenza virus than were macrophages from control animals. The purpose of this study was to investigate the in vivo effectiveness of nonspecific immune stimulation with BCG on influenza virus infection in mice. Immunization with BCG resulted in significant protection of mice. Also, the local (nasal) route of immunization was more effective than the systemic (intraperitoneal) route against the intranasal inoculum of virus, a finding which suggests that important role of local immunity, i.e., either earlier stimulation of secretory antibody or nonspecific cell-mediated immunity. The time course of the resistance ot infection suggests that interferon was not the protective mechanism.

Since oral immunization against influenza might be much more convenient than the aerosol or intranasal route, this study was undertaken to compare various routes of immunization with respect to the antibody response and protection. Mice were either not immunized, immunized intranasally, orally, or rectally. - As compared to the control group, statistically significantly more animals in all of the immunization groups developed antibody in the bronchial washings and showed stimulated alveolar macrophages with the largest percent developing antibody and stimulated cells in the nasally immunized group. However, the difference between the three vaccine groups was not statistically significant. - Following challenge with live virus there was a significant rise in lung lavage cells only in the unimmunized, challenged control group. There was no significant rise in the immunized group. - These results suggest that while the respiratory route of immunization may lead to slightly better local antibody production and protection, the oral route is a promising method, and should be tried in humans.

In order to compare the antibody response in serum and secretions from healthy young subjects and the elderly (greater than 60 years), volunteers were immunized with the commercial inactivated influenza virus vaccine, by the usual (parenteral) route or orally. Also, young and old mice (mean age, 20 months) were orally immunized with live influenza virus. The older mice responded with a very slight rise in their serum and respiratory tract antibody levels compared with the young mice but showed no diminution in protection against lethal viral challenge. Elderly volunteers showed only slight serum antibody responses after parenteral immunization compared with the young. Neither group demonstrated a rise in serum antibody following oral immunization. With respect to the secretory IgA (SIgA) antibody response, certain differences were noted between the young and the elderly: the preimmunization levels of antibody to influenza virus were significantly greater in nasal secretions and saliva in the elderly as compared to the young volunteers, and the salivary antibody response was diminished in the elderly. This lack of a salivary antibody response in the elderly was explicable by the inverse relationship between the preimmunization SIgA antibody titers and the response to immunization. Oral immunization led to no more side effects than observed in the placebo control group.

An effective influenza virus vaccine should be capable of inducing protection against both the homologous strain of virus and the heterologous strains representing antigenic drift. For evaluation of the protection provided by an attenuated influenza virus vaccine, volunteers were immunized intranasally with either placebo or influenza A/England/42/72 (H3N2) virus vaccine in a double-blind fashion in two doses administered two weeks apart. Forty-seven subjects were challenged 30-100 days after the second dose with either the homologous or a virulent heterologous strain of virus [A/Dunedin/73 (H3N2)]. The vaccine resulted in good clinical protection against challenge with both the homologous and heterologous strains of virus. The rates of protection against infection (as judged by antibody responses, irrespective of signs and symptoms) were also good (72% and 60% against the homologous and heterologous strains, respectively). Thus, immunity induced by this attenuated influenza virus vaccine extends to provide protection against a related but nonidentical influenza virus.

In an effort to evaluate a new Conjoint Psychiatric-Medical Unit, depressed patients treated on the service are compared with depressed patients treated on the same unit when it was a psychiatric service. Recidivism, return to responsibilities, and patient satisfaction are the parameters that are compared, and no significant differences are noted. These findings would suggest that the new Inpatient Service appears to be an effective treatment modality for depressed patients.

By ingestion of subunit-killed influenza virus vaccine in the form of enteric-coated capsules, local synthesis of secretory IgA (sIgA) antibody was stimulated in human nasal secretions. A fairly equal antibody response initiated by oral and intramuscular administration was demonstrated in the nasal secretions, although a systemic immune response was not elicited from ingestion of the vaccine. If the secretory antibody response resulted from absorption of antigen and transport to the respiratory mucosa, systemic (serum) antibody would be expected. Therefore these findings support the hypothesis that specialized collections of lymphoid cells in the small intestines have IgA precursor cells which circulate and populate distant mucosal sites. A number of studies have suggested that protection against mucosal infection by a variety of respiratory viruses correlates better with the presence and level of sIgA antibody than with serum antibody. The orally administered vaccine was associated with no more side effects than placebo, in contradistinction to the intramuscular route. Thus, the oral method of influenza vaccination could prove to be superior in providing for immunological protection due to equal secretory antibody stimulation, improved convenience and less toxicity.

