bluuebunny/crossref_metadata_2025 huggingface dataset:
TRADITIONAL ANIMAL SCREENING TESTS
Authors: Noel Peter R. B.
Published: October 2009

It is fundamental that before new chemicals may enter the environment of man, they should seem to be (i) desirable and (ii) reasonably safe. Although new chemicals should be treated as separate entities, there is little evidence in general terms to suggest that there is an alternative to screening tests in intact animals, despite the deficiencies of techniques about which much is written.

The object of toxicological studies is two-fold, to demonstrate (i) possible reactions irrespective of dosage of new compounds and (ii) the probability in biological terms of these reactions occurring near therapeutic doses (an attempt to prove a negative, the absence of toxicity).

Criticism of techniques is easy, especially when considering individual compounds. This introductory paper has attempted to draw attention to the logic which forms the basis of animal screening tests, whilst at the same time commenting on (i) deficiencies due to lack of information and (ii) changes that are likely in the future which will improve extrapolation of results to man. Evidence that traditional tests will be superseded in the foreseeable future appears to the author to be minimal when the whole field of testing new chemicals is considered.

The general principles relating to animal studies are "guidelines" which should allow an element of flexibility to treat individual chemicals on their own merits.
SERUM PROGESTERONE IN DIABETIC PREGNANCY
Authors: Klebe J. G. , Gæde P.
Published: October 2009

The serum concentration of progesterone during pregnancy was followed in 74 diabetic women with uncomplicated pregnancies. According to the White classification the subjects included class B, C and D patients.

It is shown by comparison with a reference group of normal pregnant women, that diabetics in the late part of pregnancy have normal or high levels of serum progesterone, and a reference interval for uncomplicated, diabetic pregnancies is computed.

The progesterone level in serum is correlated to the pregnanediol excretion in urine and a significant correlation (2α < 0.05) is found between the progesterone concentration (nmol/l serum) and the pregnanediol concentration (μmol/l urine). In contrast, no significance is seen, when the progesterone concentration is correlated to the amount of pregnanediol (μmol/24 h) excreted during the day.

A highly significant correlation (2α < 0.001) is shown between the serum concentrations of progesterone and placental lactogenic hormone (HPL).
THE USE OF RODENTS FOR STUDIES OF TOXICITY IN CONTRACEPTIVE RESEARCH
Authors: Leonard B. J.
Published: October 2009

After nearly two decades of clinical use of oral contraceptives, clinical studies have shown a few rare adverse reactions, including jaundice, venous thrombosis and pulmonary embolism, ischaemic cerebrovascular effects, hypertension, amenorrhoea, breakthrough bleeding, anxiety, depression, weight gain, and changes in libido. Preclinical studies in rodents dosed with oral contraceptives did not and would not be expected to reveal side effects of such low incidence.

A carcinogenic effect can be produced in certain strains of mice and rats when oestrogens, progestogens and combinations of these hormones are given in high doses throughout their life span. The susceptibility to tumour induction by hormonal contraceptives is not consistent in different strains of mice and rats, and if there is little or no predictive value in rodents it is difficult to see how they can provide useful information of the potential carcinogenicity of any of these compounds in women. Ideally, carcinogenic testing of oral contraceptives should be conducted in animal species which have a similar metabolic disposition of the drugs and similar feedback mechanisms which control ovulation and menstruation to that of women: subhuman primates and guinea pigs possess some of these characteristics.

Many previous studies indicate that carcinogenic tests in rodents have not been carried out in a very satisfactory manner.

Improvements which are suggested include the use of strains with a low spontaneous tumour incidence, strains which are free of oncogenic viruses, and standardised diet. The use of extremely high doses should be avoided.

To date there is no convincing evidence that oral contraceptives are carcinogenic in women, but further epidemiological studies following prolonged treatment will provide the most meaningful evidence.
SERUM LEVELS OF HUMAN CHORIONIC SOMATOMAMMOTROPIN (HCS) IN NORMAL AND ABNORMAL PREGNANCIES
Authors: Lebech Paul E. , Borggaard Birgit
Published: October 2009

Serum levels of human placental chorionic somatomammotropin (HCS) were determined by radioimmunoassay (immunosorbent) in 800 pregnancies, normal as well as pathological. The normal group comprised 200 pregnant women (254 estimations).

Correlation has been found to exist between the placental weight and the HCS levels as determined in the last few weeks before onset of labour. In connection with twin pregnancies HCS levels were found to be in the upper end or above the normal range. In cases of anencephaly HCS levels were found to be normal with low values of oestrogen excretion in urine.

Other examples may be mentioned in support of the importance of the HCS estimation to the evaluation of the placental function.
URINARY OESTRIOL EXCRETION IN DIABETIC PREGNANCY
Authors: Klebe J. G. , Winkel P. , Lyngbye J.
Published: October 2009

Urinary oestriol excretion during pregnancy was followed in 159 diabetics with uncomplicated pregnancies. According to the White classification this sample included 35 class B, 59 class C, and 65 class D patients. These classes did not differ significantly in respect to the oestriol excretion and were, therefore, pooled and compared to a reference group of 36 non-diabetic subjects with uncomplicated pregnancies.

The level of oestriol excretion during the last trimester was higher in the diabetics than in the controls.

