Assessment of in silico models for acute aquatic toxicity towards fish under REACH regulation.

We evaluated the performance of eight QSAR in silico modelling packages (ACD/ToxSuite™, ADMET Predictor™, DEMETRA, ECOSAR, TerraQSAR™, Toxicity Estimation Software Tool, TOPKAT™ and VEGA) for acute aquatic toxicity towards two species of fish: Fathead Minnow and Rainbow Trout. For the Fathead Minnow, we compared model predictions for 567 substances with the corresponding experimental values for 96-h median lethal concentrations (LC50). Some models gave good results, with r2 up to 0.85. We also classified the predictions of all the models into four toxicity classes defined by CLP. This permitted us to assess other parameters, such as the percentage of correct predictions for each class. Then we used a set of 351 substances with toxicity data towards Rainbow Trout (96-h LC50). In this case the predictability was unacceptable for all the in silico models. The calculated r2 gave poor correlations (≤0.53). Another analysis was performed according to chemical classes and for mode of action. In the first case, all the classes show a high percentage of correct predictions, in the second case only narcotics and polar narcotics were predicted with good confidence. The results indicate the possibility of using in silico methods to estimate aquatic toxicity within REACH regulation, after careful evaluation.

Comparison of in silico models for prediction of Daphnia magna acute toxicity.

Eight in silico modelling packages were evaluated and compared for the prediction of Daphnia magna acute toxicity from the viewpoint of the European legislation on chemicals, REACH. We tested the following models: Discovery Studio (DS) TOPKAT, ACD/Tox Suite, ADMET Predictor, ECOSAR (Ecological Structure Activity Relationships), TerraQSAR, T.E.S.T. (Toxicity Estimation Software Tool) and two models implemented in VEGA on 480 industrial compounds for 48-h median lethal concentrations (LC50) to D. magna, matching them with experimental values. The quality of the estimates was compared using a standard statistical review and an additional classification approach in which the hazard predictions were grouped using well-defined regulatory criteria. The regression parameters, correlation coefficient being the most influential, showed that four models (ADMET Predictor, DS TOPKAT, TerraQSAR and VEGA DEMETRA) had similar reliability. These performed better than the others, but the coefficient of determination was still low (r2 around 0.6), considering that at least half the predicted compounds were inside the training sets. Additionally, we grouped the results in four defined toxicity classes. TerraQSAR™ gave 60% of correct classifications, followed by DS TOPKAT, ADMET Predictor™ and VEGA DEMETRA, with 56%, 54% and 48%, respectively. These results highlight the challenges associated with developing reliable and easily applied acceptability criteria for the regulatory use of QSAR models to D. magna acute toxicity.

Median raphe cyst of the penis: a report of two cases with immunohistochemical investigation.

Penile median raphe cysts are uncommon benign lesions occurring predominantly in the ventral aspect of the glans penis of young men. We observed two cases: those of a 67-year-old patient and a 22-year-old patient. The epithelial lining of the cysts was composed of pluristratified small cells that focally showed rows of columnar cells above the inner surface as well as a monolayered mucinous columnar epithelium. A columnar cell lining predominated in the younger patient. The cytokeratin (CK) immunostaining pattern of the two cysts (CK7(+++), CK13(+++), CK20(-), CAM 5.2(+)) supports the interpretation of a columnar mucinous epithelium undergoing immature urothelial metaplasia. Carcinoembryonic antigen immunostaining positivity of the columnar cells is probably related to the dysembryogenetic cloacal nature of the cysts. Neuroendocrine differentiation of sparse cells interspersed in the pluristratified epithelium was documented by immunohistochemical staining for chromogranin and synaptophysin. Cilia were not identified in the columnar cells by light microscopy or by antidynein immunohistochemistry.

Cutaneous ciliated cyst: a case report with immunohistochemical evidence for dynein in ciliated cells.

