Human Volunteer Experiments Research Articles

Molecular mechanisms of antigenic variation in Neisseria gonorrhoeae.

Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease gonorrhoea. Gonorrhoea has been recorded in man throughout the medieval and modern eras and possibly since biblical times (Cheng, 1988). This long association between N. gonorrhoeae and humans can be attributed to:(1) an efficient mode of transmission; (2) a high percentage of asymptomatic carriers; (3) the rare occurrence of lethality, and (4) the ability of the bacterium to avoid an immune response. This Gram-negative diplococcus (the gonococcus) does not colonize any other ecological niche besides the human body. A consequence of this limited host range is a lack of a valid animal model. Therefore, a majority of facts concerning gonococcal pathogenesis result from in vitro studies, supported by information gained by occasional experiments in human volunteers. The focus of this chapter is to examine mechanisms used by the bacterium to evade the immune response. Selected topics on other aspects of gonococcal pathogenesis will be presented but for wider analysis the reader is referred to review articles about gonorrhoea by Cannon and Sparling (1984) or Brooks and Donegan (1985) and specifically about antigenic variation by Seifert and So (1988), Swanson and Koomey (1989), or Meyer et. al. (1990).

β-Cyclodextrin as an excipient in solid oral dosage forms: in vitro and in vivo evaluation of spray-dried diazepam-β-cyclodextrin products

Diazepam-β-cyclodextrin and diazepam-lactose products were prepared by spray-drying. Complex formation could be demonstrated by differential scanning calorimetry and by application of a so-called “ether-wash” method, for diazepam-β-cyclodextrin but not for diazepam-lactose. Intrinsic dissolution rates were measured using a rotating disc method. The results indicated that, for the drug tested, complexation played only a minor role in dissolution rate enhancement. Both the processing of the drug and the excipient as well as the solubility and amount of the excipient used seemed to be rate-determining factors. Release rates from tablets and capsules were measured using the USP paddle method. For the capsules an enhancement of the dissolution rate by complex formation of the drug with β-cyclodextrin, was only found when low stirring rates were used (20 rpm). The difference in dissolution rate, as obtained at 50 and 20 rpm, can be explained by the presence of an aggregate at the bottom of the beaker at low stirring rates. In the microenvironment around the aggregate the solubility of the drug is enhanced by complex formation. Absorption experiments in human volunteers showed also an increased absorption of diazepam by β-cyclodextrin complexation.

Whole-body MR imaging and spectroscopy with a 4-T system.

The clinical potential and limitations of magnetic resonance imaging and spectroscopy at 4 T were investigated with the use of a newly constructed system, which has been in use since January 1987. The magnet has a warm bore that measures 1.25 m in diameter, and its homogeneity in a sphere with a diameter of 50 cm is better than +/- 2.5 ppm. It was hypothesized that the improvement in the signal-to-noise ratio (S/N) afforded by the higher field strength would be useful in reducing imaging time and in improving spatial resolution. In experiments in human volunteers, believed to be the first in which an entire human body was exposed to a magnetic flux density of that magnitude, the subjects were exposed to 4 T for 10-30 minutes. They showed no changes in well-being or heart activity. The expected gain in spectral resolution due to chemical-shift scaling was achieved with the 4-T system, and an improvement in S/N was verified for phosphorus at 34 and 68 MHz. In sodium imaging, the high flux density appears to be useful in reducing imaging time, which should increase the usefulness of sodium imaging in evaluating brain tumors and strokes. In spectroscopy, the increase in flux density improves the quality of the spectra.

The pathogenicity of environmental campylobacters--a human volunteer experiment.

Three human volunteer experiments were performed in which river water expected to contain campylobacter organisms was ingested. Despite the ingestion of over 44,000 organisms in one experiment, the subject did not suffer any symptoms, nor were campylobacter organisms excreted, nor was an antibody response to the ingested strains detected. The campylobacter organisms ingested resembled Campylobacter jejuni on colonial and microscopic morphology but were hippurate negative, and were distinct from C. coli. These environmental campylobacter strains appear to be non-pathogenic, however they may be mistaken for C. jejuni or C. coli if they are not fully identified.

