In Vitro and In Vivo Studies of the Trypanocidal Effect of Novel Quinolines.

Therapies for human African trypanosomiasis and Chagas disease, caused by Trypanosoma brucei and Trypanosoma cruzi, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated in silico and by phenotypic studies using in vitro and in vivo models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T. cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC50s) of <3 µM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 µM) against amastigotes, showing EC50s ranging from 0.6 to 0.1 µM. All quinolines were also highly active in vitro against African trypanosomes, showing EC50s of ≤0.25 µM. The most potent and highly selective candidates for each parasite species were tested in in vivo models. Results for DB2186 were promising in mice with T. cruzi and T. brucei infections, reaching a 70% reduction of the parasitemia load for T. cruzi, and it cured 2 out of 4 mice infected with T. brucei DB2217 was also active in vivo and cured all 4 mice (100% cure rate) with T. brucei infection.

Profile of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17 cytokines in adults with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) in adults and profile of skin barrier proteins and inflammatory cytokines. OBJECTIVE: Evaluation of the expression of skin barrier proteins such as filaggrin, claudins 1 and 4 and of circulating inflammatory cytokines (Th1/Th2/Th17) in adults with AD. METHODS: Thirty-three adult patients with AD diagnosed according to the Hanifin & Rajkacriteria, and 25 healthy controls were enrolled in the study. AD severity was measured by Eczema Area and Severity Index (EASI). Laboratory assays included immunohistochemistry analysis of skin barrier proteins, such as filaggrin, claudins 1 and 4 and interleukin-17 (IL-17) from skin samples and determination of circulating cytokine levels (IL-2, 4, 5, 6, 10, 17A, TNF and IFN-γ) by flow cytometry (Cytometric Bead Array). RESULTS: We observed a reduced expression of filaggrin and claudin 1 in lesional skin of AD patients, when compared to controls. There was an inverse correlation of filaggrin expression and disease severity. In addition, IL-17 expression was enhanced in AD patients. Similarly, higher levels of inflammatory cytokines (IL-2, 5, 6, 10, 17A and IFN-γ) were found in AD patients. CONCLUSION: Our data reinforce the role of an altered skin barrier in the pathogenesis of AD. Our results show not only reduced expression of filaggrin and claudin 1 in lesional atopic skin but also inverse correlation of filaggrin expression and disease severity. Moreover, elevation of in situ IL-17 and of circulating interleukin levels in AD emphasize the systemic, inflammatory profile of this defective skin barrier dermatosis.

Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy?

RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen-activated protein kinase (Ras/MAPK) pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor-stimulated fibroblasts revealed that P-MEK1/2 was ∼50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.

Atividade antimicrobiana dos extratos metanólicos da raiz, caule e folhas de Croton pulegioides Baill. (Zabelê) / Antimicrobial activity of methanol extracts of root, stem and leaves of Croton pulegioides Baill

O uso popular de plantas medicinais continua sendo de grande interesse para a população, principalmente em países em desenvolvimento, nos quais o acesso à medicina alopática ainda é muito restrito. Assim, além de sua importância na medicina tradicional, o conhecimento das plantas pode fornecer para a indústria farmacêutica, direta ou indiretamente, princípios ativos de interesse terapêutico. No presente trabalho foi avaliada a atividade antimicrobiana dos extratos metanólicos secos de Croton pulegioides Baill. obtidos a partir da raiz, do caule e das folhas nas concentrações de 25, 50 e 100mg/mL utilizando o método de difusão em Agar (técnica de poços) frente a cinco cepas Gram-positivas, três cepas de fungos e três cepas de bactérias Gram-negativas. Na execução do estudo foi utilizado o antibiótico Gentamicina (100µg/mL) no teste com bactérias, e Cetoconazol (300µg/mL) para as Candidas verificando-se, ao mesmo tempo, a ausência de atividade para o diluente DMSO 20% em água. Na observação dos resultados evidenciaram-se halos de inibição indicando atividade dos extratos metanólicos da raiz, caule e folhas, nas concentrações de 50 e 100mg/ml, frente Bacillus subtilis AM 04; dos extratos metanólicos da raiz e do caule, nas concentrações de 50 e 100mg/ml, frente Staphylococcus aureus AM 103 (ATCC 6538); e do extrato metanólico do caule, nas concentrações de 50 e 100mg/ml, frente S. epidermidis AM 235. Por outro lado, todos os extratos foram inativos nas concentrações avaliadas frente às bactérias Gram-negativas utilizadas no estudo (Pseudomonas aeruginosa AM 206, Escherichia coli AM 1050 e Klebsiella pneumoniae AM 410). Referente à atividade sobre fungos, os extratos metanólicos da raiz e do caule inibiram, nas três concentrações avaliadas, o crescimento de Candida tropicalis AM 1181 e C. albicans AM 1140, enquanto o extrato das folhas, inibiu o crescimento de C. tropicalis AM 1181 nas concentrações de 50 e 100mg/ml e de C. albicans AM 1140 apenas na concentração de 100mg/mL. Finalmente o extrato metanólico das folhas, na concentração de 100mg/mL, foi o único a inibir o crescimento de Candida krusei. Os resultados preliminares apresentados pelo presente trabalho sugeriram que a espécie Croton pulegioides Baill. apresentou resultados promissores quanto ao potencial antimicrobiano.