Cutaneous ciliated cysts (CCCs) are rare benign lesions predominantly occurring in the lower limbs of young women. We observed such a lesion in the perineal region of a 12-year-old girl. The histogenetic interpretation of CCCs is controversial. The similarity of the epithelial lining of the cyst to the salpingeal epithelium supports the hypothesis of a Müllerian heterotopia. Strong dynein positivity observed immunohistochemically in the apical portion of CCC lining cells suggests the integrity of the ciliary apparatus. There was a marked similarity between a CCC and normal salpingeal epithelium in the mode of staining for dynein, whereas the dynein reactivity of bronchial epithelial cells showed larger cytoplasmic aggregates of positive material in proximity to the nucleus. No immunohistochemical staining for estrogen or progesterone receptors was identified in our observation, although this finding could have supported the Müllerian histogenetic hypothesis. To the best of our knowledge, this is the first time that antidynein immunohistochemistry has been applied to paraffin-embedded samples from human surgical pathology.

Scanning electron microscope study on the efficacy of root canal wall debridement of hand versus Lightspeed instrumentation.

AIM: The aim of this in vitro study was to compare the efficacy of root canal wall debridement following hand versus LightSpeed instrumentation. METHODOLOGY: Twenty recently extracted single-rooted teeth were paired and randomly placed into two treatment groups of 10 teeth each. In group 1, a step-back instrumentation without initial coronal flaring with stainless steel Hedstroem files was used; group 2 was instrumented with Ni-Ti LightSpeed instruments. Both groups had the same irrigation regimen: 2.5% NaOCl and a 15% EDTA solution. The teeth were then decoronated and each root split longitudinally into two halves to be examined using the scanning electron microscope (SEM). The presence of superficial debris and smear layer was evaluated by a standardized grading system, and the resulting scores submitted to nonparametric statistics. RESULTS: Under the conditions of this study, the removal of superficial debris was generally excellent with both canal preparation techniques. Both techniques resulted in variable presence of residual smear layer, with a canal wall covered by smear layer as the predominant characteristic. Generally, the amount of smear layer was greater in the apical than in the middle third of the root, however, this difference was statistically significant (P < 0.005) only in hand-instrumented teeth. The use of LightSpeed instruments was associated with significantly more (P < 0.05) smear layer presence in the middle region of the root when compared with hand instrumentation. In addition, less smear layer was present in the apical region following LightSpeed instrumentation than stainless steel hand files, but this difference was not statistically significant. Differences in debridement between the two halves of the same root were more evident with LightSpeed than manual instrumentation, however, there was no statistical significance. CONCLUSIONS: It may be inferred that the choice between hand and LightSpeed instrumentation should be based on factors other than the amount of root canal debridement, which does not vary significantly according to the instruments used.

Should scrotal calcinosis still be termed idiopathic?

We observed so-called idiopathic scrotal calcinosis in a 36-year-old man who was cured successfully by simple excision of the affected skin. Histologically, the nodular lesions consisted of calcified amorphous basophilic masses and small granules within the dermis. One rounded aggregate of calcified basophilic material showed a slight positivity on immunostaining for cytokeratin. Some intact epidermoid cysts were also present, suggesting that dystrophic calcification, and possibly inflammation and rupture of epidermoid cysts, may be the main pathogenetic mechanism of the disease in most reported cases. In our opinion, the term idiopathic should refer to the individual cases that are etiologically undefined rather than the whole category of scrotal calcinosis.

So-called nasal glioma: case report with immunohistochemical study.

The so-called nasal gliomas (nasal cerebral heterotopias) are rare, congenital, benign masses of neurogenic origin with intra or extranasal location, or both. An intranasal case is reported in a 7-month-old infant who successfully underwent surgery with the intranasal approach. The tumor had no intracranial extension and the child is free of disease after a three-year follow-up. Immunohistochemical study confirmed the glial (GFAP+) and neuronal (NSE+) nature of the cells composing the mass. In addition to the clinical behavior, the benign nature of the tumor is also indicated by the negativity of Ki67 (MIB-1) and p53 proliferation markers as well as by CD44 negativity. As far as we know, this is the first reported case of nasal glioma subjected to immunohistochemical investigation of proliferation activity.

Missed hysteroscopic detection of uterine carcinoma before endometrial resection: report of three cases.

