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We give bounds for the Betti numbers of projective algebraic varieties in terms of their classes (degrees of dual varieties of successive hyperplane sections). We also give bounds for classes in terms of ramification volumes (mixed ramification degrees), sectional genus and, eventually, in terms of dimension, codimension and degree. For varieties whose degree is large with respect to codimension, we give sharp bounds for the above invariants and classify the varieties on the boundary, thus obtaining a generalization of Castelnuovo’s theory for curves to varieties of higher dimension. [ABSTRACT FROM AUTHOR]

We show that if the degree of a nonsingular projective variety is high enough, maximization of any of the most important numerical invariants, such as class, Betti number, and any of the Chern or middle Hodge numbers, leads to the same class of extremal varieties. Moreover, asymptotically (say, for varieties whose total Betti number is large enough) the ratio of any two of these invariants tends to a well-defined constant. [ABSTRACT FROM AUTHOR]

Review of the literature reveals 76 cases of fibrous histiocytoma of the deep structures of the head and neck. To this we have added 11 of our own cases, and analyzed the total group to determine clinical and histological features of a high risk population. Age, sex, presence of pain, location of tumor, size of tumor, and local invasion appear to be important clinical criteria. Bizarre giant cells, numerous and atypical mitoses, necrosis, and inflammation appear to be important histologic features. The treatment of choice is wide local excision. Chemotherapy appears to produce tumor regression. [ABSTRACT FROM AUTHOR]

Two pairs of glomic bodies ('paraganglia') occur in the larynx as originally described by German authors. They were independently found in 18 of 25 serially sectioned adult larynges. The superior laryngeal glomus is situated in the supraglottic larynx in the adult and neonate. The inferior laryngeal glomus is positionally more variable, usually occurring between the cricoid cartilage and the first tracheal ring in the adult and may extend to the thyroid gland. Three neonatal larynges were also examined for comparison. The glomera show no developmental enlargement and appear histologically identical. No glomic tissue was found in neonatal tracheas. Reports of laryngeal paraganglionic tumors or chemodectomas are reviewed and show anatomic correlation with the naturally occurring bodies. [ABSTRACT FROM AUTHOR]

The platinum(II)-based complex cisplatin is one of the most frequently used antitumour agents; however, a high incidence of harmful side effects and the frequent emergence of acquired resistance are the major clinical problems. The novel platinum(IV)-based complex LA-12 exhibits a high efficacy against cancer cell lines, including cisplatin-insensitive cells, but the mechanisms by which LA-12 perturbs cell growth are unclear. We tested the effects of LA-12 on the p53 response and demonstrate that LA-12 induces unique changes in the profile of gene expression compared with cisplatin and doxorubicin. Furthermore, the ability of LA-12 to disrupt cellular proliferation is greatly enhanced by the expression of p53 and p53/47 indicating both p53-dependent and p53-independent effects of LA-12. Exposure of the human cancer cell lines H1299, A2780, BT549 and BT474 to LA-12 alters the expression of p53 and p53/47 in both a time-dependent and dose-dependent manner. Treatment of cells with a low concentration of the drug results in accumulation of p53 and p53/47 concomitant with their posttranslational modification, whereas a high dose results in the disappearance of both the forms of p53. The distinct p53 activation profile of LA-12 compared with cisplatin and doxorubicin provides a molecular explanation for the ability of this drug to treat cisplatin-resistant cells and indicates its potential usefulness as an alternative antitumour agent in first-line therapy or as a second-line therapy in patients with acquired cisplatin resistance.

The oral anti-tumor activity of a novel platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand was evaluated and compared with another platinum(IV) complex satraplatin. The human carcinoma xenografts of colon HCT116, prostate PC3, and ovarian A2780 and A2780/cisR (resistant to cisplatin) were used to evaluate the in-vivo anti-tumor activity. The daily x 5 repeated dose regimen in equimolar doses of LA-12 and satraplatin, administered in 2 cycles, was selected for this evaluation. All doses of LA-12 and satraplatin were significantly effective in comparison with the control. The activities of LA-12 in all doses and all used tumor xenografts were higher than equimolar doses of satraplatin. The highest effect was reached with LA-12 at a dose of 60 mg/kg. The shapes of growth curves of ovarian carcinoma A2780 and its subline resistant to cisplatin after therapy with LA-12 were very similar. This shows that LA-12 is able to overcome resistance to cisplatin.