Potential of inductively coupled plasma mass spectrometry for trace element metabolism studies in man.

A new inorganic mass spectrometric technique is described which allows sensitive, rapid and economic determination of trace element concentrations and isotope ratios in aqueous samples. This paper illustrates the potential of the technique in one particular application area, namely the measurement of strontium isotope ratios in human blood and urine following ingestion of an enriched stable strontium isotope. The data from a human volunteer experiment illustrate the viability of the analytical method, with measurement precisions of +/- 0.2% (1 sigma) achieved for the isotope ratio in urine samples, which contained approximately 300 ng 86Sr in the volume required for analysis. Measurement precision is limited by counting statistics.

Measurement of the magnetic susceptibility effect in high-field NMR imaging

The magnetic susceptibility effect often obtained in clinical NMR imaging is analysed and a measurement method of the magnetic susceptibility effect is proposed. The method of extraction of the susceptibility effect alone in high-field NMR imaging where usually the chemical shift and main magnetic field inhomogeneity effects are intermingled with the susceptibility effect is discussed. The proposed susceptibility measurement uses the susceptibility weighted echo-time encoding technique (SWEET) to modulate the NMR signal as a function of echo time with which the image intensity can be weighted. Both phantom-oriented physical experiments and human volunteer experiments were performed to demonstrate the usefulness of the technique for human imaging.

Role of spreading-factor (hyaluronidase) on bronchial response to acetylcholine challenge in dog.

Patients with non-specific chronic lung diseases are very sensitive against external challenge. Experiments in human volunteers and in animals it has been shown that many substances can make bronchial system hyperreactive without causing any direct effect. The mechanisms involve in the process of hyperreactive bronchial system are, so far, not clear. It is conceived in this study that membrane permeability might play an important role in this process. This possibility has been studied in anesthetized dogs by subjecting them to hyaluronidase aerosol. This enzyme is supposed to change the membrane permeability by acting on the ground substance. The animals were first challenged with acetylcholine to obtain the basic responsiveness. Then the animals were subjected to hyaluronidase aerosol and challenged with acetylcholine again. Results confirm the hypotheses that membrane permeability plays an important role in hyperreactive bronchial system.

Evaluation of carticaine—a new local analgesic

Carticaine, formerly known as Hoe 40045, is a new local analgesic which has been subjected to a series of experiments in human volunteers using electrical stimulation to assess the effect. Six solutions of different strengths and vasoconstrictor additions, including two control solutions (mepivacaine) were tested. Vitality tests were performed at regular intervals with a Bofors pulp tester. Carticaine in 2% and 3% solutions with an adrenalin content of 3.3, 5 and 10 μg/ml showed excellent frequency of analgesia and a relatively long lasting effect. It was especially notable that carticaine without vasoconstrictor was not able to produce reliable analgesia, while only a minute amount of adrenalin (3.3 μg/ml) improved the parameters radically. From comparison with other results on carticaine it is suggested that 2% solutions probably are sufficient for dental and oral surgical procedures when adrenalin in concentrations of 3.3, 5 or 10 μg/ml is added.

Experiments in human volunteers with adenovirus type 8.

Experiments in human volunteers with adenovirus type 8.

An indication as to identity between the infectious diarrhea in Japan and the afebrile infectious nonbacterial gastroenteritis by human volunteer experiments.

An indication as to identity between the infectious diarrhea in Japan and the afebrile infectious nonbacterial gastroenteritis by human volunteer experiments.

The nonamebic nonbacillary diarrheal disorders.

