Immunization schedules for the new human diploid cell vaccine against rabies

The records of 340 patients treated surgically over the 20 year period 1950 through 1969 at this clinic for primary epidermoid carcinoma of the anterior two-thirds of the tongue were reviewed to evaluate the effectiveness of elective versus therapeutic radical neck dissection in their treatment. There has been a change in the clinical presentation of this disease, with more people presenting at an earlier stage, with a smaller primary lesion and fewer cervical node metastases. The over-all survival rate has shown a marked improvement to 69 per cent at five years. The proportion of women afflicted has increased. The status of the cervical nodes is a major prognostic factor, the determining five year survival rate being reduced from 78 to 26 per cent if the nodes are metastatically involved. It cannot be directly proved that removal of occult metastasis to the neck by elective radical neck dissection before nodes are clinically detectable leads to a better survival rate partly because the two groups being compared are selected and not randomly assigned. However, the marked tendency for carcinoma of the tongue to metastasize regionally at some time in its course, the significant error in clinical evaluation of the neck, the significant conversion of clinically negative nodes to positive in patients not treated with radical neck dissection, the poor prognosis after treatment of conversion from clinically negative into positive and the fact that more than half of the deaths are due to uncontrolled disease of the neck alone, make us strongly favor the principle of elective radical neck dissection to enhance the survival time in the group of patients without clinical evidence of nodal involvement. With current surgical expertise, the mortality and morbidity rates of simultaneous radical neck dissection are low, and the potential benefit of the procedure outweighs its potential risks. Obviously, elective radical neck dissection, if beneficial, would most likely be so in patients with the highest likelihood of having occult metastasis.     

Requirement for multiple lymphocyte subsets in protection by a live attenuated vaccine against retroviral infection

STUDY DESIGN: A case report and literature review of thoracic hyperkyphosis deformity secondary to glucocorticoid-induced osteoporosis in Cushing's disease. OBJECTIVES: To identify the pathophysiology of glucocorticoid-induced osteoporosis and to outline the diagnosis and treatment options for a patient with severe spinal deformity secondary to unrecognized excess glucocorticoid activity. SUMMARY OF BACKGROUND DATA: Glucocorticoid-induced osteoporosis is seen in patients exposed to supraphysiologic levels of endogenous or exogenously administered glucocorticoids. In these patients, glucocorticoids act to suppress bone formation and increase bone resorption by indirect and direct effects. These patients have a high prevalence of trabecular bone loss, resulting in much higher rates of vertebral body collapse and pathologic fracture and thus causing an increased propensity toward kyphotic spinal malalignment. METHODS: The literature was reviewed and case reports studied. This case report highlights the pathophysiology of the disease process that caused the spinal deformity and the surgical intervention used to correct the kyphotic deformity after the metabolic problem was resolved. RESULTS: This patient has responded well to treatment and surgical intervention to correct a thoracic hyperkyphotic deformity without complication. CONCLUSIONS: Unrecognized endogenous production of glucocorticoids in Cushing's disease should be considered in young adult patients with progressive osteoporotic spinal deformities.     

Immunogenic characterization of a tissue culture-derived vaccine that affords partial protection against avian coccidiosis

The immunogenicity of a tissue culture-derived vaccine generated from an Eimeria tenella-infected cell line in a serologically defined bird line, and the ability to confer protection against homologous challenge in young chicks was examined. The cell line, SB-CEV-1/F7, was infected with E. tenella sporozoites and the resulting 72-h postinfection cell-free supernatants were adjuvanted and used to immunize Leghorn chicks homozygous for the B19 haplotype. Peripheral blood and splenic lymphocytes from these immunized birds proliferated in vitro in response to both sporozoite and SB-CEV-1/F7 tissue culture-derived parasite antigens. In addition, splenic immune lymphocytes obtained from birds previously exposed to E. tenella in vivo responded to these tissue culture-derived parasite antigens in vitro. To evaluate the efficacy of the vaccine, B19B19 chicks were vaccinated s.c. with adjuvanted 72-h postinfection cell-free supernatants or an ammonium sulfate precipitate derivative thereof, orally boosted, and then subjected to homologous parasite challenge at 10 d of age. The level of protection (body weight gain, cecal lesions) was assessed 6 d after challenge. Performance results from four battery trials demonstrated that vaccinated birds were significantly protected against weight loss compared to unimmunized, challenged controls. In addition, in two of the four trials, vaccinated birds were significantly protected against lesions. These results provide strong evidence that tissue culture-derived parasite antigens obtained from the E. tenella-infected SB-CEV-1/F7 cell line are immunogenic in birds and can provide partial protection against E. tenella clinical coccidiosis.     

