Descriptive epidemiology of isolated anal anomalies: a survey of 4.6 million births in Europe.

The prevalence of anal anomalies among 4,618,840 births recorded in 33 EUROCAT registries between 1980 and 1994 was 4.05 per 10,000 births. Of the 1,846 recorded cases, 672 (36.4%) were isolated anal anomalies while 1,174 (63.6%) occurred together with other anomalies. Only isolated anal anomalies were analyzed in this study: 75.5% were atresias, 10.1% of which were above and 89.9% were below the level of the levator ani muscle. Fistula occurred in 53% of supralevator and 37% of infralevator atresia. Other anal anomalies were ectopic anus (3.4%), congenital anal fistula (14.7%), and persistent cloaca (0.9%). There was a predominance of males in anal atresia without fistula (male to female (M:F) ratio was 6.7 for supralevator and 2.3 for infralevator atresia), but no significant sex difference in atresias with fistula. There was a predominance of females in ectopic anus and congenital anal fistula (M:F = 0.11 and 0.36 respectively). High frequencies of fetal deaths were recorded in supralevator atresia without fistula (8.3%) and in persistent cloaca (11.1%). Mean gestational length and mean birth weights were reduced for persistent cloaca but were within normal limits for other isolated anal anomalies. Odds ratios (ORs) for mothers above 35 years were increased for supralevator atresia without fistula, supralevator atresia with fistula, and congenital anal fistula. ORs for mothers below 30 years were slightly increased for supralevator atresia without fistula and decreased for persistent cloaca. There were marked differences in prevalence and distribution of anal anomalies among the EUROCAT registries. The results indicated that there are epidemiological differences among the various types of anal anomalies which might reflect different embryological origins.

Papyrus Prisse. Egyptien 187. Enseignement de Ptahhotep (75-123)

Vers 75 à 123.Maximes 4 à 6 et début de la 7e.

Cetuximab in combination with chemoradiotherapy prior to surgery in patients with resectable, locally advanced esophageal carcinoma : a prospective, multicenter phase lb-ll trial of the Swiss Group for Clinical Cancer Research (SAKK 75/06) : 4570

Background: Cetuximab significantly enhances efficacy of radiotherapy and chemotherapy in head and neck cancer. We investigated the safety and feasibility of adding cetuximab to neoadjuvant chemoradiation of locally advanced esophageal cancer. Methods: Pts with resectable, locally advanced squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus or gastroesophageal junction (staged by EUS, CT and PET scan) were treated with 2 cycles of induction chemotherapy (docetaxel 75mg/m2, cisplatin 75mg/m2 q3w and weekly cetuximab 250mg/m2), followed by concomitant chemo- immuno-radiation therapy (CIRT: docetaxel 20mg/m2, cisplatin 25mg/m2 and cetuximab 250mg/m2 weekly five times concomitant with 45 Gy radiotherapy in 25 fractions); followed by surgery 4-8 weeks later. The phase I part consisted of 2 cohorts of 7 patients each, without and with docetaxel during CIRT, respectively. Interpatient dose-escalation (adding docetaxel during CIRT) was possible if < 2 out of 7 pts of the 1st cohort experienced limiting toxicity. Having finished the phase 1 part, 13 additional patients were treated with docetaxel-containing CIRT in a phase II part. Pathological response was evaluated according to the Mandard classification. Results: 27 pts from 12 institutions were included. As of today, results from 20 pts are available (cohort 1: 7, cohort 2: 7, phase ll : 6). Median age was 64yrs (range 47-71). 11 AC; 9 SCC. 19 pts (95%) completed CIRT (1 pt stopped treatment during induction therapy due to sepsis). 17 pts underwent resection (no surgery: 1pt for PD, 1pt for cardiac reasons). Grade 3 toxicities during CIRT included anorexia 15%, dysphagia/esophagitis 15%, fatigue 10%, nausea 10%, pruritus 5%, dehydration 5%, nail changes 5% and rash 5% .1 pt suffered from pulmonary embolism. 13 pts (65%, intention-to-treat) showed a complete or near complete pathological remission (cohort 1: 5, cohort 2: 4, phase II: 4). Conclusions: Adding cetuximab to preoperative chemoradiation for esophageal cancer is safe and feasible in a community-based multicenter setting. Antineoplastic activity is encouraging with 65% pathological responders.

Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Energy and nutrient intake of Swiss women aged 75-87 years.

