Induction, suppression and inhibition of multiple hepatic cytochrome P450 isozymes in the male rat and bobwhite quail (Colinus virginianus) by ergosterol biosynthesis inhibiting fungicides (EBIFs)

Ergosterol biosynthesis inhibiting fungicides (EBIFs) have complex effects on the hepatic microsomal monooxygenase systems of vertebrate species, having been described as mixed inducers and inhibitors of cytochrome P450. In the current study, we examined the effects of two EBIFs in clinical use, clotrimazole and ketoconazole, and two agricultural EBIFs, propiconazole and vinclozolin, on hepatic monooxygenase activities and P450 apoprotein expression in the male Sprague-Dawley rat and the male bobwhite quail. EBIFs produced Type II binding spectra with hepatic microsomes from both species and were effective inhibitors of methoxyresorufin O-demethylase, an activity selective for P450 isozymes in gene family 1. However, the EBIFs varied widely in their effectiveness as inducers of P450 isozymes in gene families 1, 2, 3 and 4, both within the same species and between species. In the rat, clotrimazole was the most effective inducer, increasing expression of CYP 3A isozymes over 450-fold, CYP 2B1/2 30-fold and CYP 1A1/2 12-fold and suppressing expression of CYP 2C11 nearly 70%. By contrast, in the quail, clotrimazole was the least effective inducer. In quail, vinclozolin and propiconazole elevated total P450 content 10- and 7-fold, respectively. The induction response also appeared to be mixed, but in this case consisted of a 5-fold induction of P450s in gene family 1A, a 3-fold induction of P450s in gene family 3A and 4A, and induction of protein(s) from gene family 2, cross-reactive with antisera against rat CYP 2C11 and CYP 2A1. A protein that was cross-reactive with antibodies raised against rat CYP 2B1 was decreased with EBIF treatment. In conclusion, EBIFs have complex patterns of induction, suppression and inhibition of cytochrome P450 isozymes in both mammals and birds, which vary according to both the fungicide and the species.     

Neuromodulation of transplanted gonadotropin-releasing hormone neurons in male and female hypogonadal mice with preoptic area brain grafts

Implantation of normal preoptic area (POA) tissue into the third ventricle of adult hypogonadal (HPG) mice provides a source of GnRH neurons that innervate the host median eminence and stimulate reproductive development in the sterile mutants. To further evaluate graft-host integration, the effects of N-methyl-D,L-aspartic acid (NMA) and opiate antagonists on LH secretion in HPG mice with POA transplants (HPG/POA) were tested. NMA challenges significantly stimulated LH secretion in 10 of 11 HPG/POA females. Only 5 of 12 HPG/POA males responded to the same treatment. Administration of the opiate antagonists naloxone or naloxone methiodide was ineffective in stimulating LH release in any mice, but opiate antagonist pretreatment significantly potentiated the LH secretory response to NMA in female, but not male, HPG/POA mice. A potential anatomical substrate for this facilitation may be the beta-endorphin-immunoreactive innervation of the POA grafts in all HPG/POA brains examined. beta-Endorphin fibers were also present in the median eminence in the vicinity of GnRH outgrowth from the grafts. However, similar innervation patterns in HPG/POA males that did not respond to opioid antagonism suggests that this is not sufficient. We tested whether the sex difference in HPG/POA responsivity to neuromodulation is related to the steroid milieu in the hosts. 17 beta-Estradiol (E2) treatment facilitated the LH secretory response of male HPG/POA to NMA challenges whether animals were castrated and given an E2 capsule prior to graft implantation or one week before testing two months after graft surgery. Intact or vehicle (sesame oil)-treated, castrated HPG/POA males rarely responded to NMA challenges, yet graft-derived GnRH innervation of the hosts' median eminence was comparable in all treatment groups. GnRH challenge testing indicated that pituitary sensitivity of the HPG/POA males was not significantly altered by E2 treatment, suggesting that estrogen acted centrally. These results indicate that the activity of grafted GnRH neurons may be modulated by endogenous opioids of host origin as well as by the hormonal milieu.     

Novel phosphate mimetics for the design of non-peptidyl inhibitors of protein tyrosine phosphatases

Benzylic alpha,alpha-difluorosulfonates, alpha,alpha-difluorotetrazoles, and alpha,alpha-difluorocarboxylates of type 5 and 6 were synthesized and examined as potential phosphate biosteres for PTP1B inhibition. The alpha,alpha-difluorosulfonates and alpha,alpha-difluorotetrazoles were found to be more effective inhibitors than the analogous compounds bearing the fluoromalonyl group, a phosphate biostere currently being used for PTP inhibition.     