A regression analysis based on data from the last trimester revealed that during this period the oestriol excretion increased at a higher rate in the diabetics than in the controls.

It is concluded that the use of the oestriol excretion in non-diabetics with uncomplicated pregnancies could be misleading as a reference for diabetics, especially in the last weeks of pregnancy.
THE TRANSVERSE DIAMETER OF THE PELVIC INLET IN DIABETIC WOMEN IN RELATION TO AGE AT ONSET OF DIABETES
Authors: Mølsted-Pedersen Lars
Published: October 2009

X-ray pelvimetry of 156 pregnant diabetic women showed a significantly positive correlation between the transverse diameter of the pelvic inlet and age at diagnosis of diabetes.

Compared with the pelvic measurements in a control group of 50 nondiabetic, puerperal women, the transverse diameter of the pelvic inlet was significantly shorter among diabetic wcmen whose diabetes had set in before the age of 13 and significantly longer among diabetic women whose diabetes had been diagnosed after the age of 21. The shorter transverse diameter of the pelvic inlet in women with early-onset diabetes is related to the diabetic disease. The changes are non-specific, and their cause is unknown. The pelvic changes may contribute to the frequently complicated course of delivery in these women.
HEMOGLOBIN F IN NEWBORN INFANTS OF DIABETIC MOTHERS
Authors: Davidsen Otto
Published: October 2009

The relative concentration of hemoglobin F was determined by use of agar gel electrophoresis in the cord blood from 38 infants of diabetic mothers and 94 infants with non-diabetic mothers.

The relative concentration of hemoglobin F was found to be negatively correlated to the gestational age of the infants. In infants of diabetic mothers the concentration was insignificantly higher than would be expected from their gestational age, and comparable to that of infants of non-diabetic mothers of about 2 weeks lower gestational age.

In the diabetes group hemoglobin F was correlated neither to the increased birth weight of the infants nor to the severity of the maternal diabetes.
ALPHA1-FETOPROTEIN AND CARBONIC ANHYDRASE B AND C CONCENTRATION IN CORD BLOOD FROM NEWBORN INFANTS OF DIABETIC MOTHERS
Authors: Nørgaard-Pedersen B. , Klebe J. G.
Published: October 2009

Erythrocyte carbonic anhydrase (CA) concentration B and C and the α1-fetoprotein (AFP) concentration was determined in cord blood from 45 newborn infants of diabetic mothers (IDM). The concentration of these quantities has separately been compared with the corresponding concentration in cord blood from normal newborn infants with the same gestational age. No difference was found except for AFP, where a significantly (P < 0.05) higher concentration was found in some infants of insulin treated diabetic mothers.
CONTRACEPTION IN DIABETIC PATIENTS
Authors: Wiese J. , Osler M.
Published: October 2009

A retrospective investigation was made of contraception in diabetic women delivered in our department in 1969 and 1970. Seventy-nine (69 per cent) answered the questionnaires. About one third had found the contraceptive instruction insufficient. A shift from conventional to intrauterine contraception and sterilization was seen, but nearly 25% of the patients were still using conventional methods, mainly the condom. The patients consider this an unreliable method. Thirty-three patients were using intrauterine contraception. Although 10 of them had bleeding irregularities, all were satisfied with the method. Sterilization had been performed on 17 patients, all of whom were fully satisfied and had experienced no side effects. Four of 11 insulin-requiring diabetics, who have used combined oestrogen-progesterone medication have had difficulties in the regulation of the diabetes. Of 24 unwanted pregnancies 12 occurred since the hospitalization in 1969 and 1970. In diabetic women the contraceptive method should either be sterilization, intrauterine device or low dose progestagens, and only in a few cases conventional.

A thorough contraceptive instruction as well as a close control of the diabetic women are of importance in order to avoid unplanned pregnancy.

The best way to achieve this is by having an out-patient clinic in connection with the obstetrical department to supervise contraception in all diabetic women in the area.
NON-HUMAN PRIMATES IN CONTRACEPTIVE RESEARCH
Authors: Goldzieher Joseph W. , Joshi Sharad , Kraemer Duane C.
Published: October 2009

An extensive review of the use of non-human primates in contraceptive research was compiled in December 1971. An effort has been made to update certain topics from that symposium, specifically (1) similarities and differences between humans and other primates with respect to gametogenesis and gamete transport, implantation and ovum development, sexual cycles and sexual behaviour; (2) metabolism of steroids in nonhuman primates; (3) certain metabolic effects of steroids in non-human primates, canines, and humans; and, (4) the relevance of certain aspects of toxicity, such as tumorigenesis, when studied in non-human primates and other species.
BILIARY EXCRETION AND HEPATOTOXICITY OF CONTRACEPTIVE STEROIDS
Authors: Smith Robert L.
Published: October 2009

The naturally occurring oestrogens and certain synthetic sex hormones, particularly those with a 17α-alkyl function, can interfere with hepatic excretory function by impairment of biliary excretion. This may be manifest in abnormal liver function tests or it may appear as cholestatic jaundice.

The naturally occurring and synthetic sex hormones undergo extensive biliary excretion and enterohepatic circulation but the extent to which this occurs varies with species and structure. They appear in bile in the form of conjugates and metabolic conjugation is crucial for their biliary excretion. Impairment of metabolic conjugation, for genetic reasons, or because the presence of an inhibitor may lead to defective biliary excretion of steroids.

