[Carl Troester, 1880-83 as veterinarian in Tokyo]. / Carl Troester, 1880-83 als Rossarzt in Tokyo.

Carl Troester (1856-1928), royal Prussian junior veterinary surgeon, has been sent by command of His Majesty to Tokyo to teach at the Agricultural Faculty Japanese students in veterinary medicine. Instruction language is English. The course of instruction comprises 36 hours per week. He gains the acknowledgement of his pupils and in 1883, on dismissal he has been received by the Tenno. His career at the military veterinary academy in Berlin leads to the position of veterinary brigadier and professor. With the construction of the sanitary institute he has raised himself a memorial.

Optimal prediction of stiff oscillatory mechanics.

We consider many-body problems in classical mechanics where a wide range of time scales limits what can be computed. We apply the method of optimal prediction to obtain equations that are easier to solve numerically. We demonstrate by examples that optimal prediction can reduce the amount of computation needed to obtain a solution by several orders of magnitude.

Optimal prediction of underresolved dynamics.

A method is presented for computing the average solution of problems that are too complicated for adequate resolution, but where information about the statistics of the solution is available. The method involves computing average derivatives by interpolation based on linear regression, and an updating of a measure constrained by the available crude information. Examples are given.

The influence of the flow of the reacting gas on the conditions for a thermal explosion.

The classical problem of thermal explosion is modified so that the chemically active gas is not at rest but is flowing in a long cylindrical pipe. Up to a certain section the heat-conducting walls of the pipe are held at low temperature so that the reaction rate is small and there is no heat release; at that section the ambient temperature is increased and an exothermic reaction begins. The question is whether a slow reaction regime will be established or a thermal explosion will occur. The mathematical formulation of the problem is presented. It is shown that when the pipe radius is larger than a critical value, the solution of the new problem exists only up to a certain distance along the axis. The critical radius is determined by conditions in a problem with a uniform axial temperature. The loss of existence is interpreted as a thermal explosion; the critical distance is the safe reactor's length. Both laminar and developed turbulent flow regimes are considered. In a computational experiment the loss of the existence appears as a divergence of a numerical procedure; numerical calculations reveal asymptotic scaling laws with simple powers for the critical distance.

[Pulmonary emboli of skin and hair particles after intravenous injections]. / Lungenembolien von Haut- und Haarteilchen nach intravenöser Injektion.

Among 1422 Sprague-Dawley rats treated daily for 28 consecutive days by i.v. injections, 779 animals (55.8%) showed lesions at the site of injection. 381 rats (26.8%) had pulmonary emboli with fragments of hair or skin in arterial thrombi or in giant cell granulomas. 6 weeks after cessation of treatment lesions were still found in lungs from 5 of 90 rats (5.6%) allowed to recover. In 8 of 64 Himalayan rabbits (12.5%) given 28 injections into ear veins pulmonary embolism was observed. Among 184 rhesus and cynomolgus monkeys treated daily for 28 consecutive days by injection into cephalic or saphenous veins, 167 monkeys (91%) showed lesions at the site of injection, 14 animals (7.6%) had pulmonary emboli with fragments of hair and skin in arterial thrombi or giant cell granulomas.

Two decades of control Himalayan rabbit reproductive parameters and spontaneous abnormalities in Japan.

The Himalayan rabbit, Chbb:HM, has been bred in a closed colony at our institute from 1971 through 1991. Cumulative reproductive and teratological data of 514 litters from control does in embryotoxicological Segment II studies carried out over this period are herein reported. If compared with other strains of rabbit, the observed pregnancy rate of 92.2% was high, and spontaneous mortality or abortions were rare. However, the average numbers of corpora lutea, implantation sites and viable fetuses per doe were somewhat low. A total of 30 malformations and 130 variations occurred among 2883 viable fetuses.

Pulmonary hair embolism in monkeys.