Protection against tuberculosis by a plasmid DNA vaccine

BACKGROUND: Incidence of smooth muscle tumors is increased in patients with human immunodeficiency virus infection and organ transplant recipients. Smooth muscle tumors in immunocompromised patients often occur in unusual locations and exhibit evidence of latent infection by clonal, presumably tumorigenic, Epstein-Barr virus (EBV). OBJECTIVE: To investigate the presence of EBV latent infection in smooth muscle tumors in patients with acquired immunodeficiency syndrome and in immunocompetent patients. DESIGN: Twenty-two extrauterine, extraintestinal smooth muscle and myofibroblastic tumors were reviewed pathologically, and clinical charts were screened. Tumors were malignant (15 patients), benign (6 patients), and borderline (1 patient). Tissue specimens were investigated for latent EBV infection by latent membrane protein immunocytochemistry and EBV-encoded RNA in situ hybridization. SETTING: University Hospital of the University of Nancy, France. PATIENTS: Patients were 18 adults and four children. Two adults had acquired immunodeficiency syndrome. Both had low-grade leiomyosarcomas located in adrenal gland. Moreover, in patient 1, leiomyosarcoma was multifocal in pericardium and lymph node; in lymph node, muscle tumor was adjacent to nodal and skin Kaposi's lesions. RESULTS: In both patients with acquired immunodeficiency syndrome and leiomyosarcoma, latent infection by EBV could be demonstrated in tumor cells, contrasting with absence of detectable EBV infection in adjacent non-neoplastic tissues and nearby Kaposi's lesions. Latent infection by EBV could not be demonstrated in smooth muscle and myofibroblastic tumors in immunocompetent patients. CONCLUSIONS: Latent EBV infection is associated with smooth muscle cell tumors in immunocompromised patients, but not in immunocompetent patients.     

Human diploid cell culture rabies vaccine (HDCV) and purified chick embryo cell culture rabies vaccine (PCECV) both confer protective immunity against infection with the silver-haired bat rabies virus strain (SHBRV)

The demonstration of extensive differences in the antigenic makeups of the silver-haired bat rabies virus (SHBRV) and canine rabies virus (COSRV) strains raised concerns as to whether current licensed rabies vaccines are sufficiently protective against SHBRV. NIH mouse protection test results show that both the human diploid cell culture rabies vaccine (HDCV) and the purified chicken embryo cell rabies vaccine (PCECV) protected against lethal infection with SHBRV as well as the canine rabies strain COSRV. However, in this investigation, the potencies of both vaccines in mice were found to be significantly higher for COSRV than for SHBRV. The in vivo protection data are confirmed by in vitro virus neutralizing antibody (VNA) test results which demonstrate that mice immunized with HDCV or PCECV develop significantly higher VNA titres against COSRV than against SHBRV. In contrast, VNA tests of sera from individuals immunized with HDCV or PCECV showed that humans, as opposed to mice, develop significantly higher VNA titres against SHBRV than against COSRV. These data suggest that HDCV and PCECV will protect humans against infection with the silver-haired but rabies virus strain in addition to canine rabies virus strains.     