Endometrial ablation or resection using hysteroscopy appears to be an effective treatment for menorrhagia resistant to medical therapy. Three patients with endometrial adenocarcinoma missed in the preoperative hysteroscopic and histological assessment and subjected to endometrial resection were collected in a multicenter study. One case was an early adenocarcinoma in the background of late proliferative endometrium in a 39-year-old woman. In the other two patients, ages 51 and 68, the adenocarcinoma developed in a polyp in a background of simple hyperplasia. Since hysteroscopy with endometrial biopsy might not be able to exclude the presence of an early intrauterine cancer, appropriate selection and accurate evaluation of patients are imperative before ablative surgery. Endometrial resection is preferred over endometrial laser ablation since it provides additional tissue for histologic examination.

Epithelial ovarian tumors in the reproductive age group: age is not an independent prognostic factor.

BACKGROUND: While ovarian carcinoma is rare in the reproductive age group, these younger patients are known to fare better than the older patients. To determine whether age is an independent prognostic factor, as well as to investigate the clinicopathologic profile and survival rate of young women with ovarian carcinoma, a retrospective analysis in a series of patients aged 40 years or younger was performed. METHODS: We collected data on 74 patients with borderline or invasive ovarian carcinoma treated at the Department of Obstetrics and Gynecology at the University of Florence between 1969 and 1994. The median follow-up was 72 months (range, 11-288 months). To assess the clinicopathologic profile and survival differences according to age, the series was subdivided into "very young" (30 years or younger) and "young" (31-40 years) groups of 34 and 40 patients, respectively. Survival rates (Kaplan-Meier method) were compared by the log rank test. A multivariate analysis (Cox proportional hazards) was used to determine the independent effect of each variable on survival. RESULTS: The overall 5-year and 10-year survival rates were 58.2% and 46.1%, respectively. Several prognostic factors were found significant by univariate analysis, including stage (P < 0.001), grade (P < 0.001), residual disease (P < 0.001), histologic type (P < 0.05), and age (< or = 30 years vs. 31-40 years; P = 0.009). Five year survival rates for the patients age 30 years and younger and patients age 31-40 years were 71.3% and 47.1%, respectively. In the former group, low malignant potential tumors and well differentiated carcinomas were significantly more frequent (68.8% vs. 37.5%; P = 0.01). In the multivariate analysis, only stage (I vs. >I; P = 0.004), grade (0-1 vs. 2-3; P = 0.03) and residual disease (P = 0.02) were found to be significant independent prognostic factors, whereas age (< or = 30 years vs. 31-40 years) yielded no independent information (P = 0.36). CONCLUSIONS: Epithelial ovarian cancer patients age 30 years or younger have a more favorable prognosis because of a higher rate of early stage, low grade tumors. Patients aged 31-40 years also show a more favorable disease profile and clinical outcome, although to a lesser extent, than the average ovarian cancer population. Age does not emerge as an independent prognostic factor for ovarian carcinoma in women younger than 40 years.

Gonadoblastoma with coexistent features of mixed germ cell-sex cord stroma tumor: a case report.

Gonadoblastoma and mixed germ cell-sex cord stroma tumor have been widely recognized as two separate entities on the basis of both clinical and pathological features. The typical morphological pattern of both tumor types was found by us to coexist in the same gonadal tumor in a 14-year-old 46,XY phenotypically female subject who also had a contralateral dysgerminoma. A subserous implant showing the mixed germ cell-sex cord pattern of the primary tumor was detected in the uterine body. Following therapy the patient is alive and well after a 7-year follow-up. The distinction between gonadoblastoma and mixed germ cell-sex cord stroma tumor requires discussion.

[Serum beta 2-microglobulin and HLA alloantigens in primary Gougerot-Sjögren syndrome. A possible relation with HLA-DR3 specificity]. / La beta 2-microglobulinémie sérique et les allo-antigènes du système HLA au cours du syndrome de Gougerot-Sjögren primitif. Une relation possible avec la spécificité HLA-DR3.

The relationships between some allo-antigens of the HLA system and beta 2-microglobulin (beta 2m) serum level were examined in a group of 24 subjects with primitive Sjögren's syndrome (pSS). While the beta 2m serum level of all the patients with pSS were higher at the limits of significance (p congruent to 0.05), compared to the values of the 14 control subjects, the division of the patients into two sub-groups of 14 and 10 subjects, according to the presence or absence of the haplotypes DR2 and/or DR3, pointed up a beta 2m serum level which was significantly higher in the first compared to the second (p less than 0.02) and to the group of normal subjects (p less than 0.01). Among the individual haplotypes studied, only the DR3 was observed with a significantly greater frequency (p less than 0.01) in the patients compared to the control group. The haplotype DR3 and also the B8, although at a lesser level, were found to be correlated with a high value of the serum beta 2m: p less than 0.004 and p less than 0.05 respectively. A similar association was not found for the DR2 and DRW52 specificities.

