Lymphatic absorption and metabolism of orally administered testosterone undecanoate in man

Summary [³H]-testosterone undecanoate ([³H]TU) was administered orally to 4 patients with a thoracic duct catheter after neck dissection surgery.Appearance of radioactivity in lymph, plasma and urine was measured at different times. Metabolites of TU in these fluids were investigated. Peak levels of radioactivity appeared simultaneously in lymph and plasma (2.5–5 h after administration) while the excretion in urine was highest approximately 2 h after the plasma and lymph peak. The main compounds appearing in the lymph were TU and 5-dihydrotestosterone undecanoate (5-DHTU), but 5-DHTU could not be detected. In plasma almost all metabolites were probably conjugated.During the first 24 h approximately 40% of the administered radioactivity was excreted in the urine. The total amount of radioactivity excreted in the urine during the first week was 45–48%. The predominant urinary metabolites were testosterone- and androsterone-glucuronide.The results indicate that TU is metabolized partly in the intestinal wall. The remaining TU and newlyformed 5-DHTU, at least partly, are absorbed via the lymphatic system.     

Inhibitory effect of oral administration of Lactobacillus casei on 3-methylcholanthrene-induced carcinogenesis in mice

The present study was designed to determine whether tumor induction by 3-methylcholanthrene (MC), a carcinogenic hydrocarbon, can be inhibited by oral administration of Lactobacillus casei strain Shirota (LC). C3H/HeN mice were divided into four groups and assigned to the following treatments: treated with MC and given control or LC-containing diet; treated with vehicle only and given control or LC-containing diet. MC (1 mg) was injected intradermally at 7 weeks of age and the tumor incidence was monitored; LC was mixed into a diet at a concentration of 0.05% (w/w) and the diet was fed from the day of MC injection throughout the study. Spleen cells were analyzed for the immune parameters at 12 and 16 weeks after the MC injection. Oral feeding of mice with LC reduced tumor incidence (P < 0.05). MC treatment lowered the in vitro response to concanavalin A (Con A) of spleen cells, the secretion of interleukin-2 in spleen cell culture after stimulation of the cells with Con A and the proportions of CD3⁺, CD4⁺ and CD8⁺ splenic cells. However, the analysis of the spleen cells obtained from the mice treated with MC and given the LC-containing diet revealed that these disrupted host immune parameters were maintained at the level of normal controls. These results suggest that oral feeding of mice with LC inhibits MC-induced tumorigenesis by modulating the disrupted host immune responses during MC carcinogenesis. Received: 14 April 1999     

Presence and course of the incisive canal in the human mandibular interforaminal region: two-dimensional imaging versus anatomical observations

The objective of the present study was to evaluate the presence and course of the incisive canal in the mental interforaminal region of the human mandible and to describe the occurrence of anatomical variations. Mandibles of 50 adult human cadavers were retrieved from the Department of Anatomy of the Faculty of Medicine, Katholieke Universiteit Leuven (Leuven, Belgium). Forty mandibles were edentulous, while 10 mandibles were partially dentate. Intra-oral, panoramic and tomographic imaging of the interforaminal region of the human mandible were performed. Afterwards, mandibles were sawn into vertical sections according to the respective tomographic cross-sections. The latter allowed exploration for the presence and course of an anterior prolongation of the mandibular canal. Measurements of the location of the incisive canal towards the base of the mandible were made using a digital-sliding caliper. Results indicated a well-defined incisive canal [mean (SD) inner diameter 1.8 (0.5 mm)], macroscopically observed in 96% of mandibles. The incisive canal was located on average 9.7 mm (SD 1.8 mm) from the lower cortical border and continued towards the incisor region in a slightly downward direction, with a mean (SD) distance to the lower cortical border of 7.2 (2.1) mm. It was concluded that there is an anterior intraosseous extension of the mandibular canal, denoted as the incisive canal. The latter might be considered as a true anterior extension of the neurovascular bundle. Histological and neurophysiological studies are needed to verify this hypothesis and evaluate its potential clinical implications.

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Electronic Supplementary Material The french version of this article is available in the form of electronic supplementary material and can be obtained by using the Springer Link server located at .D. van Steenberghe is holder of the Prof. P-I. Brånemark Chair in Osseointegration     

Miltefosine (Impavido): the first oral treatment against leishmaniasis

Miltefosine is a novel antileishmanial drug that has significant selectivity in both in vitro and in vivo models. Clinical efficacy was demonstrated for the treatment of visceral leishmaniasis with the advantage of oral administration over the currently recommended antileishmanial drugs that require parenteral administration. Miltefosine produces high cure rates also in patients resistant to the standard antimonial therapy.     