A novel anti-tumor platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand displaying oral activity was prepared and its oral activity was evaluated. The murine ADJ/PC6 plasmacytoma and human A2780 ovarian carcinoma tumor model were used to evaluate the in vivo anti-tumor activity of a single dose and also of repeated doses with comparison to the activity of cisplatin and of the platinum(IV) complex satraplatin. The acute toxicity of LA-12 in mice is relatively low (maximum tolerated dose 1000 mg/kg), and the effective dose is comparable to that of cisplatin and higher than that of satraplatin. The therapeutic index derived from this is very high (250). In the human tumor model, two repeated dose schedule regimens were evaluated. LA-12 exerted a significantly higher anti-tumor activity than other substances, i.e. cisplatin and satraplatin, in repeated doses on the murine ADJ/PC6 plasmacytoma tumor model. The dailyx5 repeated dose regimen was selected for further evaluation.

The pharmacokinetics of total and free plasma platinum (Pt) and Pt tissue distribution were investigated in rats after oral administration of (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) (LA-12). Plasma and ultrafiltrate were sampled until 48 h and tissue samples were taken at 24 and 48 h after single doses of 38.6 or 540 mg LA-12/kg, and after once-a-day dosing of 4.3 or 38.6 mg kg(-1) LA-12 over 14 consecutive days. Total plasma Pt concentrations increased less than proportionally to the 14-fold increase in the single dose. The mean C(max) values of 1.5 and 6.3 mg L(-1) were observed at 0.5 and 1 h, respectively, and the mean AUC values achieved were 29 and 144 mg h L(-1). The highest tissue Pt concentrations were found in the liver and kidneys. Platinum was undetectable in the brain while in other tissues (muscle, skin, heart, lungs), the concentrations were lower (after single dose) or similar (after multiple doses) when compared to the plasma C(max) values. Plasma Pt concentrations after once-a-day dosing of 38.6 mg kg(-1) were two- to three-fold less than that after a single dose while Pt concentrations in various tissues rose two- to four-fold. Accumulation of Pt was even higher in the kidneys (seven-fold) and spleen (nine-fold). After once-a-day dosing, tissue Pt levels increased proportionally with the dose within the range from 4.3 to 38.6 mg kg(-1). At the same time, the increase in total plasma Pt concentrations was 40% less than proportional. Concentrations of Pt in the plasma ultrafiltrate decreased rapidly with the initial half-life of 1 h.

The clinical investigations with three types of a three days regimen of amocarzine permitted to adjust the fixed dosing to the body weight related dosing and subsequently the administration of amocarzine from fasting state to drug intake after food. The main objective to reach a dose with predictable and sustained absorption was achieved, and this in turn proved to be onchocercacidal and safe. A combined clinicopharmacokinetic study showed enhancement and consistency of amocarzine absorption after food. Quantitative assessment of the urinary excretion confirmed the presence of the N-oxide metabolite, which qualitatively was visible by a urine colorimetry. This assay proved useful for drug monitoring. Ultrasonography of onchocercal skin nodules detected changes within the nodules following amocarzine therapy. Histology after nodul-ectomy at four months post-therapy showed that 57% of the female worms were dead, 24% necrobiotic, and 19% alive; male worms were more necrobiotic. Skin microfilariae were reduced within one week to about 10% of the initial level and after one year they remained at about 20%. Skin punch biopsies on day 5 showed that most microfilariae were dead or moribund. Ocular reduction of microfilariae was also observed, although it was slower than in the skin. The visual acuity improved within the one year's observation time. Ocular and clinical tolerability was good, with one exception of neurological disturbance, which was fully reversible. Sequential testing of the liver function showed average values within the normal range. In conclusion, a repeat low dose regimen of amocarzine (3 mg/kg twice daily post-prandially for three consecutive days) was well absorbed with predictable plasma levels, macro- and microfilaricidal with good local and systemic tolerability in patients with moderate to heavy onchocerciasis. Amorcarzine is recommended for further clinical investigations, particularly in females and juveniles. Urine colorimetry and nodular ultrasonography are recommended for optional monitoring of amocarzine.