Among 184 rhesus and cynomolgus monkeys treated daily for 28 consecutive days by injection into cephalic or saphenous veins, 14 animals (7.6%) had pulmonary emboli with fragments of skin or hair in arterial thrombi or in giant cell granulomas. 167 monkeys (91%) showed lesions at the site of injection, predominantly bleeding and chronic periphlebitis, whereas particles of skin or hair were rare around the veins (2.2%). 2 or 8 weeks after cessation of treatment no pulmonary lesions were observed and healing at the sites of injection was nearly completed in 11 of 12 monkeys allowed to recover.

"Wavy ribs". A reversible pathologic finding in rat fetuses.

A literature of 74 scientific papers addressing the occurrence of "wavy ribs" in fetuses of small rodents has been collected with the support of a computer-assisted search on MEDLINE, TOXLINE, BIOSIS and EXCERPTA MEDICA systems (1982-1993) and has been critically examined. Numerous compounds of a large variation in chemical structure and biological activity, if given to pregnant rats during the later period of organogenesis, are known to cause "wavy ribs" in their fetuses, a reversible pathologic finding which is rarely observed in untreated controls. According to literature, causative factors, like delayed development of alkaline phosphatase, decreased fetal protein, dietary contents, maternal toxicity, renal loop diuretics, myometrial constriction, endocrine disturbances and beta-adrenoceptor stimulation or blocking have been observed and discussed, but, a general explanation for the lesions is still missing. Therefore, the following hypothesis may be added: the high doses used in reproductive toxicology may induce maternal and placental circulatory disturbances leading to reductions in fetal serum proteins, with delayed development of osteoblast progenitors and low fetal serum alkaline phosphatase in the day 17-20 fetus. Normalization of the neonate's homeostasis (serum protein) leads to enhanced ossification and concomitant bone repair until weaning.

Memorial stones for the souls of animals killed for human welfare in Japan.

In Japan, at the old ports of the whaling industry, at all 365 slaughterhouses of the country, at some of the more than 90 wholesale markets of marine products, and at most of the about 170 testing facilities using laboratory animals, there are memorial stones for the souls of the animals killed for human welfare. Except at the whaling ports, where the memorials often can be dated back to the 17. century, all stones have been erected in the 20. century, most of them during the last 2 decades. The roots of this Japanese folk custom are probably in the prehistoric times of Shintoism. With the introduction of Buddhism in the 6. century, the killing of animals was considered sinful. Following the opening of the country in 1860, slaughterhouses were established.

Maternal age, reproduction and chromosomal aberrations in Wistar derived rats.

The fertility of rats ranges from one to 18 months. In standard teratogenicity testing young, mature females are used which may not reflect the situation in women above 35 years old. Reproduction among different age groups of Wistar ats (strain Chbb: THOM) was compared at 3, 6, 9, 12, 15 and 18 months. At least 20 virgin females were inseminated per age group. The copulation rate did not differ between the groups. From the maternal age of 12 months, the pregnancy rate was significantly decreased, from the age of 9 months, the litter values were significantly lowered and the resorption rates were increased. Maternal age did not influence the incidence of fetal variations and malformations. Additionally, the chromosomal aberration rate in the bone marrow was evaluated in male and female rats. Twelve animals of each sex were scheduled per group, and studied at the age of 1, 3, 6, 12, 15, 18, 21 or 24 months. In males, the aberration rate increased continuously from 0.18 through 3%, while in females the increase continued from 0.33 to 2.29% at 15 months old when a plateau was reached. When testing new compounds for embryotoxicity or genotoxicity in female rats, the animals should be of comparable age to man in order to avoid a misinterpretation of spontaneous abnormalities. From these studies, however, it was concluded that the use of higher age groups of female rats in teratogenicity studies would not improve the risk assessment.

Calcified foci at the junction between adrenal cortex and medulla of rhesus monkeys.