Lichen sclerosus and squamous hyperplasia of the vulva. A clinical study of medical treatment.

One hundred thirty-eight cases of nonneoplastic epithelial disorders of the vulva treated with medical therapy from 1984 to 1988 were evaluated at the University of Florence, Florence, Italy. The 67 cases of lichen sclerosus were treated with testosterone propionate or progesterone ointment for 32 weeks. The 31 cases of squamous hyperplasia were treated with corticosteroid ointment for 16 weeks. The 40 patients with lichen sclerosus associated with squamous hyperplasia were treated with corticosteroid ointment for 12 weeks and then with testosterone propionate ointment for another 20. To evaluate the efficacy of the treatments, the patients were examined before and after therapy. The evaluation took into account the symptoms and gross appearance of the lesions, which were given a score of 1-3. Considering all the cases evaluated, a total regression of symptoms occurred in 82 patients (59.4%), while a partial regression occurred in 37 (26.8%). Furthermore, there was a total regression of gross changes in 68 cases (49.3%) and a partial one in 43 (31.1%). The best results were obtained with squamous hyperplasia, which lichen sclerosus, alone or associated with squamous hyperplasia, yielded less successful results.

Subclinical vulvar papillomavirus infection.

Eighty-eight cases of subclinical human papillomavirus (HPV) vulvar infection were detected in a consecutive colposcopic series of 968 women. Three patterns of acetowhite lesions had a 72% predictive value (88/122) for histologically assessed HPV. The prevalence of subclinical vulvar HPV in self-referred patients was 7.9% (73/918); it was 9% (88/968) in the overall series and significantly higher in younger patients (age less than 25 years: 21/106, or 19.8%) or in those with cervical HPV or cervical intraepithelial neoplasia (CIN) (40/100, or 40%). Routine inspection of the vulva after acetic acid lavage in association with a Papanicolaou test might help identify Papanicolaou-test-negative patients at high risk of developing cervical HPV or CIN. Treatment with beta-interferon (2,000,000 IU daily intramuscularly for 10 days) was given to 30 consecutive patients, but the results were poor: regression was observed in only 2 cases.

Clinico-pathological profile of endometrial carcinoma in young women (under 40 years of age).

Twenty primary endometrial carcinomas in 40 year-old or younger women were collected from a series of 845 carcinomas and newly re-evaluated. The typical histological profile was well-differentiated adenocarcinoma (30%) or adenoacanthoma (35%); however, a case of adenosquamous carcinoma and an exceptional malignant mixed mesodermal tumor were also observed. No tendency for myometrial infiltration (M0) was displayed by 11 (55%) of the cases, while 6 were M1 and 3 were M2 infiltrating neoplasias. Adenomatous hyperplasia was associated with cancer in 53% of the 15 assessable cases. Histopathological diagnostic problems were elicited in 5 cases only. Typical Stein-Leventhal syndrome occurred in 7 patients (35%), while polycystic ovaries were observed in 15 cases (75%). Usually, the patients were obese (40%) and nulligravida (65%). All but one case were stage I disease. Prognosis seems to be excellent following surgery.

Is hysteroscopy of value in the investigation of female infertility?

A prospective multicentre study was designed to ascertain the value of hysteroscopy in the evaluation of female infertility. The study comprises 619 CO2 hysteroscopies in women complaining of infertility. Four hundred and ninety nine examinations (80%) were performed without anaesthesia or cervical dilatation. Twenty eight cases of malformation were diagnosed. Adhesions were found in 68 patients (11%), polypi in 56 (9.1%) and submucous fibroids in 51 (8.2%). Endometrial hyperplasia was diagnosed by hysteroscopy in 67 patients, but there was only 42% histological correlation. Examination of the tubal ostia by hysteroscopy revealed 26 patients (4%) with unilateral tubocornual polyps and one with bilateral polyps. The correlation with hysterosalpingography (HSG) in 185 patients was poor. In 20% where the HSG was reported as normal there were hysteroscopically demonstrable lesions whereas there were false positive findings at HSG in 35% of cases. Hysteroscopy is the only technique which provides an accurate clinical evaluation of the uterine cavity although it does not provide significant information about the cervical canal or fallopian tubes.