OBJECTIVE: Reliable data about the nutrient intake of elderly noninstitutionalized women in Switzerland is lacking. The aim of this study was to assess the energy and nutrient intake in this specific population. SUBJECTS: The 401 subjects were randomly selected women of mean age of 80.4 years (range 75-87) recruited from the Swiss SEMOF (Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk) cohort study. A validated food frequency questionnaire (FFQ) was submitted to the 401 subjects to assess dietary intake. RESULTS: The FFQ showed a mean daily energy intake of 1544 kcal (+/-447.7). Protein intake was 65.2 g (+/-19.9), that is 1.03 g kg(-1) body weight per day. The mean daily intake for energy, fat, carbohydrate, calcium, magnesium, vitamin C, D and E were below the RNI. However, protein, phosphorus, potassium, iron and vitamin B6 were above the RNI. CONCLUSION: The mean nutrient intake of these free living Swiss elderly women was low compared with standards. Energy dense foods rich in carbohydrate, magnesium, calcium, vitamin D and E as well as regular sunshine exposure is recommended in order to optimise dietary intake.

Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T-Cell Rejection Function in Tumors.

Tumor progression is facilitated by regulatory T cells (Treg) and restricted by effector T cells. In this study, we document parallel regulation of CD8(+) T cells and Foxp3(+) Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of CTL antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8(+) T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8(+) tumor-infiltrating lymphocytes (TIL) expressed PD-1, whereas one third to half of CD8(+) TIL coexpressed PD-1 and CTLA-4. Double-positive (PD-1(+)CTLA-4(+)) CD8(+) TIL had characteristics of more severe dysfunction than single-positive (PD-1(+) or CTLA-4(+)) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8(+) TIL dysfunction and led to tumor rejection in two thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8(+) and CD4(+) T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T-cell function. When used in combination with GVAX vaccination (consisting of granulocyte macrophage colony-stimulating factor-expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector T cells and maintaining tumor Tregs, and that PD-1/PD-L1 pathway (CD274) blockade augments tumor inhibition by increasing effector T-cell activity, thereby attenuating Treg suppression. Cancer Res; 73(12); 3591-603. ©2013 AACR.

Determination of picogram levels of midazolam, and 1- and 4-hydroxymidazolam in human plasma by gas chromatography-negative chemical ionization-mass spectrometry.

Midazolam is a widely accepted probe for phenotyping cytochrome P4503A. A gas chromatography-mass spectrometry (GC-MS)-negative chemical ionization method is presented which allows measuring very low levels of midazolam (MID), 1-OH midazolam (1OHMID) and 4-OH midazolam (4OHMID), in plasma, after derivatization with the reagent N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide. The standard curves were linear over a working range of 20 pg/ml to 5 ng/ml for the three compounds, with the mean coefficients of correlation of the calibration curves (n = 6) being 0.999 for MID and 1OHMID, and 1.0 for 4OHMID. The mean recoveries measured at 100 pg/ml, 500 pg/ml, and 2 ng/ml, ranged from 76 to 87% for MID, from 76 to 99% for 1OHMID, from 68 to 84% for 4OHMID, and from 82 to 109% for N-ethyloxazepam (internal standard). Intra- (n = 7) and inter-day (n = 8) coefficients of variation determined at three concentrations ranged from 1 to 8% for MID, from 2 to 13% for 1OHMID and from 1 to 14% for 4OHMID. The percent theoretical concentrations (accuracy) were within +/-8% for MID and 1OHMID, within +/-9% for 4OHMID at 500 pg/ml and 2 ng/ml, and within +/-28% for 4OHMID at 100 pg/ml. The limits of quantitation were found to be 10 pg/ml for the three compounds. This method can be used for phenotyping cytochrome P4503A in humans following the administration of a very low oral dose of midazolam (75 microg), without central nervous system side-effects.

Dermatofibrosarcoma presenting as a nodule in the breast of a 75-year-old woman: a case report.

ABSTRACT: INTRODUCTION: Dermatofibrosarcoma protuberans is a rare neoplasm of soft tissues and its location in the breast is extremely uncommon. Confusion is possible with other primary breast lesions. CASE PRESENTATION: A 75-year-old Caucasian woman presented with a mass in her left breast 21 years after being diagnosed with invasive ductal carcinoma of the right breast, treated by a right mastectomy and axillary dissection followed by radiotherapy and breast reconstruction. Mammography revealed a dish-shaped skin nodule formation in the upper outer quadrant of her left breast. Echography confirmed the presence of a lesion measuring 1.4 x 0.8 cm. Based on imaging, the diagnosis was a probable angiosarcoma. Due to the presence of a pacemaker for cardiac arrhythmia and full anticoagulation therapy for a pulmonary embolism, magnetic resonance imaging and a biopsy were not done. We proceeded directly to a quadrantectomy and the final diagnosis revealed a dermatofibrosarcoma protuberans, 1. 8 cm in its greatest microscopic dimension, located 0.1 cm from the upper surgical margin. To ensure the wide resection margins required for this type of neoplasm, a re-excision was performed. CONCLUSION: A dermatofibrosarcoma protuberans of the breast is an uncommon discovery. The aim of this case report is to highlight the importance of the surgical procedure in cases of the discovery of dermatofibrosarcoma protuberans. Re-excision may be necessary to ensure adequate resection margins.