The roles of perforin- and Fas-dependent cytotoxicity in protection against cytopathic and noncytopathic viruses

In vitro, T cell-dependent cytotoxicity is mediated by two distinct mechanisms, one being perforin-, the other Fas-dependent. The contribution of both of these mechanisms to clearance of viral infections was investigated in mice for the non-cytopathic lymphocytic choriomeningitis virus (LCMV) and the cytopathic vaccinia, vesicular stomatitis (VSV) and Semliki forest (SFV) viruses. Clearance of an acute LCMV infection was mediated by the perforin-dependent mechanism without measurable involvement of the Fas-dependent pathway. For the resolution of vaccinia virus infection and for resistance against VSV and SFV, however, neither of the two pathways was required. These data suggest that perforin-dependent cytotoxicity mediated by T cells is crucial for protection against non-cytopathic viruses, whereas infections with cytopathic viruses are controlled by nonlytic T cell-dependent soluble mediators such as cytokines (IFN-gamma against vaccinia virus) and neutralizing antibodies (against VSV and SFV).     

Intestinal protection against Strongyloides ratti and mastocytosis induced by administration of interleukin-3 in mice

A case control study of AIDS related sclerosing cholangitis indicates that it has no overall influence on prognosis, but is responsible for a striking reversal of the usual inverse correlation of age and survival in HIV infection. Pain, the principal symptom, was controlled in surviving patients with analgesics alone. Twenty consecutive patients with AIDS related sclerosing cholangitis, defined from at least two characteristic lesions at endoscopic retrograde cholangiopancreatography, were followed for a minimum of 10 months or until death. Median age was 33.5 years (range 27-50). All had abdominal pain; 11 had diarrhoea. Alkaline phosphatase was > 2X normal in 13, but the bilirubin was raised in only three. The median CD4 was 0.024 x 10(9)/l (0.005-0.341). Thirteen had cryptosporidiosis, six had active cytomegalovirus, five had no gastrointestinal pathogen. Three patients are alive without AIDS related sclerosing cholangitis symptoms at 10, 11, and 21 months. Seventeen have died at median 7 (1-23) months. Cytomegalovirus therapy had no apparent influence. The initial CD4 was < 0.11 in all those dying within six months, but correlation of CD4 with prognosis was otherwise poor. Controls, matched for age, CD4, and opportunistic infections had virtually identical overall outcome (median survival 7.5 months) and the expected worse prognosis with increasing age. Increasing age, however, appeared protective in AIDS related sclerosing cholangitis (r = +0.6; p < 0.05): this is not explained by disproportionate degrees of immunosuppression, nor by opportunistic infections.     

Economical production of rabies vaccine on cell cultures

By producing the rabies vaccine from cell culture, this vaccination has become safe, with minimal postvaccinal reactions. The first vaccine according to this technology was produced by Pavle (Paul) Fenje, former chief of department of the Pasteur Institute in Novi Sad. Many cell cultures have been introduced so far for the rabies virus multiplication: primary hamster kidney, fetal bovine kidney, chick embryo, continuous cell line monkey kidney (VERO), human diploid cell (HDC), etc. Some possibilities of an economical rabies vaccine production from a continuous BHK-21 cell line have been discussed and recommended.     

Failure of postexposure treatment of rabies in children

In the female mouse, dapsone (50-500 mg kg-1, p.o.) caused a dose-related methaemoglobinaemia which peaked at 0.5-1 h with recovery to baseline values occurring by 4 h. Cimetidine (100 mg kg-1, p.o.), a known inhibitor of several hepatic P450 isozymes administered 1 h before dapsone, prevented the methaemoglobinaemia. In-vitro, dapsone required activation by mouse hepatic microsomes to cause methaemoglobin formation in mouse erythrocytes and cytotoxicity to human mononuclear leucocytes. In both instances, the toxic effects were markedly reduced by cimetidine. Daily dosing of mice with dapsone (50 mg kg-1, p.o.) for 3 weeks induced a blood dyscrasia, characterized by a fall of platelet and white blood cell counts, which was inhibited by cimetidine (100 mg kg-1, p.o. daily). It is concluded that an active metabolite of dapsone arising from a P450-dependent pathway is involved in the genesis not only of the methaemoglobinaemia but also the blood dyscrasia arising from repeated administration of the drug in this species.     