The occurrence of calcified foci at the junction of adrenal medulla and cortex in monkeys obtained from toxicity studies during a 10-year period is reported. The survey included reinvestigated adrenal samples from 274 male and 270 female rhesus monkeys and 52 male and 52 female cynomolgus monkeys. The incidence of calcified foci was 46% in male and 45% in female rhesus monkeys, and 6% in male cynomolgus monkeys, while their females did not show the lesion. In male rhesus monkeys, the mean number of foci was 4 for both glands, in females, 2 for the right and 4 for the left one. Initial stages indicated that the lesions develop possibly from focal apoptosis of medulla cells followed by a dystrophic mineralization. No correlation was observed concerning dose groups, test article, study length, testing facility, origin of monkeys, their sex, age, diet or final body weight. The foci of mineralization were dystrophic, species-specific in the rhesus monkey and possibly related to stress. The location of the foci at the cortico-medullary junction, precisely the location of the remnants of the fetal zone, may indicate their origin from this zone.

Beta-adrenoceptor tocolysis and effects on the heart of fetus and neonate. A review.

A literature of 92 scientific papers addressing the effects of beta-adrenoceptor stimulation on the heart have been collected with the support of a computer-based MEDLINE system and critically examined. Neither in animal experiments nor in a wide clinical use of tocolytics for more than two decades has a risk for the hearts of fetus and neonate been confirmed, because there is no or only very little stimulating action on the beta-adrenoceptors of fetal and newborn's hearts as their sympathetic innervation is still immature.

Developmental and regressive changes in the testes of the Himalayan rabbit.

The testes of 81 Himalayan rabbits, controls in toxicity studies, and 113 purpose-bred rabbits of various age groups from birth to 2 years were studied. In mature male rabbits, regressive changes in the seminiferous tubules including the multinucleated spermatid giant cells were common and showed a tendency for age-related and seasonal differences. The finding is considered as a remnant of the previous seasonal and possibly also social testicular regression in wild living animals. The giant cells develop from the syncytium of the germinative epithelium and have parallels in phylogenesis.

[M. von Ardenne's multi-step cancer therapy and variations--universally applicable in oncology? Documentation No.23]. / Krebs-Mehrschritt-Therapie nach M. von Ardenne und Varianten--universell einsetzbar in der Onkologie? Dokumentation Nr. 23.

M. von Ardenne advances 2 concepts for the treatment of cancer: the Multistep-Cancer-Therapy (MCT) and the O2-Multistep-Immunostimulation (O2-MIS). Since the properties of cancer tissues postulated by. M. von Ardenne are considered common to all malignant tumours, MCT and O2-MIS can be employed in any type of malignancy. These concepts are recommended for cancer therapy and prophylaxis. The 1989 concept consists of the combination of O2-MIS (thymus) for 18 days followed by MCT on the 19th day. O2-MIS can be done on an outpatient basis, whereas MCT must be carried out in hospital. An investment of 5000 to 10,000 Fr. is needed to provide O2-MIS in a medical practice. In 1959, Prof. Dr. h. c. mult. M. von Ardenne transferred from research in the field of physics to cancer research. He published the basic concept of MCT in 1965, from which the Oxygen-Multistep-Therapy (SMT) and the O2-MIS were later derived. Most of the proponents are found in the former Federal Republic of Germany, where the SMT-Society is responsible for the dissemination of the ideas and apparatus. The mechanism of action of MCT consists of the irreversible occlusion of tumor blood vessels as a result of "elective over-acidification of the cancer cells and tumour tissue by stimulating the aerobic fermentation metabolism of cancer cells discovered by O. Warburg in 1924". O2-MIS, on the other hand, works by potentiating non-specific defences. Contrary to his claims, von Ardenne has so far been unable to demonstrate a reproducible efficacy either for the MCT or for O2-MIS against cancer in man. Despite a supposedly large number of patients treated, no clinical trials have yet been published.(ABSTRACT TRUNCATED AT 250 WORDS)

[Factor AF2--the 4th column in tumor therapy. Documentation No.22]. / Factor AF2--die vierte Säule in der Tumortherapie. Dokumentation Nr. 22.