Sensitivity analysis, dominant factors, and robustness of the ECETOC TRA v3, Stoffenmanager 4.5, and ART 1.5 occupational exposure models

Occupational exposure modeling is widely used in the context of the E.U. regulation on the registration, evaluation, authorization, and restriction of chemicals (REACH). First tier tools, such as European Centre for Ecotoxicology and TOxicology of Chemicals (ECETOC) targeted risk assessment (TRA) or Stoffenmanager, are used to screen a wide range of substances. Those of concern are investigated further using second tier tools, e.g., Advanced REACH Tool (ART). Local sensitivity analysis (SA) methods are used here to determine dominant factors for three models commonly used within the REACH framework: ECETOC TRA v3, Stoffenmanager 4.5, and ART 1.5. Based on the results of the SA, the robustness of the models is assessed. For ECETOC, the process category (PROC) is the most important factor. A failure to identify the correct PROC has severe consequences for the exposure estimate. Stoffenmanager is the most balanced model and decision making uncertainties in one modifying factor are less severe in Stoffenmanager. ART requires a careful evaluation of the decisions in the source compartment since it constitutes ∼75% of the total exposure range, which corresponds to an exposure estimate of 20-22 orders of magnitude. Our results indicate that there is a trade off between accuracy and precision of the models. Previous studies suggested that ART may lead to more accurate results in well-documented exposure situations. However, the choice of the adequate model should ultimately be determined by the quality of the available exposure data: if the practitioner is uncertain concerning two or more decisions in the entry parameters, Stoffenmanager may be more robust than ART.

Efectividad del 3,4- dimetilpirazolfosfato (DMPP) en naranjo dulce en el noreste Argentino

El objetivo del trabajo fue evaluar el efecto del 3,4-dimetilpirazol fosfato (DMPP) en la eficiencia de la fertilización amoniacal, en naranjo dulce [Citrus sinensis (L.) Osbeck] 'Valencia late' sobre suelo arenoso, en la provincia de Corrientes, Argentina. Durante tres campañas se trabajó en un huerto de naranjo 'Valencia late' injertado sobre lima de Rangpur (Citrus limonia, Osbeck), sobre un suelo tipo Udipsamment alfico. Se utilizó un Diseño de Bloques Completos al Azar con cuatro repeticiones, parcela útil una planta más borduras, con los tratamientos: 1. (Testigo) 150 kg de N ha-1 (fertilizante 15-6-15-6); T2. 75 kg de N ha-1 (sulfonitrato de amonio (SNA) 26 % N) tratado con DMPP (0,8% respecto al N amoniacal); T3. 150 kg de N ha-1 (SNA 26 % N), tratado con DMPP (0,8% respecto al N amoniacal). En el otoño se tomaron muestras foliares de ramas fructíferas, determinándose contenido de N, P y K. En la cosecha se determinó producción por planta (kg) y se evaluó calidad de frutos. Los resultados obtenidos permiten establecer que en suelos arenosos, el agregado de DMPP mejora la eficiencia de la fertilización nitrogenada. Con igual aporte nitrogenado, se incrementan los rendimientos y las concentraciones foliares de N y con la mitad de la dosis se logran rendimientos equivalentes al testigo.

Estimativa por infravermelho da concentração da unidade estrutural b-O-4 em ligninas de angiospermas tropicais

Five Björkman lignins, codified as AM, LL, GG, PP and AP, were isolated from wood species of Aspidosperma macrocarpum Mart., Lophanthera lactescens Ducke, Gallesia gorazema (Vell.) Miq., Peltogyne paniculata Bth. and Aspidosperma polyneuron Muell. Arg., respectively. Analyses of the lignins were carried out by Fourier transformed infrared spectroscopy using an experimental technique, Diffusely Reflected Infrared Fourier Transformed (DRIFT), admitting in the original spectra a band at 1500 cm-1 as an internal reference. Application of a deconvolution technique made possible to estimate the percentage per mol of b-O-4 unit content around 65.5% to AM, 68.0% to LL, 71.0% to GG. 73.4% to PP and 75.0% to AP, toward AM

An easy and direct method for the synthesis of 1,2,4-triazole derivatives through carboxylic acids and hydrazinophthalazine

We have developed an easy method for the synthesis of thirteen compounds derived from 1,2,4-triazoles through a carboxylic acid and hydrazinophthalazine reaction, with a 75-85% yield mediated by the use of agents such as 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride and 1-hydroxybenzotriazole. The operational simplicity of this method and the good yield of products make it valuable for the synthesis of new compounds with pharmacological activity.

Valtiotieteellinen Yhdistys 75 vuotta

Juhlapuhe 24.9.2010.