[The current influenza-grippe situation. Consequences for general practice].
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Biomedical subjects
Publications and source records attributed to J Werner.
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Circulating interferon was found in volunteers immunized with 3.0 ml and 1.0 ml doses of human diploid cell strain (HDCS) rabies vaccines. Peak interferon titres were observed 17--25 hours after primary vaccination and the response diminished upon revaccination. The response was dose-related and did not correlate with the antigenic value of the vaccines or with the titre of infections virus in the vaccines before inactivation.
A long term study with bivalent live influenza vaccine was carried out in 18 subjects with no previous history of egg protein hypersensitivity. Experimental conditions included a nine-fold vaccination schedule with collection of serum and nasal fluid. The parameters studied were determination of serium and local antibody formation as well as the demonstration of specific IgE antibodies in serum and nasal fluid. Our major interest was directed towards the question of potential sensitization after repeated doses of non-purified oral vaccine. The close medical follow-up of the subjects revealed no clinical signs of atopic reaction. There were no complaints regarding adverse reactions usually following local application of live influenza vaccines. Determination of total serum IgE rederately elevated levels before, during und after the trial; one vaccinated subject showed high concentrations prior to vaccination with no significant change during the experiment. That individual was ultimately classified atopic with a pronounced hypersensitivity to egg protein. Nevertheless this person tolerated nine doses of vaccine without side reactions and showed no significant increase in total or specific IgE antibodies. Concentrations of IgE in nasal secretion of non-atopic subjects are less than 2U/ml, whereas they are frequently higher in allergic patients and in the presence of nasal IgE levels greater than 4 U/ml one would expect a specific reaction to challenge allergens. In our vaccinees nasal IgE values were consistently within normal range, at no time exceeding 2.6 U/ml, even the atopic subject did not exhibit higher levels in nasal fluid. A correlation between systemic and local IgE antibodies revealed no pathognostic relations; in addition to this, specific IgE-serum-antibodies as measured in the RAST against ovalbumin allergen did not show any correlation to vaccination. These data present good evidence for the innocuity of the vaccine with regard to its repeated application in man.
46 patients, who suffered from chronic renal insufficiency (serum creatinine: 1,4-14,9 mg%) and had not yet been dialysed, were given a secretin-pancreozymin-test. Statistical evaluation of the results and comparison with a healthy reference group showed amylase secretion, total secretory volume and bicarbonate secretion to be significantly reduced in patients with serum creatinine levels above 4,0 mg%. No signs of secondary hyperparathyroidism (laboratory data, osseous changes) were observed. Blood base excess and increased serum creatinine levels were significantly related. Together with influences of low protein diet metabolic acidosis going along with chronic renal insufficiency is consequently considered to be the pathogenic factor responsible for alterations in the exocrine function of the pancreas and for the occurrence of chronic pancreatitis.
A comparative study on the formation of hemagglutination inhibiting antibodies after vaccination with 3 different types of Influenza Vaccines (Whole virion, Splitvirion, and Subunit type) was performed in adults and children. The study populations were homogeneous as regards age and pre-immunization antibody profile. The following results were obtained: 1) Strain specific conversion rates for the A component (A/Victoria/3/75 H3N2) were 77% with the whole virion vaccine, 79% with the Splitvirion vaccine and 91% with the Subunit vaccine. The antibody conversion factors calculated on the basis of the geometric mean titers (GMT) were 5.0, 6,7 and 9.0 respectively. A fourfold increase in titers was observed in 68% of vaccinees with the whole virion vaccine, in 55% of vaccinees with the Splitvirion vaccine, and in 70% of vaccinees with the Subunit vaccine. 2) Local antibody formation on the basis of conversion rates yielded values of 18% (whole virion), 22% (Splitvirion), and 28% (Subunit vaccine). 3) Systemic antibody responses revealed predominantly strain and subtype specificity as opposed to local antibody formation which was also directed towards older sybtypes. This phenomenon was more pronounced in adults than in children. 4) A significant correlation was found between the local antibody production and the concentration of hemagglutination inhibiting serum antibodies as well as between the IgA concentration in nasal wash fluid and the percentage of individuals exhibiting local antibody formation in the upper respiratory tract system. 5) In children 6-14 years of age the antibody conversion rates were found to be 91-100% for the A component with the 3 vaccines under study. The GMT for the respective vaccines A, B and S ranged from 1:170 over 1:139 to 1:211. 6) With regard to the induction of hemagglutination inhibiting antibodies to the B component of the vaccine (B/Hongkong/8/73) either vaccine proved to be of insufficinet potency. Though conversion rates of 6/ to 77% (60-90% in children) were observed the GMT range was only 1:17 to 1:21 (1:21 to 1:35 in children). Only 29 to 35% of the adults and about one half of the children developed antibodies of greater than or equal to 1:40 after vaccination. With regard to this observation it has to be discussed whether one shouldn't consider monovalent A vaccines for future use in influenza vaccination campaigns.