The employment of medicinal plants as a folk custom remains important to the present time, mainly in developing countries, where access to allopathic medicine is restricted. Besides their importance in traditional medicine, the knowledge on these plants can, directly or indirectly, provide information about the active ingredients involved, which may be of interest to the pharmaceutical industry. The present study evaluated the antimicrobial activity of dried methanolic extracts of Croton pulegioides Baill, extracted from its roots, stalk, and leaves, at the concentrations of 25, 50 and 100mg/ml. These were diffused in wells with an Agar medium, to which five strains of Gram-positive, three strains of fungi and three strains of Gram-negative bacteria had been added. For this study, the antibiotic Gentamicin (10µg/100µL) was used in tests with bacteria, and Ketoconazole (30µg/100µL), with Candidas. When DMSO diluted in 20% water was used, no activity was observed. The results produced evidence of inhibition halos, which indicates the activity of the methanolic extracts from the roots, stalk and leaves at the concentrations of 50 and 100 mg/ml for Bacillus subtilis AM 04; activity of the methanolic extracts from the roots and stalk at the concentrations of 50 and 100mg/ml for Staphylococcus aureus AM 103 (ATCC 6538); and activity of the methanolic extract from the stalk at the concentrations of 50 and 100mg/ml for Staphylococcus epidermidis AM 235. There was no activity in the concentrations studied for the Gram-negative bacteria (Pseudomonas aeruginosa AM 206, Escherichia coli AM 1050 and Klebsiella pneumoniae AM 410). With respect to fungal activity, the methanolic extracts from the roots and stalk inhibited Candida tropicalis AM 1181 and C. albicans AM 1140 at the three concentrations studied. The extract from the leaves inhibited the growth of C. tropicalis AM 1181 at the concentrations of 50 e 100mg/ml and C. albicans AM 1140 only at the concentration of 100mg/ml. Finally, the methanolic extract from the leaves, at the concentration of 100mg/ml, was the only one to inhibit the growth of Candida krusei. Preliminary results from this study suggest that the Croton pulegioides Baill showed promising results as a potential antimicrobial agent.

Impacts of warming on aquatic decomposers along a gradient of cadmium stress.

We evaluated the effects of cadmium and temperature on plant-litter decomposition by examining diversity and activity of aquatic fungi and leaf consumption by Limnephilus sp., a typical invertebrate shredder of Iberian streams. Freshly fallen leaves were immersed in a stream to allow microbial colonization, and were exposed in microcosms to a gradient of cadmium (≤11 levels, ≤35 mg L(-1)). Microcosms were kept at 15 °C, a temperature typically found in Iberian streams in autumn, and at 21 °C to simulate a warming scenario. The increase in temperature stimulated leaf decomposition by microbes, fungal reproduction and leaf consumption by the shredder. Conversely, increased cadmium concentrations inhibited fungal reproduction and diversity, and leaf consumption by the invertebrate. Cadmium concentration inhibiting 50% of fungal reproduction, microbial decomposition and leaf consumption by the shredder was higher at 15 °C than at 21 °C, suggesting that higher temperatures can lead to increased metal toxicity to aquatic decomposers.