The natural oestrogens and contraceptive steroids tend to undergo extensive enterohepatic circulation which causes them to persist in the body. This factor has an important bearing on their pharmacokinetics and this has not been adequately considered.

The hepatic dysfunction induced by natural and synthetic sex hormones may affect the capacity of the liver to excrete other compounds of endogenous (e. g. bilirubin) and exogenous (e. g. other drugs) origin.

The mechanism(s) whereby natural and synthetic sex hormones impair hepatic excretion is not known. These compounds can influence various factors involved in biliary excretion such as metabolic conjugation, hepatic uptake and secretion and permeability of the biliary tree. Steroid induced changes in bile composition may be important in both cholestasis and in the formation of lithogenic bile.
SCREENING FOR MUTAGENIC HAZARDS OF POTENTIAL CHEMICAL CONTRACEPTIVES IN THE MALE
Authors: Bateman A. J. , Jackson H.
Published: October 2009

At first sight it might appear that effective contraception, by preventing reproduction, makes mutagenesis irrelevant. The fallacy of this reasoning is explained. The ways in which mutation would constitute a hazard in man are presented. The nature of the mutation process is described and the manner of origin of the several kinds of mutation. A selection of the most appropriate of the many methods for recognising mutagens is briefly presented.

Known mutagens should be excluded from use as contraceptives. Consideration of the possible approaches to contraceptive action in the male gives hope of discovering effective compounds which are non-mutagenic.
SPECIAL REQUIREMENTS FOR TESTING SPERMICIDES
Authors: McConnell Robert F.
Published: October 2009

Vaginal antifertility agents are an important part of the overall contraceptive armamentarium. Maximum effort should be placed on programs to improve their present status with regard to their contraceptive efficacy, ease of administration and general aesthetic acceptability.

Initial testing for spermicides has been dependent on a series of in vitro screening methods incorporating human sperm with spermicides and utilizing immobility or sperm death as the end point. Confusion has existed in interpretation of results using different test systems. The International Planned Parenthood Foundation Agreed Test for Total Spermicide Power is now being used in most laboratories as the standard screening method. The test does not detect acrosomal proteinase inhibitors which may be useful vaginal antifertility agents. New screening methods must be developed.

Vaginal irritation has been assessed in the dog, monkey and rabbit. It is suggested that the ten day rabbit vaginal irritation study be used as an additional standard method to establish tolerances for new vaginal antifertility agents.

Toxicity studies have ranged from 30 to 180 days and have been conducted in rabbits, dogs and monkeys. Additional animal studies may be necessary to assess teratogenicity and carcinogenicity. As new vaginal antifertility agents are developed, new means of assessing their activity must be developed. The frog and rabbit models described will be of value as additional screening methods.
SPECIAL REQUIREMENTS FOR HORMONE RELEASING INTRAUTERINE DEVICES
Authors: Zaffaroni Alejandro
Published: October 2009

In order to understand the special requirements for the assessment of human toxicity for hormone releasing intrauterine devices it is necessary first to describe the constitution of one such system. The uterine progesterone system developed in our laboratories is the hormonal intrauterine system which has been most extensively tested clinically. It releases 50 μg per day of progesterone in continuous form. It has been designed to have a one-year period of functional life and it constitutes the first once a year hormonal fertility control agent and the first hormonal system which is target specific.

A number of unique features in the design and construction of this new and intrinsically safe hormonal system are described.
The sialic acid content in mouse female reproductive organs as a quantitative parameter for testing the estrogenic and antiestrogenic effect, antiestrogenic depot effect, and dissociated effect of estrogens on the uterus and vagina
Authors: Nishino Y , Neumann F
Published: October 2009

The hormone dependency of the vaginal SA content in mice has been investigated in the present study.

In intact animals, the SA concentration is significantly higher in diestrus than estrus. In ovariectomized animals, natural sex steroids have characteristic effects on the SA content:

E2 at a small dose produces a slight increase in the vaginal SA concentration as the result of the moderate mucification of the epithelium. With increasing doses, the SA concentration is decreased, thereby the vaginal epithelium is cornified and stratified. Progesterone, given alone, has no effect, but it increases the SA concentration on the simultaneous administration of E2. The extensive mucification is induced by the combined treatment.

Testosterone produces also a slight increase in the SA concentration due to mucification. This androgen restores the E2 effect on the SA content up to the level of the castrated control.

These results with natural sex steroids are discussed in relation to their histomorphological effects on some of the female sexual organs.
A METHOD FOR PARTIAL DECAPITATION OF CHICKEN EMBRYOS; ITS LIMITATIONS AS A SUBSTITUTE FOR ADENOHYPOPHYSECTOMY – AN EVALUATION OF "EQUIVALENT" METHODS IN AMNIOTES
Authors: Betz T. W.
Published: October 2009

A procedure for partial decapitation, some apparent and possible sources of variation, implications, limitations and validation of the operation as "adenohypophysectomy" are described and considered.

Usually 75% of "fertilized" eggs contain embryos eligible for surgery at ~38 hours of incubation and often 90 % of these can be operated upon successfully. The procedure requires 1.5 to 2 minutes per embryo. Mortality is high, but enough partially decapitated embryos can be obtained for quantitative studies even to the onset of hatching.

