Safety of Therapeutic Fever Induction in Cancer Patients Using Approved PAMP Drugs

William Coley, between 1895 and 1936, treated hundreds of cancer patients using infusions of fever inducing bacerial extracts. Similar experiments were done by Klyuyeva and co-workers in the 1940ies in Russia using trypanosoma extracts. Many remissions and cures were reported. We have conjectured that pathogen associated molecular pattern substances (PAMP) are the molecular explanation for the beneficial treatments in both groups. We could show that a combination of PAMP can eradicate solid tumours in cancer mice if applied several times. Accordingly, we suggested to combine PAMP containing approved drugs to treat cancer patients using a protocol similar to the old fever induction regimen. In this retrospective phase-1 study we report on the fever induction capacity and safety of applications of bacterial extracts, combinations of bacterial extracts with approved drugs, and combinations of approved drugs in 131 mainly cancer patients. Adverse reactions were those which can be expected during a feverish infection and mild. Over 523 fever inductions, no severe adverse reaction was observed.     

Methodisches zum Gradientenproblem

Ohne Zusammenfassung     

Sialate O-acetylesterases: key enzymes in sialic acid catabolism

Sialate 9(4)-O-acetylesterases (EC 3.1.1.53) have been isolated from equine liver, bovine brain and influenza C virus. In this latter case, the esterase represents the receptor-destroying enzyme of the virus. The kinetic properties of these enzymes were determined with Neu5,9Ac2 and in part with 4-methylumbelliferyl acetate and Neu5,9Ac2-lactose. The Km values vary between 0.13 and 24 mM and the Vmax values from 0.55 to 11 U/mg of protein. The pH optima are in the range of 7.4-8.5, the molecular masses at 56,500 and 88,000 Da. In addition to a fast hydrolysis found for aromatic acetates, such as 4-methylumbelliferyl acetate or 4-nitrophenyl acetate, N-acetyl-9-O-acetylneuraminic acid is de-O-acetylated at the highest relative rate. Other substituents at the 9-position, such as lactoyl residues, or acetyl groups at other positions within the side chain are not hydrolyzed. Neu4,5Ac2, however, is a substrate for all 3 enzymes. The hydrolysis rates of this ester function, which renders sialic acids resistant to the action of sialidases, vary from 3 to 100% relative to Neu5,9Ac2. Whereas Neu5,9Ac2-lactose is hydrolyzed by the bovine and viral esterases, other O-acetylated sialic acids in glycoconjugates are only attacked by the enzyme from influenza C virus and not by that from bovine brain. The esterase from horse liver also releases 4-O-acetyl groups from equine submandibular gland mucin. By incubation with appropriate substrates and inhibition studies, carboxylesterase, amidase and choline esterase activities were excluded, as well as the cleavage of other acyls, e.g., butyryl groups. Thus, the enzymes investigated belong to the acetylesterases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intraoperative coagulation activity--a defined group of trauma surgery patients

Analyses of blood coagulation in a defined group of patients before, during, and after trauma-surgery confirms an intraoperative trigger-mechanism, that causes postoperative thromboembolic complications. They also proof the correlation between extent of tissue-lesion and extent of triggering, this was previously presumed from the postoperative incidence of thromboembolic complications. Apart from the usual blood coagulation tests the following parameters where analysed: Factor VIII: C, Ristocetin-Co-factor, Factor Xa, AT III, TAT, Reptilase-time, tPA, D-dimers, and FPA. Simultaneously, it was shown, that a preoperative prophylaxis of thrombosis can prevent an intraoperative increase of Factor Xa, that plays a key role in postoperative thromboembolic complication. The increased intraoperative turnover of coagulation factors, which is necessary for physiologic blood coagulation, is not prevented.     

Effect of diclofenac on plasma levels of immunoreactive prolactin, follicle stimulating hormone, luteinizing hormone, thyrotropin, and beta-endorphin in humans

Prostaglandins have been shown to modulate the secretion of several pituitary hormones, suggesting that therapeutic doses of nonsteroidal anti-inflammatory drugs may change basal hormone levels. In this study, plasma levels of prolactin, follicle stimulating hormone, luteinizing hormone, thyrotropin and beta-endorphin were determined in 6 healthy men after administration of diclofenac, a prostaglandin synthesis inhibitor. The subjects were given 75 mg intramuscularly and 50 mg orally at 08.00 h the first day, 50 mg orally at 08.00, 12.00 and 20.00 h the second day and an additional 50 mg orally at 08.00 h the third day. Blood samples were collected throughout these 3 days. Diclofenac resulted in a significant and sustained decrease in plasma level of prolactin (p less than 0.005). The other hormones did not demonstrate significant change following diclofenac administration. These data suggest that administration of a prostaglandin synthesis inhibitor, such as diclofenac, selectively alters basal pituitary secretion of prolactin in humans without a detectable effect on plasma levels of other pituitary hormones. This study supports the hypothesis that prostaglandins are necessary for maintaining basal level of prolactin secretion in man.     

Organization of the orthogon – main and minor nerve cords

The central nervous system of flatworms has been regarded as comprised of the bilobed brain, the longitudinal cords and the connecting transverse commissures forming a so called orthogon. The peripheral nervous system comprises the submuscular and subepidermal plexuses. As a confusion in the terminology of the longitudinal nerve cords has prevailed, two concepts have been introduced, the main nerve cords (MCs) and the minor cords. The MCs have been defined as the pair of longitudinal nerve cords that (1) start with strongest roots in the brain, (2) consist of wide fibre bundles and (3) are associated with more neurons (particularly amninergic marker neurons) than the other cords. Longitudinal nerve cords in other positions are thinner and have less pronounced contact with the brain. They have collectively been named minor cords. Support for the special status of the MCs has been obtained from studies of the neuroanatomy of Catenulida, Macrostomida, Proseriata, Tricladida and Lecithoepitheliata and of parasitic flatworms. Using the above mentioned criteria for the MCs and the results of recent studies, we present the following hypothese: The MCs in all flatworms correspond to each other and have a common origin. This revised version was published online in July 2006 with corrections to the Cover Date.     

Investigation of the visual cytoscreening of conventional gynecologic smears. I. Analysis of slide movement

In order to elucidate the process of visual cytoscreening, graphic and electronic recordings of the stage movements in visual screening of conventional gynecologic smears were carried out. More than 400 recordings have been evaluated. The screening consisted of alternating movements, with a mean duration of 180 milliseconds, and stops of about 230 milliseconds. Variations of the screening pattern due to the specimen diagnosis were hidden behind the rather obvious individual behavior and reactions to inhomogenity of material distribution. The detection threshold was found to vary with the diagnostic situation. A lowering of the detection threshold was especially reflected by an increase of the overlap in screening direction and an increased number of fields of view with stop times of more than 350 milliseconds. A substantial part of the specimen was only seen during movements; the fraction of the specimen area covered during the stops was found to vary between 41% and 93% for screenings in the daily routine work.