1D and 3D anthropometric data application on public transport vehicle layout and on oil and gas laboratories work environment design.

The goal of this paper is to present 1D and 3D anthropometric data applied to two distinct design situations: one related to the interior layout of a public transport vehicle and another one related to oil and gas laboratories work environment design. On this study, the 1D anthropometric data were extracted from the Brazilian anthropometric database developed by INT and the 3D anthropometric data were obtained using a Cyberware 3D whole body scanner. A second purpose of this paper is to present the 3D human scanning data as a tool that can help designers on decision making.

Application of digital image processing for the generation of voxels phantoms for Monte Carlo simulation.

This paper presents the application of a computational methodology for optimizing the conversion of medical tomographic images in voxel anthropomorphic models for simulation of radiation transport using the MCNP code. A computational system was developed for digital image processing that compresses the information from the DICOM medical image before it is converted to the Scan2MCNP software input file for optimization of the image data. In order to validate the computational methodology, a radiosurgery treatment simulation was performed using the Alderson Rando phantom and the acquisition of DICOM images was performed. The simulation results were compared with data obtained with the BrainLab planning system. The comparison showed good agreement for three orthogonal treatment beams of (60)Co gamma radiation. The percentage differences were 3.07%, 0.77% and 6.15% for axial, coronal and sagital projections, respectively.

Desponte e embebição em sementes de noni (Morinda citrifolia L. ) / Lopping and soaking in seeds of noni (Morinda citrifolia L. )

O trabalho teve como objetivo testar a germinação em sementes de noni sob diferentes tempos de embebição, com e sem o desponte das sementes. Para isso, instalou-se um experimento em casa de vegetação no delineamento inteiramente casualizado com 10 tratamentos e 4 repetições de 25 sementes , sendo constituídos por: 1. Testemunha; 2. Sementes com desponte do lado oposto ao embrião; 3. Sementes intactas com 12 horas de embebição; 4. Sementes intactas com 24 horas de embebição; 5. Sementes intactas com 36 horas de embebição; 6. Sementes intactas com 48 horas de embebição; 7. Sementes com desponte com 12 horas de embebição; 8. Sementes com desponte com 24 horas de embebição; 9. Sementes com desponte com 36 horas de embebição e 10. Sementes com desponte com 48 horas de embebição. As características avaliadas foram: porcentagem de emergência, Índice de velocidade de emergência, altura de plântulas, comprimento de raiz e peso de massa seca das plântulas aos 46 dias após a instalação do experimento. Houve diferença significativa entre os diferentes tempos de embebição e o tratamento 10 (Desponte com 48 hs de embebição) que obteve os melhores resultados para a percentagem de emergência, índice e velocidade de emergência e peso seco. Quanto a altura de plântula, o tratamento 1 (Testemunha) foi o maior, enquanto no tratamento 2 (desponte) se verificou o maior comprimento de raiz. Embora não tenha diferido da testemunha, o melhor tratamento foi o uso do desponte + 48 horas de embebição.

The study aimed to test the germination of seeds of noni under different soaking times, with and without the seed emerges. For this, an experiment was installed in a greenhouse in a completely randomized design with 10 treatments and 4 replicates of 25 seeds, being composed of: 1. Witness 2. Seeds with the blunt side opposite the embryo 3. Intact seeds with 12 hours of soaking, 4. Intact seeds with 24 hours of soaking, 5. Intact seeds with 36 hours of soaking, 6. Intact seeds with 48 hours of soaking; 7. Seeds with cutting with 12 hours of soaking; 8. Seeds with cutting with 24 hours of soaking; 9. Seeds with cutting with 36 hours of soaking and 10. Seeds with cutting with 48 hours of soaking. The characteristics evaluated were: percentage of emergence, speed of emergence index, seedling height, root length and weight of the dry mass of seedlings 46 days after the experiment. There were significant differences between the different times of soaking and treatment 10 (cutting with 48 hours of soaking) who obtained the best results for the percentage of emergency and emergency speed index and dry weight. The height of the seedling, one treatment (control) was the highest, while in treatment 2 (blunt) registered the largest root length. Although the witness did not differ, the best treatment was the use of blunt + 48 hours of soaking.

Percentage depth dose evaluation in heterogeneous media using thermoluminescent dosimetry.