Other apparently less accurate, precise, efficient and/or simple ways to remove adenohypophyseal influence during development in amniote embryos include: electro-cautery or -coagulation, X-rays, laser beams, inhibitors, anti-sera and decapitation. Surgical partial decapitation is a practical device for adenohypophyseal developmental endocrinology of chicken embryos.
CELLULAR LOCALIZATION OF SOMATOSTATIN IN ENDOCRINE-LIKE CELLS AND NEURONS OF THE RAT WITH SPECIAL REFERENCES TO THE A1-CELLS OF THE PANCREATIC ISLETS AND TO THE HYPOTHALAMUS
Authors: Hökfelt Tomas , Efendić Suad , Hellerström Claes , Johansson Olle , Luft Rolf , Arimura Akira
Published: October 2009

With the indirect immunofluorescence technique somatostatin, a recently isolated and structurally characterized hypothalamic tetradecapeptide, which inhibits growth hormone release, has been traced in different tissues of the rat. Somatostatin or somatostatin-like immunoreactivity (SLI) was present in both neurons and endocrine-like cells.

Somatostatin positive nerve cell bodies were observed in the periventricular region in the anterior parts of the hypothalamus and in probable nerve endings in the external and internal layer of the median eminence and in the pituitary stalk and in the ventromedial, arcuate and ventral premammillary nuclei and to a small extent in the periventricular region. Somatostatin positive nerve fibers were also found in the posterior pituitary, indicating the existence of a third neurosecretory hypothalamohypophysial system, and in nerves in different layers of the wall of the small and large intestine. These nerves may possibly be of sensory nature since some cell bodies of the spinal ganglia showed a weak immunofluorescence.

Somatostatin or SLI was found in certain cells localized in the periphery of the pancreatic islets. In parallel studies with glucagon antibodies it could be established that the somatostatin positive cells and the glucagon positive cells were not identical but localized extremely close to each other. Furthermore, with the Hellman-Hellerström silver staining technique it could be shown that virtually all somatostatin cells are argyrophilic and vice versa. Somatostatin positive cells thus constitute the so-called A1-cells (D-cells). Glucagon positive cells, on the other hand, do in all probability not exhibit argyrophilia. The occurrence of probable somatostatin containing cells in the pancreatic islets is of special interest in view of several recent studies demonstrating an inhibitory action of this peptide on glucagon and insulin secretion.

Somatostatin or SLI was found in a rather small number of cells in the thyroid gland with a parafollicular position. These cells exhibited a positive immunofluorescence also after pretreatment of the antiserum with calcitonin. Furthermore, endocrine-like cells in the stomach and in the intestine were also somatostatin positive. A large number of cells in various tissues, especially in the lamina propria of the gastro-intestinal tract, showed a strong fluorescence both after incubation with control serum and with FITC conjugated serum alone.

The present results indicate that somatostatin or a somatostatin-like peptide(s), in addition to its inhibitory action on growth hormone release, may play a physiological role at many other levels of the organism.
IMMUNOGLOBULIN SYNTHESIS AND ITS INDUCTION IN B-LYMPHOID CELLS
Authors: Askonas Brigitte A.
Published: October 2009

Several aspects of synthesis and assembly of Ig molecules in small lymphocytes and in differentiated plasma cells are summarized.

Some attempt has been made to analyse at the molecular level what happens on conversion of a lymphocyte to a mature cell secreting high levels of Ig. For this study LPS activation of murine B-lymphocytes into division and maturation served as a model system. A rapid rate of mitosis and high rate of H-mRNA synthesis appeared to precede the high levels of Ig production, suggesting a translational block on H-mRNA until the cell had organized its endoplasmic reticulum and matured.

In vivo, with the exception of T-independent antigens, it is unlikely that B-cell maturation is an automatic sequel to division stimuli. We are largely ignorant in this area but possible regulatory signals which achieve a dissociation of B-cell division and maturation are discussed.
STEPS IN THE HUMAN REPRODUCTIVE PROCESS SUSCEPTIBLE TO IMMUNOLOGICAL INTERFERENCE
Authors: Diczfalusy Egon
Published: October 2009

In an attempt to analyze the specific phases in the chain of reproductive events which might be susceptible to controlled immunological interference, a brief review is given of some of the current concepts of the physiological regulation of the cardinal steps of the human reproductive process, such as spermatogenesis, epididymal sperm maturation, ovulation and the menstrual cycle, sperm transport in the female organism, capacitation, fertilization, tubal transport of the fertilized ovum, implantation and early embryonic development.

The necessary prerequisites for the large scale use of a safe immunological method seem to suggest that an in-depth study of the specific constituents of unique biologically active principles (enzymes, hormones) present in suitable extracts of human sperm and/or human placenta might offer an attractive lead for the development of fertility regulating methods based on active immunization.
IMMUNOCYTOLOGICAL METHODS FOR THE IDENTIFICATION AND LOCALIZATION OF ANTIGENS
Authors: Avrameas Stratis
Published: October 2009

Immunocytologic techniques allow the study of antigenic cellular constituents by optical or electron microscopy. Antibodies labelled with tracers such as fluorochromes, enzymes, radioactive isotopes, or large electron-dense molecules form the basis of these techniques. The immunochemical procedures involved in the preparation of such conjugates are well defined. Satisfactory results, however, also depend upon the proper preparation and processing of the tissue or cell suspension being studied.
CHEMICAL DISSECTION OF MAMMALIAN SPERMATOZOA
Authors: Gall W. E. , Millette C. F. , Edelman G. M.
Published: October 2009

