Use of mechanistic information to derive chemical-specific adjustment factors - Refinement of risk assessment.

When extrapolating data from animal toxicological studies a default factor (dUF) of 100 is applied to derive a heath based guidance value. The UF takes into account the interspecies differences (ID) and the intraspecies variability (IV). When re-evaluating the safety of phosphates used as food additives nephrocalcinosis was identified as the critical endpoint. The underlying mechanism for nephrocalcinosis was attributed to the precipitation of calcium phosphate in the kidney, depending on its solubility, irrespective of the species and the population. Based on the mechanism, the volume of primary urine, for which the glomerular filtration rate (GFR) was used as a proxy, was considered to be the only parameter relevant for ID and IV. Median value of GFR in rats was 4.0 ml/min/kg bw. In humans it was 1.6 ml/min/kg bw in healthy adults and 0.9 in elderly. These values were calculated from the distribution of the GFR data from 8 studies in rats (n = 191), 16 studies in adults (n = 1540) and 5 studies in elderly (n = 2608). Multiplying the distribution of the ratio rat/healthy humans (ID) with the distribution of the ratio healthy humans/elderly human (IV) resulted in a phosphate specific factor of 4.5 (3.3-6.7) (median; 25th - 75th percentile).

Considerations on nonclinical approaches to modeling risk factors of suicidal ideation and behavior.

Given the serious nature of suicidal ideation and behavior (SIB) and the possibility of treatment-emergent SIB, pharmaceutical companies are now applying more proactive approaches in clinical trials and are considering the value of nonclinical models to predict SIB. The current review summarizes nonclinical approaches to modeling three common risk factors associated with SIB: aggression, impulsivity, and anhedonia. For each risk factor, a general description, advantages and disadvantages, species considerations, nonclinical to clinical translation, and pharmacological validation with respect to treatments associated with SIB are summarized. From this review, several gaps were identified that need to be addressed before use of these nonclinical models can be considered a viable option to predict the relative risk for SIB. Other future directions that may compliment these nonclinical approaches, including the use of selectively-bred or genetically-modified rodent models, transgenic models, gene expression profiling, and biomarker analysis, are discussed. This article was developed with the support of the DruSafe Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org).

[Cryptorchism yesterday and today. Update study programmed in interdisciplinary services]. / Il criptorchidismo ieri e oggi. L'odierno studio programmato in "servizi interdisciplinari".

It is more than 25 years that several Authors stress the need of an early treatment of undescended testis both mono or bilateral. The pathogenesis of undescended testis is still unknown, but some suggestions about the hormonal role has been formulated. From these considerations "interregional groups to study the cryptorchidism" has been formed, in order to use the same parameters of evaluation: auxologic studies, cytogenetic analysis, hormonal tests, dynamic hypophyseal functionality test, medical treatment, surgical treatment, biopsies, postoperative hormonal treatment, seminal evaluation after 20 years of life. From all these studies a protocol has been planned, including a treatment by HCG associated with urophollitropine as pure FSH stimulating effect and an eventual surgical treatment before the 5th years of life.

[Cryptorchism: long-term results in subjects evaluated in a conjugal infertility service (monolateral cryptorchism fertility)]. / Il criptorchidismo: esiti a distanza in soggetti depistati in servizi di sterilità matrimonaiale (la fertilità di criptorchidi monolaterali).

Infertile male subjects because of cryptorchidism have an overall rate of 0.5-1%. Undescended testis even if treated by surgery and/or hormonal therapy have a bad seminal map. However in Author's experience, the hormonal treatment give a significant improvement in terms of fertility. Biopsies carried out on undescended testis demonstrated an early cellular damage of the testis.

[Ultrastructural analysis of human ejaculate from infertile subjects]. / Analisi dell'ultrastruttura dell'eiaculato umano in soggetti infertili.

It has been demonstrated that the semen of infertile patients contains at high percentage of abnormal forms and no clear answer has been so far provided to the questions of which malformations are compatible with male fertility, which malformations are responsible for the infertility and which is the percentage of defective cells that gives rise to infertility. In this study the eiaculates of 56 patients of suspected male infertility were used as material. The semen samples were fixed for 2 hr at room temperature in 4% glutaraldehyde in 0.05 M cacodilate buffer + 0.018% CaCl2 + 6.6% sucrose, post-fixed in 1.5% OsO4 in same buffer + 6.6% sucrose, dehydrated and embedded in Spurr. The samples were sectioned with Reichert OMu3 ultratome. The sections, contrasted with uranyl acetate and lead citrate, were examined in a Feol M T8 E.M. The varieties of sperm malformations are described and classificated into morphological categories based upon the type of alteration and the cellular portion in which the malformation appeared. From this research we have got the following conclusions: 1) an absolute correlation between microscopical, ultrastructural defects and functionality of spermatozoa does not exists; 2) the submicroscopic analysis contributes to a more accurate definition of the eiaculate; 3) the high variability of the ultrastructural defects needs that the submicroscopical analysis of the human semen must be supplemented by a quantitative evaluation.