Chimeric influenza viruses incorporating epitopes of outer membrane protein F as a vaccine against pulmonary infection with Pseudomonas aeruginosa

Peptide 10 (NATAEGRAINRRVE, residues 305-318 of mature protein F) is one of two linear B-cell epitopes within outer membrane protein F of Pseudomonas aeruginosa both of which have been shown to elicit whole cell-reactive antibodies and to afford protection in animal models against P. aeruginosa infection. Influenza A virus was chosen as a vector to present this epitope in a human-compatible vaccine. Various lengths of the peptide 10 epitope ranging from a 5-mer (GRAIN), 7-mer (AINRRVE), 8-mer (TAEGRAIN), 9-mer (GRAINRRVE), 11-mer (AEGRAINRRVE) to a 12-mer (TAEGRAINRRVE) were attempted to be presented into the antigenic B-site of the hemagglutinin (HA) of live recombinant influenza virus. Using PCR, DNA sequences encoding these various peptide 10 lengths were inserted into the HA gene of influenza A/WSN/33 virus. By using a reverse-genetics transfection system, RNA transcribed in vitro from these chimeric HA genes was reassorted into infectious virus. To date chimeric viruses have been rescued and purified containing the peptide 10 5-mer, 7-mer, 8-mer, and 11-mer. RT-PCR and sequencing have confirmed the presence of P. aeruginosa sequences in the HA RNA segment of each chimeric virus. Each of the four chimeric viruses produced to date was used to immunize mice to determine the ability of each chimeric virus to elicit antibodies reactive with whole cells of P. aeruginosa. The immunization protocol consisted of a series of three intranasal inoculations, followed by two intramuscular injections of the chimeric virus. The chimeric virus incorporating the 11-mer elicited IgG antibodies that reacted with various immunotype strains of P. aeruginosa in a whole cell ELISA at titers of 80 to 2,560, whereas the chimeric virus incorporating the 8-mer elicited whole cell-reactive IgG antibodies at titers of 320 to 2,560. These data suggest that these two chimeric viruses may have vaccine efficacy against P. aeruginosa infection. These studies may result in the development of a chimeric influenza virus-protein F vaccine which would prove to be suitable for use in children with cystic fibrosis for the prevention of pulmonary colonization of these children with P. aeruginosa.     

Persistence of humoral immunity to rabies 1100 days after immunization and effect of a single booster dose of rabies vaccine

OBJECTIVES: To investigate the relationship between excessive endogenous production of nitric oxide (NO) and the low systemic vascular resistance (SVR) syndrome after cardiac surgery. DESIGN: Prospective, case-control. Cases defined by low SVR postoperatively (< 750 dyn/s/cm-5), and matched with controls (> 900 dyn/s/cm-5). SETTING: Cardiothoracic intensive care unit (ICU) in a tertiary care hospital. PARTICIPANTS: Forty-four patients after cardiac surgery. INTERVENTIONS: Collection of plasma and urine samples after identification. MEASUREMENTS AND MAIN RESULTS: Plasma and urine nitrate concentrations were measured as an index of endogenous NO production. Hemodynamic, inotropic, and outcome data were collected. Median nitrate concentrations did not differ between cases and controls (plasma, 58 mumol/L, v 62 mumol/L, p = 0.43; urine, 399 mumol/L v 404 mumol/L, p = 0.38). Times to extubation and intensive care unit (ICU) discharge were prolonged in patients with low SVR (17.8 hours v 8.7 hours, p = 0.021; 2.5 days v 1.2 days, p = 0.019, respectively). CONCLUSIONS: No association between "low SVR syndrome" and endogenous NO production was found. Patients with low SVR after cardiac surgery required a longer period of inotropic and ventilator support, with delay in discharge from the ICU. The risk and cost implications of this syndrome support further research.     

Oral immunization of macaques with attenuated vaccine virus induces protection against vaginally transmitted AIDS