The purpose of this study is to investigate the influence of lung heterogeneity inside a soft tissue phantom on percentage depth dose (PDD). PDD curves were obtained experimentally using LiF:Mg,Ti (TLD-100) thermoluminescent detectors and applying Eclipse treatment planning system algorithms Batho, modified Batho (M-Batho or BMod), equivalent TAR (E-TAR or EQTAR), and anisotropic analytical algorithm (AAA) for a 15 MV photon beam and field sizes of 1 x 1, 2 x 2, 5 x 5, and 10 x 10 cm 2 . Monte Carlo simulations were performed using the DOSRZnrc user code of EGSnrc. The experimental results agree with Monte Carlo simulations for all irradiation field sizes. Comparisons with Monte Carlo calculations show that the AAA algorithm provides the best simulations of PDD curves for all field sizes investigated. However, even this algorithm cannot accurately predict PDD values in the lung for field sizes of 1 x 1 and 2 x 2 cm 2 . An overdosage in the lung of about 40% and 20% is calculated by the AAA algorithm close to the interface soft tissue/lung for 1 x 1 and 2 x 2 cm 2 field sizes, respectively. It was demonstrated that differences of 100% between Monte Carlo results and the algorithms Batho, modified Batho, and equivalent TAR responses may exist inside the lung region for the 1 x 1 cm 2 field.

Antinociceptive effects of the essential oil of Mentha x villosa leaf and its major constituent piperitenone oxide in mice.

Mentha x villosa Huds (Labiatae) is an aromatic herb widely used in folk medicine. Since the essential oil of the herb has many pharmacological activities, including antispasmodic effects, we determined whether the oil and its major constituent, piperitenone oxide (PO), have antinociceptive activity. The essential oil of M. x villosa (EOMV) and PO administered orally at 200 mg/kg (vehicle: 0.1% Tween 80 in water) significantly reduced the writhings induced by acetic acid from control values of 59.5 +/- 3.1 s (N = 10) to 31.9 +/- 2.8 s (N = 10) and 23.8 +/- 3.4 s (N = 10), respectively. When administered at 100 and 200 mg/kg, EOMV reduced the paw licking time for the second phase of the formalin test from the control value of 20.6 +/- 2.1 s (N = 13) to 5.3 +/- 2.2 s (N = 12) and 2.7 +/- 1.2 s (N = 18), respectively. At 100 and 200 mg/kg, PO reduced this second phase to 8.3 +/- 2.7 s (N = 12) and 3.0 +/- 1.2 s (N = 10), respectively. This effect of EOMV and PO was not reversed by naloxone. EOMV and PO had no significant effect on the first phase of the formalin test. As evaluated by the hot-plate and tail immersion test, EOMV and PO, at doses up to 200 mg/kg, showed no analgesic activity. These results show that EOMV and PO have antinociceptive activity and suggest that this effect is probably an indirect anti-inflammatory effect, which does not involve the central nervous system.

Antinociceptive effects of the essential oil of Mentha x villosa leaf and its major constituent piperitenone oxide in mice

Mentha x villosa Huds (Labiatae) is an aromatic herb widely used in folk medicine. Since the essential oil of the herb has many pharmacological activities, including antispasmodic effects, we determined whether the oil and its major constituent, piperitenone oxide (PO), have antinociceptive activity. The essential oil of M. x villosa (EOMV) and PO administered orally at 200 mg/kg (vehicle: 0.1% Tween 80 in water) significantly reduced the writhings induced by acetic acid from control values of 59.5 ± 3.1 s (N = 10) to 31.9 ± 2.8 s (N = 10) and 23.8 ± 3.4 s (N = 10), respectively. When administered at 100 and 200 mg/kg, EOMV reduced the paw licking time for the second phase of the formalin test from the control value of 20.6 ± 2.1 s (N = 13) to 5.3 ± 2.2 s (N = 12) and 2.7 ± 1.2 s (N = 18), respectively. At 100 and 200 mg/kg, PO reduced this second phase to 8.3 ± 2.7 s (N = 12) and 3.0 ± 1.2 s (N = 10), respectively. This effect of EOMV and PO was not reversed by naloxone. EOMV and PO had no significant effect on the first phase of the formalin test. As evaluated by the hot-plate and tail immersion test, EOMV and PO, at doses up to 200 mg/kg, showed no analgesic activity. These results show that EOMV and PO have antinociceptive activity and suggest that this effect is probably an indirect anti-inflammatory effect, which does not involve the central nervous system.