Psychiatry has been integrated into the Department of Internal Medicine at the West Virginia University School of Medicine as a means of ameliorating the educational and patient care deficiencies engendered by the traditional mind-body dichotomy in medical education. A major project derived from this merger of clinical and teaching activities has been the transformation of the university hospital psychiatric ward in to the Conjoint Medicine Service. This service, to which patients with a variety of emotional and medical problems are admitted, is staffed by medical house officers and a general internist in a close collaborative relationship with the Department of Psychiatry. The nursing care is oriented toward patient education, exemplified by group sessions. House staff and students are trained to recognize and evaluate the underlying emotional and interrelational factors which affect each patient's health status and prognosis as a routine part of a comprehensive medical work-up. Student and patient acceptance of this integrated approach has been enthusiastic.

The content of alpha-1-antitrypsin in the serum, alveolar lavage fluid, and alveolar macrophages of smokers and nonsmokers was studied. Bronchoalveolar lavage was used to obtain alveolar fluid and macrophages from normal volunteers, and alpha-1-antitrypsin and albumin were measured using the electroimmunodiffusion technique. The serum level of inhibitor was not different between the two groups, while the total lavage fliud content of alpha-1-antitrypsin was increased in the smokers. The level of alpha-1-antitrypsin was also significantly greater (P less than 0.001) in the alveolar macrophages of the smokers suggesting the possibility of chronically increased alveolar levels in the cigarette smoker as a possible protective mechanism against proteolysis.

The effects of attenuated rubella virus infection upon cell-mediated immunity of human volunteers were studied. The volunteers received the vaccine either by nose drops or by the subcutaneous route. Changes in cell-mediated immunity in terms of delayed cutaneous sensitivity to recall antigens, phytohemagglutination stimulation, and spontaneous migration inhibitory factor-like activity were studied at various time periods after infection. Spontaneous migration inhibitory factor-like activity was studied on supernatants of the lymphocytes obtained from the volunteers and incubated for 72 h in the absence of any antigens. A significant proportion of the volunteers showed suppression of one or more parameters of cell-medicated immunity tested by week 2 of infection compared to the control; however, there was no correlation between suppression of the various parameters studied. No difference was noticed in the incidence of cell-mediated immunity suppression between nose drops and subcutaneous route groups.

Recent studies have suggested that intranasal administration of antigen can induce local cell-mediated immunity in lung lavage cells. The present study was designed to examine the changes in composition of lung lavage cells and their capacity to produce the lymphokine migration inhibitory factor after intranasal immunization with BCG in guinea pigs. Results indicate that guinea pigs responded to respiratory tract BCG infection with an increase in immunocompetent cells in the bronchoalveolar tract and with production of migration inhibitory factor. After local pulmonary BCG administration, the total number of cells increased as compared with that of the uninfected animals, the increase being statistically significant within 2 weeks. This marked increase in the total cell population is due to a more than doubling of the number of macrophages in the lavage fluid. Animals also developed at this time positive delayed hypersensitivity to intradermally administered purified protein derivative. A significant increase in the total lymphoid cells and macrophage population was observed again at 6 weeks after sensitization, suggesting that the response is biphasic in nature. At 6 weeks, however, there was also a significant rise in total lymphocytes and T cell population in addition to macrophage numbers. This increase in T cells correlated with an increase in production of migration inhibitory factor in the presence of purified protein derivative. These data suggest that the immune response of the respiratory tract after BCG challenge involves increased recruitment of immunocompetent cells locally at the site of infection and that these cells are capable of producing effector molecules in terms of the elaboration of migration inhibitory factor.

Alum-precipitated and soluble, purified M protein vaccines were prepared from type 3 and type 12 group A Streptococcus. Adult volunteers were assigned to one of three groups: group I received placebo by both parenteral and intranasal routes; group 2 received vaccine parenterally (either type 3 or type 12) and placebo intranasally; and group 3 received placebo parenterally and vaccine intranasally (either type 3 or type 12). Subjects were inoculated three times at montly intervals. Thirty to 50 days after the last dose, all subjects were challenged with homologous streptococci applied to the oropharynx. Six subjects (30%) vaccinated subcutaneously had definite illness, three (15%) had probable illness, and 11 (55%) had no illness. In the group vaccinated intranasally, four (14%) had definite illness, two (7%) had probable illness, and 22 (79%) had no illness. Fifteen controls (42%) had definite illness, and 21 (58%) had no illness. The rate of colonization was significantly lower in recipients of intranasal vaccine. Average clinical scores and vaccine side effects were also decreased in subjects vaccinated intranasally. Induced serum antibody as measured by passive hemagglutination was not a reliable predictor of resistance to streptococcal pharyngitis. Penicillin was administered to all subjects five days after challenge. No sequelae of streptococcal infection or other complications occurred. Thus, local immunization with M protein apparently may reduce both colonization and clinical illness after challenge with homologous streptococci.