Mammalian spermatozoa have been dissected by a variety of chemical techniques to yield free heads, tails with attached midpieces, and tails without mitochondria. By brief exposure to trypsin, mouse and rat spermatozoa were cleaved at the junction of the head and the tail, while human, guinea pig and rabbit spermatozoa were cleaved by trypsin only after prior incubation with a sulphhydryl reducing agent. Treatment with acid or base cleaved spermatozoa of all species examined. In contrast, exposure of spermatozoa to 1 % sarkosyl NL-97 resulted in the quantitative cleavage of mouse cells without noticeable effect on the spermatozoa of the other species. Mitochondria were removed from the midpiece of intact sperm and isolated tails by gentle shaking after treatment with reducing agents. Homogeneous populations of spermatozoan subcellular components were obtained by density gradient centrifugation. Ultrastructural analysis showed that cleavage of mouse spermatozoa by trypsin occurs at a specific location in the neck of the cell without observable damage to other cell structures. The basal plate remained attached to the head structures. In contrast cleavage of spermatozoa by sarkosyl or acid left the basal plate attached to the spermatozoan midpiece. Sarkosyl also removed the plasma membrane and extracted mitochondrial components. Treatment with acid or base also resulted in vesiculation of the plasma membrane and dissolution of the acrosome. Molecular probes have also been used to facilitate mapping of the cell surface. Each mouse spermatozoon has about 107 receptors for the lectin concanavalin A. Binding of fluorescein-labelled concanavalin A indicated that the majority of the receptors is in the acrosomal region; this polar distribution was confirmed by measurement of the number of sites on purified heads and tails. In addition, the low molecular weight probe ANS bound to the plasma membrane of spermatozoa from all species examined, with immediate immobilization of the cells. Ethidium bromide bound to the spermatozoan head without affecting motility.
HL-A, FERTILITY AND NATURAL SELECTION
Authors: Amos D. Bernard
Published: October 2009

The antibodies occasionally produced in gravid females usually cause no adverse effects and the mother may become hyporesponsive. Exceptions may occur in some cases of abortion where frequency of antibodies appears to be unduly high. Sperm antigens in the mouse include T locus alleles as well as H-2 and H-Y. The T locus is involved in differentiation. T locus alleles are expressed on early but not late embryos. A search for similar factors in man is in progress. The antigenic differences between sperm and mother and between foetus and mother may be important in natural selection. It is possible that the union of sperm with ovum is non-random and that the ovum can select "compatible" sperm through recognition of cell surface markers present on sperm. Immunologic differences between mother and foetus may cause local "graftversus-host" reactions in the placenta. This leads to increased placental size and may be a factor in hybrid vigour as well as a protective device.
LONG TERM HAZARDS IN IMMUNOLOGICAL METHODS OF FERTILITY CONTROL
Authors: Mitchison N. A.
Published: October 2009

Long term problems associated with future immunological methods of fertility control include the following: (1) reversibility, (2) unscrupulous use, (3) unphysiological intervention giving rise, among other possibilities, to carcinogenesis, (4) deleterious genetical selection operating on antigens, and (5) deleterious genetical selection operating on the immune response. The first three of these constitute a hazard to individuals, and the last two to populations. None is considered to constitute a threat so serious as to inhibit further research on the subject. We should keep under review future developments in relevant areas of immunology, including particularly cell-cell cooperation as a mechanism in autoimmunity, and immune response genes as the objects of immunoselection. It will be important also to come to terms with the social, political, and economic consequences of any cheap, widely-applicable form of birth control, such as might develop from immunological research.

The possibility is raised of wide-spread immunisation against a synthetic immunological determinant, as an aid to fertility control. Another possibility is to make women grandchildless.
STUDIES ON LOW INSULIN RESPONDERS
Authors: Efendić S. , Cerasi E. , Elander I. , Thornqvist Christina , Fick G. , Berglund B. , Luft R.
Published: October 2009

The insulin responses to intravenous glucose infusion (GIT) and oral administration of glucose (OGTT) were measured in 226 control subjects and 25 chemical or mild maturity-onset non-obese diabetics. In addition, intravenous glucose tolerance tests (IVGTT) were performed in all subjects.

The insulin response to GIT was analyzed by parameter identification in a mathematical model. This model assumes that glucose initiates insulin release by an immediate action, the magnitude of which is given by parameter KI. In addition, glucose induces a time-dependent potentiation (KP) of its initiating action. Insulin release is also modulated by negative feedback inhibition (KB), which displays an intermediary time course between KI and KP. The computer analysis of GIT allows the identification of a further parameter, KG, which defines sensitivity to endogenous insulin. In addition, a hypothetical plasma insulin value at 10 min was calculated, called IP, and reflecting the response to a standard glucose stimulation. Finally, the insulinogenic index (ΔI/ΔG) for the 10 min value of GIT was calculated.
V. EFFECTS OF THE ANTI-ANDROGEN TSAA-291 ON THE ANDROGEN-RECEPTOR COMPLEX FORMATION FROM [3H]TESTOSTERONE IN RAT VENTRAL PROSTATES
Authors: Sudo Katsuichiro , Yoshida Keiji , Kimura Yoshiaki , Nakayama Ryo
Published: October 2009