Testicular biopsy of azoospermic men with vas deferens malformation using two different techniques.

A morphological analysis was carried out on testicular biopsies of men with obstructive azoospermia as consequence of vas deferens malformations as compared with biopsies from fertile men. For each case the biopsies were processed with two different techniques: routine histological procedure, and semithin sections of specimens processed for electron microscopy. Four parameters were considered: tubular morphology, testicular biopsy score count (TBSC), tubular diameter, and germinal cell density. The data were quantified and analyzed by statistical tests. The biopsies of azoospermic men present a higher frequency of tubular sections with "tubular blockage," "sloughing" and cellular degeneration, lower values of TBSC, and lower germinal cell density. The results appear to be of relevant interest in relation to the existence of long-term testicular alteration following vasectomy.

[Indications for hormone therapy of male secretory sterility]. / Indirizzi di terapia ormonale della sterilità secretoria maschile.

The latest therapeutic approaches to male sterility with particular reference to endocrine criteria (homologous gonadotropins, GN RH and similar, androgens, antioestrogens, thyroid hormones, etc.) and the many complex diagnostic problems still encountered are reviewed. The experiment with homologous associated gonadotropins (hMG + hCG) is particularly interesting. A significant sample (3815 dyspermic subjects identified between January 1966 and September 1981 in the Niguarda-Ca' Granda Hospital's Fertility and Sterility (Clinic) revealed an apparently normal seminal report (at least at minimum values compatible with fertility) in 74.8% of cases and a positive biological refutation (onset of pregnancy in apparently normal partners) in 17.9% of subjects judged suitable for treatment.

[Indications for hormone therapy of female secretory sterility]. / Indirizzi di terapia ormonale della sterilità secretoria femminile.

Female dysendocrine sterility has displayed a statistical incidence of 3.4% since 1967 in Milan's fertility and sterility centres. It is always marked by clear-cut clinical situations. Of these, particular interest is attached to anovulation (62.4% of cases), both with the cycle and with anovularity, ovarian micropolycystosis (2.7%), both as Stein ovary and as micropolycystic ovary, disturbances of ovary endocrine secretion: lutein deficiencies (21.2%) in the form of both brief and inadequate luteal phase. Treatment is aimed at possibly discontinuous reinstatement of ovulation. Clinical and pharmacological experiments over the last twenty years have put forward many "inducers". Mention is made of four personal approaches: --clinical employment of homologous gonadotropins (hMG + hCG), sequentially rather than paired, when poor gonadotropin secretion accompanied by insufficient endogenous oestrogenic activity is the main feature. Investigation from June 1964 to December 1981, coupled with monitorisation and personalisation of the treatment, initially through daily checks of total and fractionated oestrogenuria, and in recent years preferably through plasma 17-beta oestradiol or urinary enzyme determinations, has given a different slant to the reported disadvantages of gonadotropic management: hyperstimulation frequent multiple pregnancies, frequent multiple miscarriages; --employment of GnRH or its analogues (indications virtually those for paired gonadotropins). Some uncertainties however, exist with regard to the contraceptive action displayed by the agonist and antagonist analogues at certain doses, and with regard to the antigonadic action GnRH appears to have, both in the depression of oestrogen and progesterone production and in the arrest of follicular maturation an ovulation; --a preference for clomiphene among the antioestrogens in cases of primarily hypothalamic dysfunction and in ovarian micropolycystosis, provided endogenous oestrogenic activity is within normal limits; --a preference for hypoprolactinaemic drugs (bromoergocriptine, lysuride) in PRL-dependency, marked solely by an appreciable increase in serum LTH, screened as functional by means of selective tests; --experimentation of epimestrol, mainly in cases of sterility due to lutein deficiency.

The role of Yp in sex determination: new evidence from X/Y translocations.