The chimeric simian-human immunodeficiency virus SHIVKU-1, bearing the envelope of human immunodeficiency virus type 1 (HIV-1), causes fulminant infection with subtotal loss of CD4(+) T cells followed by development of AIDS in intravaginally inoculated macaques and thus provides a highly relevant model of sexually transmitted disease caused by HIV-1 in human beings. Previous studies using this SHIV model had shown that the vpu and nef genes were important in pathogenesis of the infection, and so we deleted portions of these genes to create two vaccines, DeltavpuDeltanefSHIV-4 (vaccine 1) and DeltavpuSHIVPPc (vaccine 2). Six adult macaques were immunized subcutaneously with vaccine 1, and six were immunized orally with vaccine 2. Both viruses caused infection in all inoculated animals, but whereas vaccine 1 virus caused only a nonproductive type of infection, vaccine 2 virus replicated productively but transiently for a 6- to 10-week period. Both groups were challenged 6 to 7 months later with pathogenic SHIVKU-1 by the intravaginal route. All four unvaccinated controls developed low CD4(+) T-cell counts (<200/microliter) and AIDS. The 12 vaccinated animals all became infected with SHIVKU-1, and two in group 1 developed a persistent productive infection followed by development of AIDS in one. The other 10 have maintained almost complete control over virus replication even though spliced viral RNA was detected in lymph nodes. This suppression of virus replication correlated with robust antiviral cell-mediated immune responses. This is the first demonstration of protection against virulent SHIV administered by the intravaginal route. This study supports the concept that sexually transmitted HIV disease can be prevented by parenteral or oral immunization.     

Protection against lethal murine coccidioidomycosis by a soluble vaccine from spherules

The formaldehyde-killed, whole-spherule vaccine, which is protective against lethal challenge of laboratory animals with Coccidioides immitis, was fractionated. It yielded a soluble, multicomponent, subcellular fraction termed the 27K vaccine. This vaccine, when it was accompanied by adjuvant, protected mice against lethal intranasal and intravenous challenge with C. immitis.     

Human contamination by baits for vaccinating foxes against rabies in France

During 1992 and 1993, 4.4 million of baits have been distributed in France over 121,381 km2 for vaccinating foxes against rabies. Phone calls and visits addressed to the local veterinary authorities and to the centres for human antirabies treatment have been recorded according to an appropriate questionnaire. 70 persons declared to have found and sometimes to have touch a bait, 38 of them received a antirabies treatment. Only 9 children (less than 10 year old) handled a bait. Activities that led to find a bait have been: walking in the countryside or hunting (50% of cases), gardening or playing in the garden or near home (35%) and farming (13%). Often dogs were the first to discover the baits and led to a contact of humans with the vaccine in 54% of cases. No casualty occurred. The frequency of these reports decrease by 80% during the period which is considered to be the result of a better information and awareness of the public.     

Effects of frequent intranasal administration of adjuvant-combined influenza vaccine on the protection against virus infection

In previous papers, we have shown that Escherichia coli heat-labile enterotoxin B subunit, supplemented with a trace amount of the holotoxin (LTB*) could be used as a potent adjuvant for a nasal influenza HA (haemagglutinin) vaccine in humans. The present study was designed to determine whether the effectiveness of a combined LTB*-HA vaccine could be limited by preexisting immunity to LTB and how many times the adjuvant-combined vaccine could be administered intranasally without reducing its protective efficacy in BALB/c, C3H and B10 mice. The magnitude of both nasal and serum Ab responses to HA vaccine was correlated with the degree of protection against virus infection. Higher doses of LTB*-combined vaccine were required for inducing high enough levels of anti-HA Ab responses to provide complete protection in low responder mice. Repeated pretreatments with LTB* alone (more than six times), which provided high levels of preexisting Abs to LTB, inhibited the induction of anti-HA Ab responses and reduced the protective efficacy of the adjuvant-combined vaccine. However, the LTB*-combined vaccine could be given repeatedly (about ten times) to mice without reducing the effectiveness of the adjuvant-combined vaccine. These results suggest that the LTB*-combined nasal influenza vaccine can be given to humans once every few years when an epidemic of influenza may occur.     

Strain-specific antibodies to wild poliomyelitis viruses as an index of the circulation of these viruses in a surveyed territory

This article explores the game of golf as it appears in the medical literature. Included are sections on the historical interaction of golf and medicine, the physiology and performance of golf, illness and injury related to golf, environmental concerns involving golf course management, physical disabilities, medical research and golf, and specific medical specialty references to golf.     