Immunohistochemical expression of interleukin-4, -6, -8, and -12 in inflammatory cells in surrounding invasive front of oral squamous cell carcinoma.

BACKGROUND: Cytokines play important roles in the diverse interactions between tumor microenvironment and malignant cells. This study evaluated the association of interleukin (IL)-4, -6, -8, and -12 expressions and clinicopathologic parameters of 35 primary oral squamous cell carcinomas (OSCCs). METHODS: Patients were staged according to the TNM clinical staging. Malignancy grading of invasive front was evaluated in hematoxylin-eosin (H&E)-stained slides. Immunohistochemical technique was performed on frozen tissue sections. Association between clinicopathologic parameters and IL expression were analyzed using nonparametric Kruskal-Wallis (alpha = 0.05) and Mann-Whitney U tests, with Bonferroni correction. Correlations between interleukins were analyzed by the Spearman coefficient. RESULTS: Expression of ILs was verified in all samples; however, this finding was not related to clinicopathologic parameters. It was not the observed correlation between ILs. CONCLUSIONS: Expression of IL-4, -6, -8, and -12 in the invasive front of OSCC is not involved with the clinicopathologic parameters of the disease.

Acute bilineal leukemia: a rare disease with poor outcome.

Most cases of acute leukemia can be assigned to the myeloid, B or T lineage. In a few cases, definitive assignment cannot be achieved because blasts express antigens of more than one lineage. A subset of these, referred to as acute bilineal leukemias (aBLLs), is characterized by the presence of more than one population of blasts, each comprising a single lineage. We identified 19 cases of aBLL, including 10 mixed T and myeloid (T-My) and nine mixed B and myeloid (B-My); no mixed B and T cases were identified. Cytogenetic data were available for 16 patients. Three of seven patients with B-My had a t(9;22)(q34q11.2), two had 11q23 translocations and one had del(9). Two of nine patients with T-My had 2p13 translocations; five had other unrelated abnormalities. Of 16 patients with outcome data, only six achieved complete remission and only two remain free of disease 2.5 and 4.5 years after chemotherapy or stem cell transplantation. aBLL is a rare disease that combines B or T and myeloid blasts. Cytogenetic abnormalities of t(9;22) and 11q23 are common in, and may be restricted to, B-My cases, while T-My cases have frequent but generally non-recurring abnormalities. Both types of aBLL are associated with poor outcome.

Vascular calcification: contribution of parathyroid hormone in renal failure.

Hyperphosphatemia is a driving force in the pathogenesis of vascular calcification (VC) and secondary hyperparathyroidism associated with renal failure. To test for the possible contribution of parathyroid hormone (PTH) to cardiovascular calcification, we removed the parathyroid glands from rats but infused synthetic hormone at a supraphysiologic rate. All rats were pair-fed low, normal, or high phosphorus diets and subjected to a sham or 5/6 nephrectomy (remnant kidney). Control rats were given a normal diet and underwent both sham parathyroidectomy and 5/6 nephrectomy. Heart weight/body weight ratios and serum creatinine levels were higher in remnant kidney rats than in the sham-operated rats. Remnant kidney rats on the high phosphorus diet and PTH replacement developed hyperphosphatemia and hypocalcemia along with low bone trabecular volume. Remnant kidney rats on the low phosphorus diet or intact kidney rats on a normal phosphorus diet, each with hormone replacement, developed hypercalcemia. All rats on PTH replacement developed intense aortic medial calcification, and some animals presented coronary calcification. We suggest that high PTH levels induce high bone turnover and medial calcification resembling Mömckeberg's sclerosis independent of uremia. This model may be useful in defining mechanisms underlying VC.

A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions.