To study antigenicity, persistence of antibody (efficacy) and reactogenicity of a new bivalent influenza subunit vaccine, Sandovac, it was given in two different concentrations (1000 and 2000 IU) to 156 subjects from two epidemiologically destinct areas (119 students from Essen, average age 22 years, 37 residents from Kassel average age 56 years). Serum antibody response was measured by hemagglutination inhibition (HI) and neuraminidase inhibition (NI) tests before, one, two and six months after vaccination. The following results were obtained: 1. Four weeks post vaccination an excellent strain specific and crossreactive (H3 N2 variant-specific) antibody response was observed. Subtype specific (H0, H1 or H2) activity could not be detected. 2. Six months post vaccination a still notably higher antibody level as compared to the preimmunization status could be demonstrated. 3. A difference, however, existed between the immune responses of the Essen student population with an average age of 22 years, and of the Kassel resident population with an average age of 56 years. The immune response being significantly better in younger vaccinees. 4. High and low concentrated vaccines revealed neither objective nor subjective differences in reactogenicity and were very well tolerated. 5. In all immunological parameters tested the double concentrated vaccine (S 2000) proved to be slightly superior to the lower concentrated vaccine (S 1000) that is officially licensed in the German Federal Republic.
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A new rapid modified micro-neuraminidase-inhibition test (ESSEN-NIT) has recently been described. This test was originally devised to facilitate large-scale screening for serum antibodies to influenza virus neuraminidase. It was shown that this test yielded results comparable to those obtained with the WHO standard procedure. Our report presents data on the comparison between the WHO method and the ESSEN-NIT with respect to their capability in detecting antigenic differences in neuraminidase of various strains of influenza A viruses belonging to the H3N2 subtype family. Two antiserums against the N2 antigens of the A/Hongkong/1/68 (X15HK) and of the A/Port Chalmers/1/73 (X42) recombinant strains were used in characterization experiments. The results obtained indicate that the ESSEN-NIT is at least as sensitive in detecting antigenic variations of neuraminidase as the WHO standard procedure. The drift of the N2 enzyme which occurred as early as 1969 and is known to continue to date, could be clearly demonstrated. Major and minor antigenic changes of neuraminidase in representative influenza isolates were equally well detected by both assays. The ESSEN-NIT offers the advantage of speed, economy, and computerized evaluation of data.
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Patients with mitral valve prolapse (MVP) frequently experience chest pain which may, expecially in older subjects and males, be difficult to differentiate from angina pectoris. Electrocardiographic (ECG) changes, ventricular arrhythmias, metabolic abnormalities and rare reports of myocardial infarction and sudden death further suggest the presence of an ischemic process in these patients. The recognition of accompanying coronary artery disease (CAD) and exclusion of other causes of ischemia, therefore, may be important in determining the prognosis and appropriate therapy for such patients.
The comparative studies undertaken by 7 laboratories in 6 countries show that the calculation of I.U.'s did not, as anticipated, minimize but actually enhanced the variability of results of rabies antibody estimations in the sera of HDCS vaccinees. The high biological variance in the method(s) may not have been considered by individual laboratories and any neglect of fundamental biostatistical laws unfortunately diminishes the theoretical advantage of using the "International Standard (I.S.)" as a "tertium comparationis". Perhaps the intrinsic variability of the I.S. should be re-evaluated and it is conceivable that a pure IgG fraction of rabies antiserum would show less variability. Intralaboratory variation might be reduced by agreeing that only a geometric mean of the I.S., and not a single value obtained in an individual test, should be used for calculation of I.U.'s. Application of the principles of biochemical and pharmacological methods, such as test-to-test control of the I.S. and its analytical variances might well enhance the reproducibility of the results. MNT, RFFIT, PRT and CFT were unable to detect antibodies in HDCS vaccinees until 7 days after the first vaccination. The establishment of methods for detecting early antibody requires further investigation.