Intramuscular administration of a new steroidal anti-androgen, TSAA-291(16β-ethyl-17β-hydroxy-4-oestren-3-one), in doses of 0.05, 0.5 and 5 mg/kg body weight reduced the in vivo uptake of [3H]testosterone by the ventral prostate of castrated rats to 78, 59 and 37% of the control level, respectively. Analysis on subcellular fractions of the prostate by gel-filtration and sucrose density-gradient centrifugation followed by thin layer chromatographic identification of testosterone metabolites revealed that 5α-dihydrotestosterone(5α-DHT) which was found to be largely bound to macromolecules in the cytosol and nucleus was the predominant metabolite even in the presence of the anti-androgen, and radioactivities corresponding to the 5α-DHT-macromolecular complexes were decreased by the anti-androgen. TSAA-291 also inhibited the in vitro formation of the 5α-DHT-macromolecular complexes in both cytosol and nucleus from minced prostates incubated with [3H]testosterone. The importance of the findings is discussed in connection with the mode of anti-androgenic action of TSAA-291 in terms of the interaction with the androgen receptor.
Pathogenesis of non-insulin dependent diabetes mellitus
Authors: Beck-Nielsen Henning
Published: October 2009

ABSTRACT. The relative importance of insulin deficiency and insulin resistance for development of noninsulin dependent diabetes mellitus is discussed. Two hypothetical models are described for obese and thin noninsulin dependent diabetics, respectively.
Hepatic microsomal enzyme activity in patients with non-insulin dependent diabetes mellitus (NIDDM) and its clinical significance
Authors: Sotaniemi Eero A , Arranto Arno J , Salmela Pasi I , Stengård Jari H , Pelkonen R Olavi
Published: October 2009

ABSTRACT. Hepatic microsomal enzyme activity was investigated in 280 patients with diabetes mellitus. The oral antipyrine test was used as an in vivo index, and cytochrome P-450 content and arylhydrocarbon hydroxylase activity, determined from liver biopsies (80 subjects), were used as in vitro indices of the liver microsomal enzyme system. Indices of both in vivo and in vitro liver metabolism were decreased in patients with noninsulin dependent diabetes (NIDDM, type 2) as compared to subjects with insulin dependent diabetes (IDDM, type 1) and with age- and sex-matched controls. Drug-induced activation of hepatic enzyme system in type 2 patients having reduced microsomal enzyme activity resulted in improved drug metabolizing ability and also improved glucose utilization. In addition, a decrease of hepatic fat content and a change in serum lipid levels were observed. The function of the hepatocellular endoplasmic reticulum, as measured by microsomal enzyme activity, hence seems to be an important factor in the regulation of glucose metabolism in type 2 diabetics.

Key words: Diabetes mellitus, microsomal enzyme activity, blood glucose, liver histology.
Metabolism and receptor binding of nandrolone and testosterone under in vitro and in vivo conditions
Authors: Bergink E. W. , Geelen J. A. A. , Turpijn E. W.
Published: October 2009

Abstract. The metabolism and receptor binding of nandrolone (N) and testosterone (T) were studied under in vitro and in vivo conditions. The results of both in vitro incubation studes with 3H-N and 3H-T in tissue homogenates from rats and in vivo infusion studies with 3H-N and 3H-T in conscious rats show the importance of the enzymes 5α-reductase and 3α/β-hydroxysteroid-oxidoreductases in the prostate and the importance of the enzyme 17β-hydroxysteroid dehydrogenase in the kidney for the effects of N and T on these tissues. Following infusion of a combined dose of 3H-N and 3H-T there is a preferential retention at the receptor of 5α-dihydrotestosterone (DHT) over 5α-dihydronandrolone (DHN), N and T (DHT ⪢ DHN > N > T) in the prostate because T is a better substrate than N for 5α-reductase and because DHT binds more strongly to the androgen receptor than DHN, N and T. In the kidney 5α-reductase is not important; there is a preferential retention of N in T (DHN and DHT were only present in small amounts) because N is less susceptible than T for metabolic inactivation by the enzyme 17β-hydroxysteroid dehydrogenase and N binds strongly to the androgen receptor. Both in vitro and in vivo studies show that N and T were relatively stable in spleen, thymus and muscular tissue (only shown in vivo) and, as a result, the same amount of N and T was bound to the receptor in these tissues in the in vivo infusion experiment.

In vitro binding studies with the androgen receptor in intact human cells show that 5α-reduction increases the affinity of T and decreases the affinity of N and of the 17α-ethyl derivative of N (3-keto-ethylestrenol).