SummaryOf the identified or hypothetical viruses that occur in the feces, the agent or group of agents that induce so-called afebrile infectious nonbacterial gastroenteritis are the only ones known to cause watery diarrhea as a cardinal sign of illness. The rest of the clinical picture of this nonamebic nonbacillary diarrheal disease consists of anorexia, nausea, vomiting, and abdominal cramps, with little or no fever. It is a common syndrome of wide geographic distribution and is highly communicable, appearing in large epidemics as well as sporadically. While the disease is ordinarily self-limited, it can be incapacitating and is of importance because of its frequency.Some epidemics of anorexia, nausea, and vomiting without diarrhea otherwise resemble outbreaks of afebrile nonbacterial gastroenteritis. Whether the respective causative agents are related is unknown. No recognized pathogen has been isolated from patients exhibiting either syndrome. Afebrile nonbacterial gastroenteritis with diarrhea can be transferred serially from one group of volunteers to another by feeding fecal ultrafiltrates. This is the chief evidence that one or more viruses may be the incitants.Reinoculation experiments in volunteers indicate that following an attack of afebrile nonbacterial gastroenteritis specific active immunity develops, and that it may last for a year or longer. Since cases recur at yearly intervals in families and communities, it is necessary to postulate that there may be more than one antigenic type. The afebrile disease can be differentiated from a febrile, non-diarrheal entity by their different incubation periods, different clinical manifestations, and lack of cross-immunity.The results of the first human volunteer experiments, reported by Reimann and his colleagues, indicated that a filterable agent could induce diarrheal disease when it was administered via the respiratory route. Some epidemiologic observations are consistent with these findings but several subsequent attempts to confirm experimental respiratory transmission in volunteers have failed. Respiratory symptoms and signs are conspicuously absent in experimentally induced attacks of afebrile nonbacterial gastroenteritis. At present the possibility that their occurrence in epidemic cases is adventitious must be strongly considered.Further characterization of the nonamebic, nonbacillary diarrheal diseases awaits comparative studies of the agents now known and the detection of new ones. This will be difficult until practicable methods of laboratory propagation and immunologic identification are discovered.

The fate of preserved bovine cartilage implants in man

Summary 1.In twelve cases of surgical bovine cartilage implants in man, ten had absorbed within two years. 2.A second surgical implant in one case was found to be destroyed more actively and more rapidly than the first. 3.Experimental implants in this case compared with controls showed on histological examination that a very marked systemic response to bovine cartilage had developed. This suggests that an antigen-antibody reaction might be responsible for the absorption. 4.Experiments in human volunteers in whom a series of bovine cartilage implants were made are described. Each successive implant showed a degree of absorption greater than the preceding, thus indicating the progressive development of a systemic response. 5.Absorption occurs first by surface erosion, then by fibrous replacement, and later by dissolution of the cartilage, as the host's reaction increases. 6.The antigenic activity of this relatively insoluble material is related to its surface area, and the variations in clinical absorption which occur are discussed in relation to this factor. 7.The long survival of block implants, e.g., to a nasal bridge, is considered to be due not only to their relatively small surface area but also to their fibrous encapsulation. 8.Evidence is given that the response elicited is specific for cartilage derived from different breeds of cattle, or perhaps even from individual animals.

AN EPIDEMIC OF INFECTIOUS HEPATITIS APPARENTLY DUE TO A WATER BORNE AGENT

The control of infectious (epidemic) hepatitis, the only pandemic disease of the present war, has been seriously handicapped by the lack of any conclusive evidence concerning its method or methods of transmission. In our recent report on the prevention and attenuation of infectious hepatitis by gamma globulin 1 there was brief mention of the epidemic in which the globulin was tested. The epidemiologic factors involved in that epidemic also were investigated, and subsequently transmission experiments in human volunteers, using materials obtained from the patients and the camp, were conducted in order to supplement and confirm the epidemiologic observations. The results of these investigations have provided information concerning the sources of the causative agent and at least one of the methods responsible for its transmission. I. THE EPIDEMIC The Camp.— The epidemic occurred in a summer camp for boys and girls located in an isolated area in the Pocono Mountains near