Isolation and initial characterization of a newfound hantavirus from California

A fatal case of hantavirus pulmonary syndrome (HPS) in northern California prompted our attempt to isolate viruses from local rodents. From tissues of two deer mice, Peromyscus maniculatus, two hantaviruses (Convict Creek virus 107 and 74, CC107 and CC74) were established in cell culture. Viral antigens, proteins, and RNAs of the first and archetypical isolate (CC107) were examined, and portions of the medium (M) and small (S) genome segments of both isolates were sequenced. Antigenically, CC107 virus and the second isolate, CC74 virus, were more closely related to Puumala virus than Hantaan (HTN) virus, though distinct from both. Northern blots of viral RNAs showed the large and M segments of CC107 to be the same size as those of HTN virus, whereas the S segment was larger. Protein gels did not reveal CC107 to have a substantially larger nucleocapsid protein than HTN virus. Partial nucleotide sequence comparisons of CC107 and CC74 viruses revealed their M segments to be highly similar to one another, while their S segments differed by more than 10%. Nucleotide and deduced amino acid sequence comparisons showed the California isolates to be closely related to the newfound hantaviruses first detected in the Four Corners area and since incriminated in HPS through wide areas of the United States.     

Ovarian torsion in prepubertal and pubertal girls: sonographic findings

OBJECTIVE: The purpose of this study is to report the range of gray-scale and color Doppler findings of ovarian torsion in prepubertal and pubertal girls to determine whether there is a difference in appearance between the two age groups. MATERIALS AND METHODS: The study population consisted of 20 patients, 11 who were prepubertal (ages 2 days to 6 years) and nine who were pubertal (ages 12-16 years), who had gray-scale sonograms and surgical confirmation of ovarian torsion. Color Doppler studies were obtained in 14 of 20 patients. All sonograms were reviewed retrospectively by two radiologists with attention to location of the twisted ovary, internal characteristics, and evidence of color Doppler flow. The results were then compared in the prepubertal and pubertal groups. RESULTS: Sonographic findings of torsion in 11 prepubertal patients included complex mass with septations and debris (6/11), cystic mass (1/11), and solid mass with peripheral cysts (4/11). The masses were located in the right lower quadrant (5/11), left lower quadrant (3/11), right adnexa (2/11), and right inguinal canal (1/11). Eight of nine pubertal patients had solid masses, and one had a thick-walled cystic mass. Torsion involved the right ovary in nine patients and the left in 11. Color patterns included central flow (3/14), peripheral flow (6/14), and absence of flow (5/14) and did not correlate with age or gray-scale findings. CONCLUSION: Sonographic findings of ovarian torsion vary with age. Neonates and young children have extrapelvic cystic or complex cystic masses, whereas pubertal girls have predominantly solid masses in an adnexal location. In both groups of patients, color Doppler signal can be documented in many twisted ovaries.     

Sex difference and testosterone modulation of pheromone-induced NeuronalFos in the Ferret's main olfactory bulb and hypothalamus

A carnivore, the ferret possesses a vomeronasal organ--accessory olfactory bulb (VNO-AOB) projection to the hypothalamus; however, little is known about its function. Pheromones in soiled bedding from estrous female ferrets or an artificial peppermint odor significantly augmented nuclear Fos protein immunoreactivity (Fos-IR), a marker of neural activation, in several main olfactory bulb (MOB) sites but not in the AOB of gonadectomized male and females. Testosterone propionate (TP) significantly augmented the MOB's neuronal Fos responses to estrous females' pheromones, but not to peppermint. Estrous odors, but not peppermint, also augmented neuronal Fos-IR in the medial preoptic area (mPOA) of female, but not male, subjects. Pheromones in soiled bedding from breeding male ferrets significantly augmented neuronal Fos-IR in the MOB and in the medial amygdala of gonadectomized, TP-treated male and female subjects. Again, male pheromones failed to influence neuronal Fos-IR in the AOB of either sex, and only females showed significant increases in neuronal Fos-IR in the lateral aspect of the ventromedial nucleus and mPOA. These results point to an essential role among higher mammals of the main olfactory epithelium-MOB projection to the hypothalamus in detecting and processing pheromones. Gonadectomized ferrets showed significant increases in sniffing behavior when placed on either female or male bedding. This occurred regardless of whether they had received TP or oil vehicle, suggesting that testosterone's facilitation of neuronal Fos responses to estrous females' odors in the MOB of both sexes cannot be attributed to increased scent gathering. Androgen receptor-IR was present in the MOB granule cell layer of male and female ferrets, raising the possibility that testosterone acts directly on these cells to augment their responsiveness to pheromones.     

M-plasty in the treatment of carcinomas located on the interglabellar region

One of the main tasks of current cutaneous surgery is to completely eliminate the tumor while avoiding unnecessary normal tissue extirpation. This is especially important when removing facial tumors close to the external canthus, mouth angles and perialar regions. In all these areas we advise fusiform excision but with distal M-plasty in the nearest angle so as to avoid angle retraction. The same is true for mediofrontal tumors, as this often causes a drawing together of the eyebrows. We have reviewed all mediofrontal excisions carried out during the last six years. M-plasty following fusiform excision was always performed in the interglabellar area. The good results achieved allow us to recommend this technique in this location.