BACKGROUND: Inactivation of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP dependent protein kinase (PKA) (PRKAR1A) leads to altered kinase activity, primary pigmented nodular adrenocortical disease (PPNAD), and sporadic adrenal and other tumours. METHODS AND RESULTS: A transgenic mouse carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline responsive promoter (the Tg(Prkar1a*x2as)1Stra, Tg(tTAhCMV)3Uh or tTA/X2AS line) developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia and other features reminiscent of PPNAD, including late onset weight gain, visceral adiposity, and non-dexamethasone suppressible hypercorticosteronaemia, with histiocytic, epithelial hyperplasias, lymphomas, and other mesenchymal tumours. These lesions were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels; the latter biochemical and protein changes were also documented in Carney complex tumours associated with PRKAR1A inactivating mutations and chromosome 17 PRKAR1A locus changes. CONCLUSION: We conclude that the tTA/X2AS mouse line with a downregulated Prkar1a gene replicates several of the findings in Carney complex patients and their affected tissues, supporting the role of RIalpha as a candidate tumour suppressor gene.

A pleiomorphic GH pituitary adenoma from a Carney complex patient displays universal allelic loss at the protein kinase A regulatory subunit 1A (PRKARIA) locus.

Carney complex (CNC) is a familial multiple endocrine neoplasia syndrome associated with GH-producing pituitary tumours and transmitted as an autosomal dominant trait. Mutations of the PRKAR1A gene are responsible for approximately half the known CNC cases but have never found in sporadic pituitary tumours. Pituitary tissue was obtained from an acromegalic CNC patient heterozygote for a common (PRKARIA)i-inactivating mutation. Both immunohistochemistry and electron microscopy showed a highly pleiomorphic pituitary adenoma. The cell culture population appeared morphologically heterogeneous and remained so after more than 30 passages. The mixture was comprised of cells strongly immunostained for GH, spindle-shaped myofibroblast-like cells, and cuboid cells with large axonal projections (negative for GH). The population appeared to have both epithelial and mesenchymal cells. Both at baseline and at passage 30, cytogenetic analysis indicated the presence of normal 46, XY diploid karyotype, whereas losses of the PRKARIA(i) locus were demonstrated in more than 98% of the cells by fluorescent in situ hybridisation, supporting this gene's involvement in pituitary tumorigenesis. Allelic loss may have occurred in a single precursor cell type that differentiated and clonally expanded into several phenotypes. Epithelial-to-mesenchymal transition may also occur in CNC-associated pleiomorphic pituitary adenomas.

[Maxillofacial trauma by defenestration: 64 cases]. / Traumatologie maxillo-faciale liée aux défenestrations: à propos de 64 cas.

OBJECTIVE: There has been little work reported in the literature concerning trauma resulting from high level falls and almost none devoted to maxillofacial trauma following defenestration. The purpose of this work was to report the first series of defenestration victims who incurred maxillofacial trauma. METHOD: This retrospective series included all patients treated at the Pitié-Salpêtrière hospital between July 1994 and July 1999, all units included: surgery intensive care, neurosurgical emergency, orthopedic surgery or maxillofacial surgery. RESULTS: Female gender predominated in comparison with studies concerning high level falls (SR=0.5) with no difference concerning age (mu=31.5, sigma2=9.1). Fifty percent of the patients had a maxillofacial involvement. Death ensued in 17.2% (11/64 patients). The height of the fall among survivors ranged from one floor to eight floors; third-floor falls accounted for 31%. Defenestration was intentional in 70.3% of the cases, accidental in 17.1% and undetermined in 12.6%. The suicide attempts involved 13 patients with maniac depressive psychosis, 11 with depression, 6 with schizophrenia, 2 with undetermined familial problems, and 12 with no specific history. Four patients were drug abusers and 3 were alcoholics. Fifty percent of the victims were living in precarious social and economical conditions. The maxillofacial injuries included: 20 mandibular fractures, 15 Lefort fractures (I, II, III or combined), 2 blow out fractures, 7 fractures of the orbital roof, 15 fractures of the malar bone, 7 fractures of the nose bones, and 11 fractures of the naso-ethmoïdo-maxillo-fronto-orbital complex. On the average, patients lost 6 dental elements. The mean Glasgow index was 7.9. Extrafacial injuries included limb fractures (89%), chest trauma (73.4%), brain lesions (67%), spinal injury (40.6%), and abdominal injury (26.5%). CONCLUSION: The psychic and social vulnerability of the defenestration patient aggravated by the trauma is a fundamental dimension which must be taken into consideration during the initial management of these patients.