Correlation between endometrial biopsy and luteal phase plasma progesterone in women complaining for couple infertility.

One hundred forty-three women complaining for couple infertility (more than 2 yr), were investigated for luteal phase deficiency (i.e. insufficient endometrial luteinization) by endometrial biopsy and serial determinations (in days -10, -7 and -4 respect the onset of the next menses) of plasma progesterone during luteal phase. One hundred-three women had the first endometrial biopsy in phase (IP), 36 had the biopsy "out of phase" (OOP). Among them 13 did not repeat endometrial biopsy, 12 had the second biopsy out of phase (and then classified as Luteal Phase Deficiency) and 11 had the second biopsy "in phase". Only the women affected by luteal phase deficiency had the plasma progesterone (mean of 3 samples) significantly lower than that of infertile women with normal endometrial luteinization. However the majority of the individual progesterone values of these two groups overlapped. The endometrial biopsy seems to be the most practicable method for investigating luteal phase deficiency in women complaining for couple infertility.

Levo-norgestrel-nova-T and precancerous lesions of the endometrium.

The authors report the preliminary data on the topical treatment of endometrial hyperplasia by an intrauterine device releasing Levo-norgestrel (LNG-Nova-T), in a series of 31 patients. The patients examined so far by endometrial biopsies performed at predetermined intervals showed a complete histological regression of the hyperplasia, regardless of its pattern.

Hysteroscopy and endometrial biopsy.

The role of hysteroscopy for a complete evaluation of luteal phase is discussed by the authors. They affirm that for a thorough evaluation a hysteroscopy may be usefully performed simultaneously to the endometrial biopsy.

Hysteroscopic evaluation of intrauterine progesterone contraceptive system as a treatment for abnormal uterine bleeding.

Intrauterine Progesterone Contraceptive System has been used in twenty patients aged 45 to 52, affected by dysfunctional uterine bleeding due to glandular hyperplasia (6 cases), focal glandular hyperplasia (8 cases), cystic hyperplasia (4 cases) and adenomatous hyperplasia (2 cases). Hysteroscopy and endometrial biopsy were performed every two months after insertion of IPCS. Complete regression or clear improvement were observed in all cases. The question if regression may be considered permanent or temporary remains to be answered.

PIP: An intrauterine progesterone contraceptive system has been used in 20 patients aged 45-52 affected by dysfunctional uterine bleeding due to glandular hyperplasia (6 cases), focal glandular hyperplasia (8 cases), cystic hyperplasia (4 cases), and adenomatous hyperplasia (2 cases). Hysteroscopy and endometrial biopsy were performed every 2 months after insertion of the system. Complete regression or clear improvement were observed in all cases. The question if regression may be considered permanent or temporary remains to be answered.

[Immune complexes and peripheral neuropathy: about two cases (author's transl)]. / Neuropatia da immunocomplessi. Considerazioni su due casi.

Two female patients aged 64 and 54 were studied, affected by a progressive, distal sensori-motor mononeuritis multiplex. A nerve biopsy specimen from the first patient, suffering from chronic active hepatitis without detectable serum hepatitis B surface antigen (HBsAg) or antibody (anti-HBs), showed segmental demyelination and widespread inflammatory and necrotizing vasculitis and perivasculitis. The second patient, affected by a localized, caeseating tuberculous infection of the right kidney, refused to undergo a nerve biopsy. Serum levels of circulating immune complexes, detected by C1q BA binding method were strongly positive in both subjects; activation of the complement system (decreased serum level of C3 and/or C4) was also present. The course of the peripheral neuropathy was progressive and worsened in the first patient whose circulating immune complexes were always detectable. On the contrary the second patient showed improvement after the nephrectomy, which coincided with a quick disappearance of the circulating immune complexes. The findings may suggest in these two patients an immune complex mediated pathogenetic mechanism like the one recently accepted for the peripheral neuropathies in the course of chronic hepatitis B.