Interepithelial cells of the oral mucosa in mice

Summary Non-epithelial mesenchymal and neuroectodermal cells occur between the keratinocytes in the stratified squamous epithelium of the oral mucosa. These cells cannot be classified adequately by light microscopy. In the present study the oral mucosa of the lip, cheek and tongue of 50 mice were studied by light and electron microscopy. 3,025 mononuclear interepithelial cells were documented and analysed.Monocytogenic macrophages, plasma cells and mast cells were not found interepithelially and cannot be regarded as a regular constituent of the epithelium. Only a few neuroectodermal cells — in mice these are exclusively Merkel cells, with no melanocytes — were localized in the epithelium. The majority of the interepithelial cell population is made up of lymphocytes (22.8%) and Langerhans cells (56.8%). They are an integral constituent of the epithelium. Lymphocytes with rounded and indented nuclei can be identified. The larger and dendritic Langerhans cells are a specific cell of squamous epithelium and also occur in the oral mucosa. Not all cells which feature the cytological characteristics of Langerhans cells contain Langerhans or Birbeck granules. Accordingly these granules cannot be considered an exclusive identification characteristic. Two types of Langerhans cells can be differentiated. 80.9% have the more or less typical appearance known from the epidermis and were termed macrophagocytoid Langerhans cells. The nuclei are irregularly indented and moderately heterochromatic. 19.1% possessed conspicuous large, spherical, euchromatic nuclei and an electron-lucent cytoplasm. These were termed reticuloid Langerhans cells. About 20% of the interepithelial cell population could not be identified, neither as typical lymphocytes nor as Langerhans cells. These were small to medium sized cells with deeply indented cerebriform strongly heterochromatic nuclei. They are similar to the Sézary cells or mycosis fungoides cells of epidermotropic human T-cell lymphomas. The lymphocytic nature of these cells has been confirmed. It seems likely that differentiation of lymphocytes to cerebriform cells occurs within the epithelium. It is further discussed whether cerebriform cells are precursors of Langerhans cells, a conclusion suggested morphologically by transitional forms. This would imply that Langerhans cells originate from lymphocytes, and that the cerebriform cell is an intermediate step of differentiation. The microenvironment of the squamous epithelium may play a role in the process of differentiation, which could explain the epitheliotropy of lymphocytes. The possibility is considered that Langerhans cells and interdigitating reticulum cells of the T-cell area of lymph nodes are identical. The close functional cooperation of Langerhans cells, lymphocytes, and interdigitating reticulum cells in immunological defenses against external antigens is discussed.The authors wish to express their sincere appreciation to Miss P. Starck and Miss I. Brandt for invaluable technical assistance in this project.     

老年人口腔白色念珠菌的分布与基因分型研究

目的研究健康老年人口腔白色念珠菌的分布、基因型特点及基因型特点与白色念珠菌分布的相关性。方法来自成都地区212例老年人分为4组：A1（男性，有义齿）；A2（男性，无义齿）；B1（女性，有义齿）和B2（女性，无义齿）。CHROMagar Candida^TM鉴定培养基、碳水化合物同化反应鉴定体系（API 20C AUX）和随机扩增片段多态性分析（randomly amplified polymorphic DNA assays，RAPD）鉴定白色念珠菌。RAPD分析健康老年人口腔白色念珠菌分离株的基因型特征。统计学分析比较不同分组健康老年人口腔白色念珠菌基因型之间的差异。结果212例受检个体中检出89株白色念珠菌（42％），A1、A2、B1、B2白色念珠菌检出率分别为56．2％、21．3％、56．6％、38％。A1组与A2组白色念珠菌检出率差异有统计学意义，P〈0．01。以JWFP和NA为随机引物的RAPD分析将白色念珠菌分为5型。RAPD分析基因型构成在A1组与A2组之间比较差异有统计学意义，P〈0．05，A1组主要以A型为主。结论健康老年人口腔白色念珠菌的检出率与义齿修复相关。义齿修复可能促进具有特定基因型特点的白色念珠菌检出率增高。     

Mechanoreceptor activity from the human face and oral mucosa

Summary The feasibility of adopting the microneurography technique (Vallbo and Hagbarth 1968) as a tool to investigate the mechanoreceptive innervation of peri- and intra-oral tissues was explored. Multi-unit activity and impulses in single nerve fibers were recorded from the infraorbital nerve in healthy volunteers. The innervation territories of individual nerve fascicles were mapped. These varied considerably but most fascicle fields comprised the corner of the mouth. Twenty-four single mechanoreceptive units were recorded. Eighteen innervated the skin of the face, and six innervated the mucous membranes of the lips or cheeks. A majority of the mechanoreceptive afferent units were slowly adapting with small and well defined receptive fields. It is suggested that the various slowly adapting responses may originate from two different types of afferent units. No afferents showed response properties similar to typical Pacinian-corpuscle afferents.     