5 mg of diazepam as well as 2.5, 5, and 10 mg of a substance from the thienodiazepine series (Bay g 5653) were compared with a placebo, following a double-blind procedure. The 149 male student volunteers were classified into introverts and extraverts. For 17 test variables including subjective and physiological measures, as well as psychomotoric and cognitive achievement variables, a 2 x 5-factorial MANOVA was computed. Effects of medication and of interactions between introversion/extraversion and medication were highly significant. Correlations of test variables with composite scores indicated that medication effects could be shown best with objective tests, while the interactions between introversion/extraversion and medication could be shown better with subjective variables. Results were discussed together with those of an earlier univariate analysis of the data using emotional stability/lability as a personality variable.
A serological study was performed in 16 volunteer subjects and 3 patients to determine the active antibody response after vaccination with HDCS vaccine alone and in conjunction with rabies immunglobulin of human origin (RIGH). When heterologous antiserum from horse or mule and any rabies vaccine is used for passive-active immunization, a pronounced interfering effect is observed, depending upon the relative concentrations of preformed rabies antibodies given and rabies virus antigen of the vaccines. When 20 IU/kg bwt of RIGH were applied simultaneously with vaccine on day 0 followed by a full series of post-exposure anti-rabies treatment, i.e. 6 doses of vaccine at days 0, 3, 7, 14, 30 and 90, no interference phenomenon was observed, as indicated by an additive effect between passive antibody and actively produced antibody. This was reflected by the observed increase of rabies antibody titre on day 7 post-vaccination and could be demonstrated in three different assays (MNT, CFT and HIT). From day 14 to day 90, no significant difference as to logarithmic increase, plateau formation and persistence of neutralizing and HI antibodies was observed between the serovaccinated and the control group. Serum samples obtained on day 455 from 12 individuals representing both study groups revealed comparable antibody values as assayed in the MNT or HIT respectively. Thus persistence and quantity of vaccine induced antibody to rabies virus, whether produced after plain vaccination or under sero-vaccination conditions, actually show no difference.
HDCS vaccine has been in official use in the F.R.G. for pre- and post-exposure vaccination of man, after having shown its superiority to the Hempt and duck embryo vaccine--as far as compatibility, antigenicity and protective capacity is concerned--since February 1977. HDCS vaccines of both manufacturers, Mérieux/Lyon and Behring/Marburg, did not produce any severe side effects in about 5000 vaccinees in West Germany when conditions of vaccine production were properly observed. The lack of neuropathogenicity of vaccines is stressed. Contamination by bacterial lipopolysaccharides, however, resulted in endotoxin shock in 32 out of 35 vaccinees with one vaccine lot. Testing for pyrogenicity of every vaccine lot should be carefully observed in future. When comparing antigenicity of different vaccine lots of both manufacturers, individual titers of complement-fixing and neutralizing antibodies were correlated with the antigenic values of the vaccines. Duration of immunity after one course of vaccination is approximately 2 years and can be extended by only 1 booster injection for an additional 3 years. Protective capacity of HDCS vaccine (using Essen scheme, 6 applications) seems to be very pronounced. So far, between 1973-1977, 68 individuals under severe risk were vaccinated post-exposure in West Germany and 45 individuals in Iran from 1975-76. No cases of rabies occurred in the vaccinees. HDCS vaccine in man induces a very early antibody response with appearance of IgM rabies specific antibodies on day 3, and IgG rabies specific antibodies on day 7 and an early IgM/IgG antibody conversion at that time.
The comparative studies undertaken by 7 laboratories in 6 countries show that the calculation I.U.s did not as anticipated minimize but actually enhanced the variability of results of Rabies antibody estaminations in the sera of HDCS vaccines. The high biological variance in the method(s) may not have been considered by individual laboratories and any neglect of fundamental biostatistical laws, unfortunately, diminishes the theoretical advantage of using the "International Standard (I.S.)" as a "tertium comparationis". Perhaps the intrinsic variability of the I.S. should be re-evaluated and it is conceivable that a pure IgG fraction of Rabies antiserum would show less variability. Intralaboratory variation might be reduced by agreeing that only a geometric mean of the I.S., and not a single value obtained in an individual test, should be used for calculation of I.U.s. Application of the principles of biochemical and pharmacological methods, such as test-to-test control of the I.S. and its analytical variances might well enhance the reproducibility of the results. MNT, RFFIT, PRT and CFT were unable to detect antibodies in HDCS vaccinees until 7 days after the first vaccination. The establishment of methods for detecting early antibody requires further investigation.