A 33-year-old man had azoospermia and tubular atrophy as in the Klinefelter syndrome but short stature. He had a 46,X,t(X/Y) (Xqter lead to p22.3::Yp11 lead to Yqter) translocation and was H-Y antigen-positive. This excludes one of the genes controlling H-Y antigen from the terminal portion of the short arm of the Y chromosome. This case and the two similar ones in the literature indicate that the proximal Yp portion is required for the differentiation of a male gonad. The pattern of X inactivation was random in the patient's fibroblasts, whereas in the lymphocytes the translocated chromosome was preferentially inactivated; comparison with other cases shows that the quantity of Y chromosome material involved in these translocations does not influence the X inactivation patterns. In the three cases with this dicentric translocation the X chromosome centromere is consistently the active one. Our case indicates that the choice of which centromere is inactivated is independent of the replication pattern of the X chromosome. Our patient and a few other relevant cases from the literature confirm that factors controlling height are located on the distal portion of Xp and of Yp.

Ultrastructural study of the decapitated sperm defect in an infertile man.

An infertile man presented a spermiogram in which 100% of the spermatozoa displayed separation of head from tail at the level of the proximal centriole. Most tails were normally structured and ended anteriorly with the proximal centriole covered by a continuous plasma membrane. In a small percentage of tails a rudimentary connecting piece was surrounded by a minute cytoplasmic mass and the middle piece was missing, whereas the chromatoid body and the spindle-shaped body were still present. Finally, a few tails had a large cytoplasmic mass surrounding either regular connecting and middle pieces or a rudimentary connecting piece continuous with the main piece. Tails of the first type had good forward motility, although the pattern of movement appeared altered. The other types were immotile or motile but without forward progression. In the loose heads the implantation fossa had failed to differentiate. The separation of heads from tails appeared to be the result of a specific morphogenetic defect and took place at different stages of spermatid differentiation, giving rise to the structurally different types of tails.

Long-term multicentre trial with TA-RO CAP, a new spermicidal product.

326 healthy couples were selected to enter the trial of a new intravaginal contraceptive called the TA-RO CAP. The trial lasted three years. Clinical and laboratory examinations were performed periodically to determine the long-term effectiveness, tolerability and acceptance. Statistical evaluation of results was performed by life-table analysis.

PIP: A new vaginal cap (TA-RO-CAP) composed of multiple spermicidal contraceptive agents was tested clinically by 326 couples to evaluate the long-term effectiveness, tolerability, and acceptance of this new contraceptive method. The CAP, in the form of a watch-glass, designed for intravaginal use, contained: benzethoniom chloride, 4.5 mg; nonoxynol 9, 39 mg; polyethylene-glycol 600, 78.6 mg; polyethylene-glycol-1500, 64.4 mg; dipropylene-glycol, 11.2 mg; mannitol, 100.8 mg; starch, 40 mg; and perfume, 1.5 mg. 230 couples (70.5%) completed the trial, which involved 4582 months of use, with each couple averaging 14 months. The total pregnancies which occurred was 26; these were divided among 3 centers. 2 of 26 pregnancies were shown to result from improper usage (insertion after coitus). 29 couples discontinued use for personal reasons, and none had any side effects during the trial. 16 of these discontinuations were provoked by the male partner. 5.5% of couples experienced mild side effects, such as redness or irritation, but only 1 case discontinued because of them. None of the women showed neoplastic degeneration of the portion or in the vagina after colposcopy and vaginal oncological cytology examinations. The statistical evaluation of this 3-year long trial is presented in a life-table.

[Genital tuberculosis and sterility]. / Tubercolosi genitale e sterilità.

The incidence of genital tuberculosis in its active and silent forms in determining in female procreational incapacity can be evaluated at about 5.03% (0.27% in active phase, 4.76% latent): these figures come from the extensive series of three Milan marriage sterility centres covering some thirty years of clinical and out-patient work (a total of 294 patients with specific genital diseases, of whom 16 in developmental phase and 278 latent). Chemotherapy, which always involves a variety of medicaments (prevalently streptomycin-isoniazide-etambutol association or rifampicin-isoniazide) can consist of the following approaches, depending on disease characteristics: - attach therapy - particularly in initially exudative forms, in acute and subacute evolutive phase and in the acute recurrences of chronic, drug-sensitive forms - using massive doses for two-three months; - basic therapy - indicated in chronic and stationary periods - with simultaneous administration of the chosen drugs and breaks in the treatment, for a period of at least six-eight months; - consolidation therapy - to be carried out even when the cure is apparently complete so as to avoid relapses - with periodic cycles lasting at least ten-twelve months. The experience can be considered highly encouraging because, quite apart from clinical cure, gestation occurred in only six cases and these gave rise to eutocic deliveries.