Ultrasonography of onchocercal skin nodules was performed with an ophthalmologic real time linear scanner with a B probe of 10 MHz. A clinical trial in Guatemala with amocarzine (CGP 6140)--a new oral macrofilaricidal compound--investigated three repeat dose regimens and one placebo control group, each group consisting of six patients. Onchocercal nodules were scanned before treatment and on day 10, 30 and 60 after start of amocarzine. A total of 28 treated and 8 additional untreated nodules were analysed and compared with the histologic findings following nodulectomy at day 60. Of the 28 treated nodules, 21 were of onchocercal origin and seven were lymph nodes. The correlation between ultrasonography and histology was good in 25 patients, but did not match in three. In 20 out of 21 treated nodules a progressive ultrasonographic change over two months was seen. Of the eight additional untreated nodules, five were of onchocercal origin, one was a lymph node, one an epidermoid cyst and in one only fibrous tissue was detected. The ultrasonography correlated well to histology in seven nodules but not in one. In five onchocercal nodules no change was observed over two months. For initial control purposes six nodules were excised around day 10, four were of onchocercal origin and two were lymph nodes. The correlation was good in four. The present results indicate that an ophthalmologic real time linear scanner can be used in the bidimensional mode as a non-invasive method to assess sequentially the events in superficial onchocercal nodules following chemotherapy with amocarzine. This is the first objective non-invasive method permitting sequential assessment of the content of onchocercal nodules and it is far superior than subjective sequential manual palpation.

Skin punch biopsies were performed in 54 selected patients with onchocerciasis participating in a clinical trial with amocarzine (CGP 6140) in Ecuador and Guatemala. Skin snipping for counting microfilariae of Onchocerca volvulus was done before treatment (day 0) and day 4 and 8 following start of the therapy which consisted of 3 mg/kg amocarzine postprandially twice daily for three consecutive days. The mean microfilarial skin density has been reduced by 45% on day 4 and 95% on day 8. Skin punch biopsies were taken on day 5, within 1 cm from the snip site on the iliac crest. Histopathologic examination revealed that the vast majority of the microfilariae in the upper as well as in the deeper dermis were degenerated or necrotic, surrounded often (57%) by minute foci of fibrinoid change of the collagen. There was usually slight, less frequently moderate eosinophilic, lympho-plasmocytic and initial histocytic inflammatory reaction in the vicinity. Microfilariae were frequently (69%) found at the dermal-epidermal junction and in the epidermis. Occasionally (7%) intra-epidermal microabscesses were noted. Microfilariae were detected also in the lumen of some dermal lymphatic vessels. Therefore it is concluded that amocarzine showed marked microfilaricidal effects in the skin of patients with onchocerciasis as evidenced histologically by mainly destroyed or moribund microfilariae which induced a mild to moderate inflammatory cell reaction.

The objective of this multidisciplinary clinical investigation was to test whether amocarzine was absorbed effectively and safely in patients of two races and either sex infected with Onchocerca volvulus while living in the holoendemic area of Esmeraldas Province, Ecuador. The prerequisite for a systemic onchocercacidal effect is the regular absorption of orally administered amocarzine. Single dosing after overnight fasting proved to produce irregular absorption of amocarzine, although some microfilaricidal effect was achieved. A pilot study with repeated low dose and postprandial administration of amocarzine showed a regular and predictable absorption with acceptable tolerability and a microfilaricidal effect lasting up to one year post-therapy. Since amocarzine and its major N-oxide metabolite are coloured agents, urine colorimetry was used to assess the urinary excretion of the N-oxide qualitatively. For the postprandial drug regimens plasma concentrations of amocarzine and its metabolite were determined at two selected time points in patients of two races and either sex; the results showed no major differences. Excision of onchocercal nodules was performed four months post-therapy. The pooled results of the histologic analysis of 100 patients with the same drug regimen read under blinded condition showed that 65% of the adult female worms were dead, 20% necrobiotic and 15% alive. The male worms were fewer and mainly necrobiotic. Control worm populations in Esmeraldas without chemotherapy showed that on the average 81.5% were alive and 18.5% dead. Amocarzine was also microfilaricidal producing a reduction of skin dwelling microfilariae to about 10% of the initial value within the first week after start of therapy and lasting for half a year at a 20% level. The reduction of ocular microfilarial was slower and reached 35-40% after one year. The general tolerability was acceptable to good. Reversible dermal reactions were usually mild and peaked as a rash in 57% of the patients on day 6. No prohibitive ocular intolerance was observed. Mild and reversible dizziness peaked on day 4 in 74% of patients. A positive reversible Romberg sign was found in 12 patients on day 4. Amocarzine, the first oral micro- and macrofilaricidal agent administered as a low dose repeat regimen (3 mg/kg twice daily and postprandial for three consecutive days) can be recommended for oral onchocercacidal therapy in adult patients. Clinical trials in juveniles should be encouraged.