The results of the present studies explain the relatively strong effect of N, or derivatives of N, compared to that of T on tissues devoid of 5α-reductase activity (e.g. muscular tissue) and they suggest that in particular there may be a strong effect of N on tissues which in addition have a high 17β-hydroxysteroid dehydrogenase activity (e.g. kidney).
Comparison of insulin regimens in the therapy of type 1 diabetes
Authors: Pelkonen Risto , Koivisto Veikko , Mustajoki Pertti
Published: October 2009

Abstract. The major problems with one or two daily subcutaneous injections of fast and intermediate acting insulins are morning hyperglycaemia and nocturnal hypoglycaemia. These problems can be avoided to a great extent by giving a third injection at bedtime. However, the kinetics of plasma free insulin during these insulin regimens is unphysiological and appropriate meal related plasma insulin peaks cannot be achieved. The new intensified methods of insulin delivery, multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII) are more physiological. Consequently, a near normal glycaemic control can be achieved with these regimens; more often with CSII than with MDI. The risk of complications of CSII is on the other hand slightly greater. The importance and need of intensified insulin therapy in the treatment of insulin dependent diabetes is not yet fully settled. At the present it is not a primary form of treatment and indicated only if the conservative insulin regimens fail.
Strategy for self-monitoring of diabetic control
Authors: Ludvigsson Johnny , Hermansson Göran
Published: October 2009

Treatment of diabetes must aim at normal metabolism. Sporadic measurements of any known parameter is not a sufficient guarantee but continous regular self-monitoring is necessary. At least in insulin dependent diabetes it seems reasonable that we should monitor the free insulin levels, but that still belongs to the future. As blood glucose gives us a good reflection of the hormonal and metabolic balance, this is a relevant parameter to follow. Glycosylated proteins, mainly hemoglobin, give only retrospective information of moderate value for the practical management of the disease. Furthermore, one should be aware of the different weak points of glycosylated hemoglobin which does not tell the only, total truth about glucose balance. Self-monitoring of blood glucose is a very valuable tool, especially when used in a systematic way. To get information covering the whole day every day tests for glucosuria have still a place, especially among children and young adults with rather short duration of diabetes. With a sensible approach it is possible to get good compliance among most patients. A combination of blood and urine glucose selfcontrol creates opportunities for a good metabolism in diabetes.

KEY WORDS: diabetes mellitus, insulin, glycosylated hemoglobin, self-monitoring, blood glucose, urine tests, motivation.
Some aspects of the metabolic and hormonal adaptation to pregnancy
Authors: Baird Joyce D.
Published: October 2009

Abstract. Metabolic adaptations to pregnancy are directed towards ensuring fetal growth and development, provision of a fetal store of energy, and the establishment of a maternal bank of energy. At any one time the demands of these objectives are competing for the available dietary energy, yet to ensure successful reproduction all three must be met. Current concepts suggest that the metabolic adaptation to pregnancy is designed primarily to safeguard against variable and restricted energy intake and that this is achieved by 1) a reduction in energy expenditure, resulting from decreased activity combined with increased metabolic efficiency, 2) phased metabolic activity affecting carbohydrate, fat and protein. Conservation of energy in maternal adipose tissue dominates the first half of pregnancy, while in late pregnancy the available energy is redirected to the fetus. This biphasic metabolism is programmed by the placental steroids whose secretion is independent of maternal diet. Internal redistribution of substrate under hormonal control is the main characteristic of the metabolic adaptation to pregnancy. The precise mechanisms underlying these adjustments have still to be defined.
Non-pituitary actions of somatostatin. A review on the therapeutic role of SMS 201-995 (sandostatin)
Authors: Lamberts Steven W. J.
Published: October 2009

Abstract. Natural Somatostatin has a short half-life (3 min), is only active after intravenous administration and causes a rebound hypersecretion of hormones after discontinuation of administration. Recently a longacting powerful Somatostatin analog was developed (SMS 201-995; Sandostatin) which has a half-life of 113 min after subcutaneous administration. After administration of this analog no rebound hypersecretion of hormones was observed. In the present review the effects of the acute administration and of long-term treatment with SMS 201-995 in acromegalic patients is discussed. In addition the potential role of therapy with Somatostatin analogs and the preliminary effects of Somatostatin and/or SMS 201-995 are discussed in disorders of gastro-intestinal function (haemorrhages, diarrhoea, pancreatitis and endocrine pancreatic tumours), diabetes mellitus, central nervous system disturbances and oncology. Finally, several aspects of the tolerance, tachyphylaxis and side effects of SMS 201-995 are discussed.
Therapy of gestational diabetes
Authors: Bellmann O.
Published: October 2009

Abstract. Even minor abnormalities of maternal carbohydrate metabolism may influence foetal development. This study aimed at examining the relations between impaired glucose tolerance and blood glucose behavior under a standardized diet in late pregnancy and at looking for the obstetrical and neonatal outcome after normalization of blood glucose profiles in gestational diabetics. The study included 97 women in the second half of pregnancy. Severely abnormal blood glucose profiles were observed in most patients with impaired glucose tolerance who had a fasting capillary blood glucose concentration above 4.7 mmol/l. Normalization could usually only be achieved by combining a strict dietary regimen with insulin treatment. The obstetrical and neonatal outcome in the group of patients treated with diet plus insulin was similar to that in the group of patients treated with diet alone.
Diabetes in pregnancy: influence of genetic background and maternal diabetic state on the incidence of skeletal malformations in the fetal rat
Authors: Eriksson Ulf J. , Dahlström V. Elisabeth , Lithell Hans O.
Published: October 2009