PIP: The diagnosis of genital tuberculosis is a long and complicated process, necessitating ematological evaluations, biological tests, istological and radiological investigations, and, often, utero-tubal insufflation and culdoscopy. Over a period of 30 years about 294 patients with different forms of genital tuberculosis were observed in 3 marriage sterility centers in Milano, Italy. Out of this total the incidence of genital tuberculosis accounted for infertility in 5.03% of cases, of which 0.27% were in the active phase, and 4.76% in the latent phase. Depending on the disease, treatment with chemotherapy can be defined as: 1) attack therapy, using massive doses for 2-3 months in initially exudative forms, and in acute evolutions and/or recurrences; 2) basic therapy, for a period of 10-12 months in chronic and stationary periods; and, 3) consolidation therapy, in periodic cycles of 10-12 months when the cure is complete and to avoid relapses. Apart from clinical cure, the experience with the patients observed was not very encouraging (only 6 patients became pregnant) and confirmed similar results obtained by other authors.

[Etiopathogenetic and clinical notes on the syndrome of the micropolycystic hyperandrogenic ovary and matrimonial sterility]. / Considerazioni eziopatogenetiche e cliniche in tema di sindrome da ovaio micropolicistico iperandrogenico e sterilità matrimoniale

The nosological, clinical, aetiopathogenetic and therapeutic aspects of hyperandrogenic micropolycystic ovary are examined with particular reference to matrimonial sterility. There is not doubt about the existence of a syndrome substantially characterized, clinically, by menstrual trouble, inability to procreate, more or less evident signs of hyperandrogenism and a tendency to obesity and, morphologically, by ovarian micropolycystic alterations of typical pathognomonic aspect: the marked production of androgens on the part of the female gonad possibly accompanied by peripheral alterations interfering with their metabolism. The syndrome is not too frequent and, in personal experience, occurs in less than 1% of the series. The main therapeutic approach remains cuneiform resection of the ovary. Still in personal experience, 21.2% of cases treated led to pregnancy but not more than eight-ten months after operation. The effect would therefore appear to be transitory and the operation is decisively rejected where unmarried women are involved.

Effects of electromagnetic fields on fecundity in the chicken.

Egg production was reduced when young laying hens were kept in contact with metal cages while being continuously exposed to the following cw fields: a vhf field at a frequency of 260 MHz, with an incident power that decreased from 100 to 4mW during the experiment; a uhf field at a frequency of 915 MHz, with an incident power of 800 mW during the first 2.5 weeks, zero during the following week, and 200 mW for the remainder of the experiment; a uhf field at 2.435 GHz, with an incident power of 800 mW; an elf electric field at a frequency of 60 Hz, with a calculated value of field strength of 1600 V/m; an elf magnetic field at 60 Hz, with a value of magnetic flux density of 1.4G. With the exception of the hens exposed to the uhf field at 915 MHz, all other treated groups laid significantly less eggs than the controls (p smaller than or equal to 0.01). This reduction (similar 15% less than the controls) began with the first 4-week production period. The egg production curves for the hens exposed to the vhf field at 260 MHz and to the uhf field at 2.435 GHz were approximately the same beginning with the sixth week of production, and they maintained comparable production levels for the remainder of the experiment. An 8% total drop in production also was experienced in the group of birds exposed to the 915-MHz field, which pulsed because of equipment failure. Egg production rate curves for the birds in the elf electric and magnetic fields were substantially different from those exhibited by birds in the other electromagnetic fields. The birds in the E-field regained a production level comparable to the controls after 11 weeks production, whereas those in the B-field dropped to 31% production, which was approximately 40% poorer than the controls by the twelfth week of production. Fertility of cocks and hens was not affected by continuous low-power vhf and uhf near-zone electromagnetic exposure or elf electric or magnetic field treatment. Fertility was exceptionally good, except for the controls and the hens exposed to the elf electric field. The hatchs of fertile and of total eggs were not significantly influenced by exposure to any of the five fields. A considerably lower incidence of male chicks was noted in the elf magnetic field treatment (32.3%). The sex ratio in the other groups appeared to be relatively normal. No macroscopic abnormalities attributable to treatments were noted in the chicks hatched or in the dead embryos.