Specificity of human bactericidal antibodies against PorA P1.7,16 induced with a hexavalent meningococcal outer membrane vesicle vaccine

A set of isogenic strains was constructed from the meningococcal reference strain H44/76 (B:15:P1.7,16) which differed only in their outer membrane protein (OMP) compositions. First, three isogenic strains lacking the expression of either class 3 (PorB) or class 4 (RmpM) OMP or both were obtained. Second, three isogenic class 1 OMP loop-deficient strains of H44/76 lacking the predicted loop 1 or 4 or both of class 1 OMP (PorA) were obtained. Third, three isogenic class 1 OMP strains which differed by point mutations in the predicted loop 4 of subtype P1.16 were constructed. Strains were constructed through transformation with gene constructs made in Escherichia coli and their homologous recombination into the meningococcal chromosome. This study describes the contribution of one of the six class 1 OMPs, PorA P1.7,16, in the development of bactericidal antibodies after a single immunization of adult volunteers with 50 or 100 micrograms of protein within a hexavalent PorA outer membrane vesicle vaccine. PorA-, PorB-, and RpmM-deficient isogenic strains were used to define the human immune response against PorA. The loop-deficient isogenic strains were used to define the contribution of loops 1 and 4 of PorA in the development of bactericidal anti-PorA antibodies. The isogenic strains carrying a point mutation in loop 4 were used to study the cross-reactivity of the induced bactericidal antibodies against target strains showing microheterogeneity. The results indicate that a single immunization with the hexavalent PorA vaccine induced a dose-dependent bactericidal immune response, which is directed mainly against PorA. The epitope specificity of antibodies is directed mostly against loop 1, although loop 4 and as-yet-unidentified epitopes of PorA P1.7,16 are also involved.     

Immunological requirements for a subunit vaccine against tuberculosis

Although the causes are different, totally blind people (without light perception) and night shift workers have in common recurrent bouts of insomnia and wake-time sleepiness that occur when their preferred (or mandated) sleep and wake times are out of synchrony with their endogenous circadian rhythms. In this article, the patterns of circadian desynchrony in these two populations are briefly reviewed with special emphasis on longitudinal studies in individual subjects that used the timing of melatonin secretion as a circadian marker. In totally blind people, the most commonly observed pattern is a free-running rhythm with a stable non-24-h circadian period (24.2-24.5 h), although some subjectively blind people are normally entrained, perhaps by residually intact retinoypothalamic photic pathways. Experiments at the cellular and behavioral levels have shown that melatonin can produce time dependent circadian phase shifts. With this in mind, melatonin has been administered to blind people in an attempt to entrain abnormal circadian rhythms, and substantial phase shifts have been accomplished; however, it remains to be demonstrated unequivocally that normal long-term entrainment can be produced. In untreated night shift workers, the degree and direction of phase shifting in response to an inverted sleep-wake schedule appears to be quite variable. When given at the optimal circadian time, melatonin treatment appears to facilitate phase shifting in the desired direction. Melatonin given prior to a night worker's daytime sleep also may attenuate interference from the circadian alerting process. Because melatonin has both phase-shifting and sleep-promoting actions, night shift workers, who number in the millions, may be the most likely group to benefit from treatment.     

Clinical presentation of experimentally induced rabies in horses

Twelve naive and nine test-vaccinated horses which developed clinical signs of rabies as a result of the required protocol of a vaccine trial were prospectively observed. Nineteen of the 21 cases were confirmed positive for rabies infection of the brain by fluorescent antibody test. The two horses with negative results had ganglioneuritis of the trigeminal ganglion or lymphocytic perivascular cuffing in the brain stem in addition to clinical signs. Average incubation period was 12.3 days and average morbidity was 5.5 days. Naive animals had significantly shorter incubation and morbidity periods (P < 0.05). Muzzle tremors were the most frequently observed (81%) and most common initial sign. Other common signs were pharyngeal spasm or pharyngeal paresis (71%), ataxia or paresis (71%), lethargy or somnolence (71%). The furious form was manifested in 43% of rabid horses and some of these furious animals initially manifested the dumb form. The paralytic form was not observed. Histopathology was characteristics for rabies. The results of this trial do not reflect on the efficacy of commercially licensed equine rabies vaccines.