Factor AF2 is an extract from the spleen and liver of sheep embryos and lambs. The product contains biotechnologically produced, chromatographically uniform, molecularly standardized polypeptides, glycopeptides, glycolipids and nucleotides, deproteinized and free of pyrogens'. Factor AF2 is intended mainly for use in 'supportive antitumour therapy', as a 'biological antiemetic and analgesic'. The proposed duration of treatment is usually more than six months. The dosage varies considerably according to the indication. The average daily costs are, therefore, between DM 4.- (prevention of recurrence) and DM 107.- (adjuvant to chemotherapy). Allergic reactions have been reported in 'rare cases'. Factor AF2 was developed in the forties by Guarnieri in Rome. Since 1984, Factor AF2 is 'biotechnologically' produced and as a 'biological response modifier' (BRM) in the oncotherapy distributed by Biosyn Arzneimittel GmbH, Stuttgart. Dr. rer. nat. T. Stiefel and Dr. rer. nat. H. Porcher are the representatives of Biosyn Arzneimittel GmbH. In the past, both worked with Vitorgan Arzneimittel GmbH (cytoplasmatic therapy according to Theurer). It is claimed that Factor AF2 contains 'immunomodulating and immunorestorative biomolecules' assignable to the BRM group. Terms and investigations from current immunological research are applied to Factor AF2. No preclinical investigations are available which demonstrate any cytostatic effect of Factor AF2. In vivo, no effects were observed on the transplanted meth-A-sarcoma in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

[Iscucin--mistletoe preparations for the pre- and postoperative treatment of malignancies. Documentation No. 21]. / Iscucin--Mistelpräparate für die prä- und die postoperative Malignombehandlung. Dokumentation Nr. 21.

Iscucin-Viscum preparations contain mistletoe from eight different host-trees and are produced according to a particular 'rhythmic' procedure and additionally 'potentialized'. Sterilization should be achieved by the addition of oligodynamic silver. The indications given are: precancerous conditions, postoperative tumour prevention, operable tumours, and inoperable tumours. Each of the eight preparations (according to host-tree) has its own list of indications. Iscucin is supposed to be injected close to the tumour between 5 and 7 p. m.; the dosage and the frequency depend on body temperature. The annual costs of Iscucin treatment are DM 140.- to 280.-, not including doctor's visits, homeopathic drugs and special diet. Koehler began to develop Iscucin in 1958 on the basis of a personal communication of Steiner made in 1924. It is produced and distributed by Wala-Heilmittel GmbH, Eckwälden. Most Wala publications have been written by H. H. Vogel, the medical advisor of Wala. Vogel combines Fromme's mesenchymal theories with the anthroposophical ideas on carcinoma development in that he designates the mesenchyma as the organic vehicle of the 'ethereal body' (Atherleib). Carcinomas develop on depletion of the mesenchymal forces; mistletoe, on the other hand, activates the mesenchyma. No preclinical or clinical investigations are available. However, the performance of controlled clinical studies is hardly possible, since the supportive measures considered to be essential cannot be applied according to a specific schedule. Iscucin is not registered in Switzerland at the IKS.

[Helixor--mistletoe preparation for cancer therapy. Documentation No. 19]. / Helixor--Mistelpräparate für die Krebstherapie. Dokumentation Nr. 19.