Bordetella pertussis adheres specifically to the cilia of respiratory epithelial cells. This ability to adhere is characteristic of virulent organisms. In order to define the contribution of various virulence factors of B. pertussis to the process of adherence, mutants deficient in single virulence factors were tested for the ability to adhere to rabbit cilia in vitro and in vivo. Two protective antigens were found to be critical to the process of adherence: filamentous hemagglutinin and pertussis toxin.

Light microscopic and immunocytologic investigation revealed focal or diffuse pituitary gonadotroph hyperplasia in 3/27 male and 3/39 female Sprague-Dawley rats over 2 years of age. Three male and 2 female rats exhibited proliferation of morphologically abnormal gonadotrophs which were described as nodules, and 4 male and 5 female rats possessed gonadotroph adenomas which contained both immunoreactive beta-LH and beta-FSH. On plastic sections at the ultrastructural level, a further female rat was found to possess focal gonadotroph hyperplasia, 2 male and 2 female rats, gonadotroph nodules and 2 male and 2 female rats gonadotroph adenomas. While extensive gonadotroph and thyrotroph hyperplasia was observed in the nontumorous portion of the 2 pituitaries harboring thyrotroph adenoma, widespread gonadrotroph hyperplasia was noted in only 2 of 13 pituitaries with gonadotroph adenoma. Gonadotroph adenomas appeared to develop from discrete foci of morphologically altered gonadotrophs. These foci probably then progressed to form nodules and subsequently adenomas. Gonadotrophs within the nodules were often similar in morphology to adenomatous gonadotrophs whereas the earlier, smaller lesions were pleomorphic or more commonly trabecular in appearance. Serum LH levels were measured in some animals. As a group, rats displaying changes in gonadotroph morphology had a higher mean serum LH level than those without these changes, however, the values ranging from 23-249 ng/ml were well within the normal serum LH levels reported in aging rats. Gonadotroph adenomas in human patients have only recently been identified with accuracy and are relatively uncommon. As in the case of rats, they do not appear to arise from a pre-existing end organ hypofunction or pre-existing gonadotroph hyperplasia. A suitable animal model, in the form of spontaneously occurring gonadotroph adenomas in aging rats, might be useful in establishing the etiology, biochemical properties and appropriate therapy for these tumors.

The carcinogenic potential of a technical-grade epoxy resin, Araldite GY 250, of which the diglycidyl ether of bisphenol A (DGEBPA) is the main component, was investigated in CF1 mice. Groups of 50 male and 50 female mice were treated for 2 yr by repeated epidermal application of a 1 or 10% (v/v) solution in acetone. The controls, 50 mice of each sex, were treated with acetone alone. The treatment had no effect on survival and no excess incidence of skin tumours occurred. A positive control group of 50 male and 50 female CF1 mice was treated by epidermal application of 2% (v/v) beta-propiolactone in acetone. In this group there was a high incidence of malignant skin tumours at the site of application and, consequently, increased mortality. Treatment with neither DGEBPA technical nor beta-propiolactone induced systemic neoplasia.