Abstract. Female Sprague-Dawley rats from two different substrains (denoted U and H rats) were made manifest diabetic (MD) with a single iv injection of streptozotocin 2–4 weeks before mating. In some MD animals insulin treatment was started 1–3 weeks before mating (denoted MDI rats) and in a majority of these animals the treatment was interrupted during two days of pregnancy, i.e. gestational days 2 + 3, 4 + 5, 6 + 7, 8 + 9 or 10 + 11. The pregnant rats were killed on gestational day 20. The offspring of MD and MDI rats of the U substrain showed skeletal malformations (micrognathia and sacral dysgenesis) at a rate up to 19%, whereas the MD and MDI fetuses of the H strain did not display any skeletal malformations. Offspring of the U strain with sacral dysgenesis exhibited lack of a tail and no staining of osseous and cartilagenous tissue in the sacral-caudal region, suggesting total absence of vertebrae. The offspring of the dibetic U rats tended to be more readily resorbed, were smaller and tended to have slightly larger placentae than those of the diabetic H rats. The severity of the diabetic state in pregnant and nonpregnant female rats – as reflected by body and kidney weights, blood levels of HbA1c, carbohydrate and lipid metabolites – did not differ significantly between the U and H rats. These results are in concert with the notion that congenital malformations result from a teratogenic insult in a genetically predisposed organism. The described malformation-prone rat strain (U) may be a suitable model for the future elucidation of teratological mechanisms in diabetic pregnancy.
LHRH, the role of LHRH (agonists) in the regulation of gonadal function
Authors: Rommerts F. F. G. , Themmen A. P. N.
Published: October 2009

Abstract. Studies which have contributed to the present knowledge about peripheral effects of LHRH agonists are reviewed and compared with studies on the mechanism of effects of LHRH on the pituitary gland. It is concluded that LHRH or LHRH agonists can directly stimulate or inhibit the activity of gonadal cells from rats but not from man. Effects of LHRH on other human or rat peripheral tissues have been observed. LHRH- or LHRH-like molecules can be isolated from rat testes, but there is not enough evidence to consider LHRH- or LHRH-like peptides as general and important paracrine factors for regulation of gonadal function. On the other hand studies with LHRH agonists have stimulated investigations on cell-cell interactions in the gonads and data have been collected which show that peptides which are less or non-related to LHRH can modulate functional properties of gonadal cells via pathways not employed by gonadotropins.
The UK diabetic pregnancy survey
Authors: Lowy C. , Beard R. W. , Goldschmidt J.
Published: October 2009

Abstract. A prospective, national survey of the UK which examined the management and outcome of pregnancy complicated by maternal diabetes is described. The perinatal mortality rate was 3.7 and 1.5 times greater than the overall UK rate and the malformation rate 6.4% and 1.9% in pregnancies where the mother had insulin-dependent and gestational diabetes respectively. In 57% of cases no blood glucose measurement was recorded in the first trimester of pregnancy. Significantly fewer malformed infants resulted from prenancies where a first trimester blood glucose was recorded, irrespective of the value. Second and third trimester blood glucose values did not predict malformation but correlated inversely with gestational age at delivery and this was the major factor predicting the outcome of pregnancy.
Influence of pregnancy on diabetic retinopathy
Authors: Serup Lisbeth
Published: October 2009

Abstract. A prospective study of the influence of pregnancy on diabetic retinopathy was started at Rigshospitalet, Copenhagen in 1979. At present 145 women with insulin-dependent diabetes have been included. Preliminarily, it seems that women belonging to White classes B and C do not develop persistant retinopathy as a consequence of pregnancy. Women with retinopathy at the onset of pregnancy deteriorate in 50% of the cases, but post-partum regression is common. Development of proliferative changes is exceptional, and proliferations developed during pregnancy in most cases disappear spontaneously after delivery. Consequently, treatment with photocoagulation during pregnancy and in the early post-partum period should be restricted. Close ophthalmological supervision during pregnancy is essential and the ophthalmologist must be aware of the spontaneous course of diabetic retinopathy in relation to pregnancy.
Developmental aspects of the offspring of diabetic mothers
Authors: Gerlini G. , Arachi S. , Gori M. G. , Gloria F. , Bonci E. , Pachi A. , Zuccarini O. , Fiore R. , Fallucca F.
Published: October 2009

Abstract. This study examined the effect of some maternal factors on the pre- and postnatal development of a group of infants of diabetic mothers (IDMs). Body weight, length and head circumference were measured at birth and at 3, 6, 12, 24, 36, and 48 months of age. No differences were observed in pre- and postterm growth when IDMs were subdivided according to the maternal White class or pregnancy complications. Poor metabolic control during pregnancy resulted in excessive and abnormal prenatal growth; the fetal weight increased progressively during the last 3 weeks of gestation, while little or no increase was observed in fetal length or the head circumference which at 37 weeks both were already higher than (length) or similar to (head circumference) those of normal babies at term. Children of mothers with poor metabolic control during pregnancy showed significantly higher values for weight and weight/height ratio in infancy than children of well controlled mothers. Female offspring contributed most to the differences.
Longterm morbidity in infants of diabetic mothers
Authors: Persson Bengt
Published: October 2009

Abstract. A study of the five year morbidity experience by a group of 73 children born to diabetic and gestational diabetic mothers in one institution between 1969 and 1972 is reported. Only one child was found to be remarkably obese. No severe neurological deficit was found and intellectual performance was normal. None had developed diabetes. Five years later the prevalence of diabetes was reassessed. Two children (3%) had developed insulin-dependent diabetes.