Helixor is an aqueous cold extract from fresh mistletoe, obtained from fir, pine and apple trees. A number of components with different possible effects were isolated: lectins, viscotoxins, alkaloids, etc. "Oncological therapy" and "stimulation of the bone marrow" are given as the main fields of indication. Pregnancy, hyperthyroidism and intolerances are given as contraindications. Depending on the type and the stage of the tumour, treatment based on a specific rhythmic schedule should be carried out for a period ranging from five years to a lifetime. A 7-ampoule pack costs 37 to 44 DM. Local inflammatory reactions occur as side effects. Fever is desirable. Helixor was developed by the Section for Leukemia and Cancer Therapy of the Gemein-schaft Fischermühle e. V. in Rosenfeld, FRG, and has been used since about 1968. It is produced and distributed by Helixor Heilmittel GmbH & Co. The origin of anticancer treatment with Helixor, a mistletoe preparation, is the anthroposophical medicine. In addition, Helixor supposedly bridges the dramatic gap between conventional and natural treatment of cancer in that it exerts both a selective cancerostatic and an immunostimulatory effect. Hardly any research has been done on the pharmacodynamics, the pharmacokinetics and the toxicity of the total extract Helixor. In vitro studies reveal a cytostatic effect on individual cell lines; animal experiments with freshly pressed juice are contradictory. Specific effects of Helixor on the immune system and its actual bearing on the tumour process have so far not been unequivocally elucidated. The three clinical-historical comparative studies contain methodological errors. They do not provide evidence of the clinical efficacy against tumours.(ABSTRACT TRUNCATED AT 250 WORDS)

[Vysorel/Isorel--cancer drug from Viscum album. Documentation No.20]. / Vysorel/Isorel--Krebstherapeutikum aus Viscum album. Dokumentation Nr. 20.

Vysorel/Isorel is an aqueous extract from fresh mistletoe (viscum album). A number of components with different possible effects have been isolated, but exact analyses of the preparation have not been published. One ampoule 'Stärke 60' of 1 ml contains the extract of 60 mg mistletoe. Vysorel/Isorel is recommended in all malignant diseases, in 'precancerous' conditions and for prevention of relapse. Vysorel/Isorel is supposed to be taken subcutaneously according to a rhythmic schedule. Drug costs for one year in precancerous conditions are approximately 900 DM, for prevention of recurrence approximately 1800 DM, in the case of inoperable tumour approximately 3800 DM. Vysorel/Isorel is also a product of the anthroposophical medicine according to R. Steiner. It is marketed by Novipharm GmbH as Isorel in Austria and as Vysorel in the Federal Republic of Germany. The clinical efficacy of Vysorel/Isorel is derived from the demonstration of proteins from mistletoe (so-called 'Vester's Protein') with cancerostatic activity in vitro. No preclinical or clinical investigations are available. None of the 33 case histories suggests that Vysorel/Isorel is effective in the treatment of malignant diseases. Vysorel/Isorel is not registered in Switzerland at the IKS. It has been permitted in Austria since 1983 and in Germany since 1986.

Maternal age, fertility and failure of teratogenicity by trypan blue in Jcl:SD rats.

The study compared the fertility of nulliparous Jcl:SD rats, young mature (12-week-old) versus middle aged (47-week-old) or old animals (64-week-old), both groups near the termination of their reproductive capability. Trypan blue (TB) was given subcutaneously at 0 (control), 10 or 50 mg/kg on days 7 through 9 of gestation to increase the malformation rate. However, no clear teratogenic action of TB was observed. The dose of 10 mg/kg TB was well tolerated, while 50 mg/kg was of severe maternal toxicity and 14 of 53 females died. In comparison with the young control group, the average per litter from middle aged or old dams was significantly decreased for implantation sites, live fetuses and fetal weight, while the percentages of pre-implantation loss and dead implants were extremely high. No increase of the malformation rate occurred with maternal aging. Histologically, middle aged and old rats exhibited age-related lesions of the pituitary, adrenals and reproductive organs with pituitary adenomas, cystic endometrium and sclerotic atrophy of uterine glands being significantly increased in non-pregnant, old rats.

Identification of newborn rats by tattooing.

Pups were identified by toe clipping or tattooing the plantar surface of the paws on day 4 after delivery. Their growth, maturation, and reproductive capability were not affected by either identification method. In the toe clipping group, however, the duration until fall in the suspension test was significantly shortened, indicating that this identification method may not be suitable for some behavioural tests. The clipping also disturbs the skeletal investigation of toes and is not recommended from the view point of animal welfare. Palm tattooing, on the other hand, satisfies the fundamental requirements for long-term identification of rats.