Proliferating cell nuclear antigen in malignant and pre-malignant lesions of epithelial origin in the oral cavity and the skin: an immunohistochemical study

Summary Proliferating cell nuclear antigen (PCNA) is a nuclear protein synthesized in the late G₁ and S phase of the cell cycle and immunohistochemical detection of the protein represents a useful marker for the proliferating fraction of cells in tissue specimens. A series of malignant and pre-malignant lesions of the oral cavity and skin were evaluated by the streptavidin biotin immunoperoxidase method for detection of this protein. Monoclonal anti-PCNA antibody (PC 10) labelled proliferating cells in all cases with varying intensity of nuclear staining. In squamous cell carcinoma (n=48), PCNA positivity correlated with the differentiation and atypia of the tumour cells; however, in poorly differentiated tumours, the relationship between PCNA expression and proliferation was lost. Basal cell carcinoma showed an increased growth fraction in tiny epithelial nests (mean 43.8, SD 6.0,n=20) than in neoplastic basal cells (mean 30.1, SD 6.9,n=8). The growth fractions were significantly higher in the pre-malignant lesions (leukoplakia, mean 22.3, SD 7.7,n=14; Bowen's disease, mean 45.2, SD 11.7,n=12; senile keratosis, mean 41.2, SD 7.0,n=12) than in the normal mucosa (mean 9.8, SD 4.9,n=10), suggesting that cellular growth fractions correlate with the degree of dysplasia in pre-malignant lesions.     

The defined attenuated Listeria monocytogenes Δmpl2 mutant is an effective oral vaccine carrier to trigger a long-lasting immune response against a mouse fibrosarcoma

Listeria monocytogenes has been proposed as a carrier to elicit major histocompatibility complex class-I restricted immune responses able to protect against tumor challenge. In this study the properties of the attenuated L. monocytogenes Δmpl2 mutant has been evaluated in vivo against a highly aggressive mouse fibrosarcoma which expresses β-galactosidase (β-gal) as a tumor-associated antigen (TAA). Immunization with the vaccine prototypes resulted in both elicitation of specific antibodies and generation of cytotoxic lymphocytes (CTL). Oral vaccination protected 55–64% of the immunized animals from tumor take (p < 0.01) and strongly reduced the average size of the tumor in the other 34–45% (p < 0.01). Vaccinated mice developed a long-lasting response, which resulted in 100% protection from a subsequent tumor challenge. Substitution of the whole TAA by its CTL-defined immunodominant epitope resulted in 43% protection, suggesting a contribution of the humoral response to the observed antitumor effect. No statistically significant differences were observed in the antitumor response when mice were immunized with strains expressing the immunodominant TAA epitope in the context of carrier proteins which were either exported or restricted to the bacterial cytoplasm. This suggests that the topology of the recombinant antigen does not play a major role in the outcome of the protective response.     

Intermediate-term toxicity of repeated orally administered doses of the anti-malarial β-artemether in dogs

The artemisinin derivative beta-artemether, an anti-malarial, was evaluated for its toxicity and tolerability in a 2-week, multiple-dose study in dogs. Eight beagle dogs (4 females, 4 males) were given beta-artemether by oral gavage 3 times daily at 45 mg/kg/dosing (a total daily dose-level of 135 mg/kg) for 2 weeks. This beta-artemether dose regime was well tolerated. Body weight changes were normal although feed consumption during the treatment period reduced compared to that of the pre-trial period. Clinical signs were transient spells of soft to liquid feces. On completion of the treatment period, the animals were sacrificed and submitted to a full macroscopic post-mortem examination. Designated organs were weighed and a complete light microscopic examination was performed on 43 selected tissues from 1 animal per sex, and on the liver, kidneys, thymus, mandibular lymph nodes and lungs of the three other animals per sex. Major findings were high liver weight and histopathologic findings of slight diffuse hepatocellular hypertrophy and distal tubular dilatation, together with flattened epithelium, in the kidneys. With the dose regime used in this trial beta-artemether produced no clinical or apparent histopathological signs of neurotoxicity in dogs.