A portable ophthalmologic real-time ultrasound linear scanner (Ophthascan) was used to determine the optic resolution of excised onchocercal nodules of Onchocerca volvulus and O. gibsoni origin. Fresh, thawed and fixed nodules were used. Following macroscopic and histologic examination it became apparent that the Ophthascan could clearly distinguish between echogenic worm coils and non-echogenic areas of necrosis. The fibrotic nodular capsule was more echogenic than the worm coils inside the nodule. The optic resolution did not permit to distinguish the internal organ structures within a worm segment. This in vitro determination of the visual resolution of an opthalmologic real-time ultrasound linear scanner is in accordance with in vivo results of an ongoing trial with a new macrofilaricide. Thus sonography can be used to visualise the interior of superficial onchocercal nodules in vivo and to follow their evolution with or without chemotherapy. The non-invasive diagnostic and sequential assessment of onchocercal nodules by sonography will be a valuable contribution in onchocerciasis, especially for the assessment of macrofilaricides.

Routine autopsy studies of hearts with coronary thrombosis, collected over a period of eleven years, showed unique morphologic features of rupture of soft atheromatous plaques. These features include: (1) irregular luminar outline: angulation, invagination, upheaval, and/or wrinkles, (2) wavy outline of atheromatous cavity, (3) volcano-like rupture with seepage or gushing of semiliquid atheromatous contents into lumen, (4) cholesterol crystals arranged in rheologic vector direction, (5) rupture of deeper intimal fibrous tissue, (6) one or multiple intimal upheavals, (7) focal thickening of contracted media, (8) vestige of volcano-like eruption with organized thrombus, and (9) old thrombotic occlusion with wavy appearance of thick intimal fibrous tissue. The authors present a dynamic model of vasoconstriction or artery spasm that accounts for these features and the rupture of soft atheromatous plaques.

Melanocytes are present in the lamina propria of the middle ear mucosa of young children to elderly adults in both whites and blacks. Melanin pigment melanin pigment also is seen in the epithelial cells, so-called melanogenic metaplasia. The melanocytes in the middle ear mucosa are of neural crest origin and their presence explains melanocytic tumors at this anatomic site.

Fifty-five adenomas were identified and characterized in the anterior pituitaries of 27 male and 39 female SD rats, over 24 months of age, by histology, ultrastructural morphology, and immunocytochemistry. Adenomas were found in 85% of male and 79% of female rats; all known adenohypophysial hormones were represented in various tumors. Prolactin (PRL)-containing adenomas were the most common (47.2%); luteinizing hormone-(LH)-containing adenomas (16.3%), immunonegative adenomas (12.7%), PRL- and growth hormone (GH)-containing adenomas (10.9%), thyroid-stimulating hormone (TSH)-containing adenomas (3.6%), adrenocorticotropin hormone (ACTH)-containing adenomas (3.6%), and GH-containing adenomas (1.8%) were also identified. Unexpected combinations were observed in 3 tumors (5.4%); a GH-LH-containing adenoma, a PRL-ACTH-containing adenoma, and a PRL-LH-TSH-containing adenoma were noted. One intermediate lobe adenoma and 1 metastatic plasmacytoma were diagnosed. It can be concluded that spontaneous pituitary adenomas in aging SD rats are potential models of the human disease because of diversity of hormone content and morphologic appearance.

A 34-year-old native women presented as an acute abdominal emergency at the Surgery Department, Missionary Hospital "Ad Lucem" in Banka-Bafang, Cameroon. She complained of colicky, epigastric abdominal pain, nausea, vomiting, constipation, and retention of flatus. At laparotomy, numerous small cystic nodules (3-8 mm in diameter) were noted in the mesentery and under the intestinal and parietal peritoneum. Histological examination of two of them revealed slightly enlarged mesenteric lymph nodes containing several parasitic pseudocysts. The parasites were diagnosed as well-preserved, encysted, Armillifer armillatus nymphs. Neither degenerative nor inflammatory granulomatous reactions were observed in the adjacent tissue. Two and a half years later, a similar attack of acute abdominal symptoms recurred. A radiological examination revealed several C-shaped or circular, dense opacities characteristic of calcified pentastomid nymphs. At laparotomy, local findings similar to those at the previous surgical examination were noted. Additionally, a few firm, whitish, calcified nodules were found in the mesentery and under the fibrous capsule of the liver.