Development of techniques for eliciting an immune response on mucosal surfaces is a relatively new area of clinical research. With the recognition of the existence of secretory immunity, independent of the systemic system, there was renewed interest in re-examining the conventional approach for optimal immunization techniques. A large body of data indicate that the majority of the secretory immunoglobulins and antibody produced to antigenic stimulation of mucosal surfaces is locally produced. Thus, antibody to C. albicans in the cervical or vaginal mucus has been shown to be of local origin and it predominantly belongs to the secretory IgA immunoglobulin class. The mechanism of antigen processing by the secretory surface leading to antibody formation remains a mystery, but it might be determined by the selective localization of antigens in the reticuloendothelial cells of the lamina propria, bronchi or small intestine. Usually application of antigen topically to the mucosal surface elicits local antibody formation to a greater extent than does parenteral immunization. On the other hand, a more pronounced systemic immune response is seen when the antigen is administered systemically. However, a number of other factors determine the quality and quantity of the immune response, e.g., the physical state of the antigen, live vs killed vaccine, dose, adjuvant, previous exposure to similar or cross-reacting antigens, and site of application of the antigen. These factors are discussed in the review. Recent observations suggest that cell mediated immunity is a component of the secretory immune system, and like the humoral mechanism, also may be partially compartmentalized.

The adjuvant activity of avridine, a synthetic lipoidal amine, incorporated in liposomes, was studied in mice immunized orally with killed influenza virus vaccine (A/PR/8/34, H1N1). Coadministration of avridine-containing liposomes and viral antigen enhanced the remote-site IgA antibody response in the respiratory tract without a concomitant serum antibody response or side effects. The results support the possible use of mucosal adjuvants for oral immunization against respiratory pathogens.

The body protects itself from disease through a variety of innate defense mechanisms and through immunity acquired both passively and actively. Passive immunization is achieved through transfer of antibody or of sensitized lymphocytes or their soluble products from an immune donor, while active immunization is achieved through stimulation of the recipient's own protective mechanism by means of exposure to the disease or to pathogens or their toxoids. Among the diseases brought under control or eradicated by means of active immunization are smallpox, polio, and measles. Vaccines for immunization against several other diseases are already being used successfully and further ones are being developed.

The percentage of lymphocyte subpopulations from the bronchoalveolar space of Balb/c-mice expressing B-(Ia), and T-(Thy 1.2, Lyt 1.2 and Lyt 2.2) cell markers was determined using monoclonal antibodies and complement in the direct cytotoxic test. The cells were obtained by lung lavage from unstimulated animals. Only 6% of total cell yield (1.1 +/- 0.8 X 10(5) cells/mouse) showed no adherence and were separated by density centrifugation. The majority (95%) of these cells were esterase-negative lymphocytes. The mice had a higher percentage of B cells (51%) and suppressor cells (14%) and a lower percentage of total T cells (45%) and helper cells (28%) in lavage fluid of lungs than in the blood.

1) Attempts were made to develop oral adjuvants against murine salmonellosis. 2) Streptomycin, levamisole and PHA show potential immunoenhancing properties against salmonella infection. 3) The mode of action of these agents remain to be elucidated. Observed results of PHA enhancement may be related to its blastogenic effects in the splenic T-cells. 4) Decrease in certain bacterial flora resulting in less antigenic competition may be the mode of action of streptomycin as adjuvant when added to oral salmonella vaccine.

The incubation fluid from 24-hr cultures of normal guinea pig small intestines was found to contain activity capable of inhibiting the migration of normal guinea pig peritoneal macrophages. Each of three different culture fluids showed macrophage inhibitory activity in the 25,000-55,000 mol wt range when subjected to Sephadex G-100 gel filtration. One of these three preparations also contained inhibitory activity in the excluded volume. The low molecular weight activity was nondialyzable and heat stable to 56 degrees for 30 min. It was destroyed by boiling for 1 hr, and its activity was reversed by 10(-4)M epinephrine. Based upon these properties it is suggested that this activity was due to migration inhibitory factor (MIF). The high molecular weight inhibitor was stable to heating and its activity was not reversed by epinephrine. This material was most likely endotoxin. The presence of MIF, which may be associated with T-cell activity in the intestine, suggests that cell-mediated immunity (CMI) could play a role in local protection against gut infections. Furthermore, its presence in normal intestinal secretions suggests that some MIF-producing cells are always being stimulated by normal flora. The question is thus raised whether further specific stimulation of local CMI in the gut could be successful.

Oral immunization of 5 volunteers with an enteric-coated inactivated influenza vaccine resulted in a significant rise of IgA-specific antibodies in tears, saliva and nasal secretion, reaching a maximum response 5-7 weeks after completion of immunization.

The infectious etiologic agents of gastroenteritis are manifold and have only recently been studied in greater depth. Part of the problem in studies pertaining to diarrhea is the difficulty in identifying fecal "pathogens" among an enormous number of indigenous fecal microorganisms. Finally, the recognition of the pathogenicity of enterotoxins has created an awareness of the complexity of gastrointestinal physiology with host-parasite interactions.