Specific (granulomatous) oral lesions of sarcoidosis: Report of two cases

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology that usually presents with bilateral hiliar adenopathies, pulmonary infiltrations, and ocular and cutaneous lesions. The specific cutaneous lesions, or granulomatous, are produced in from 9% to 37% of patients with systemic sarcoidosis. Nevertheless, few patients have been described having specific lesions from sarcoidosis in the oral mucous membrane. We present 2 patients with systemic sarcoidosis who developed specific sarcoidosis lesions in the oral mucous membrane. The first patient presented a plaque on the tongue of a chronic nature associated with facial lupus pernio. The second patient presented a rapidly growing nodular lesion on the lower lip that was in fact the presentation sign of the disease. Although infrequent, oral lesions may constitute the first sign of systemic sarcoidosis. For this reason the oral mucous membrane needs to be explored when there is suspicion of sarcoidosis, and systemic sarcoidosis must be included in the differential diagnosis of oral granulomatous lesions.

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Background Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Methods Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNy)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration. Results Diazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-¿) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord. Conclusion Taken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.

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.

Short and long-term effects of tillage systems and nutrient sources on soil physical properties of a Southern Brazilian Hapludox

Soil tillage promotes changes in soil structure. The magnitude of the changes varies with the nature of the soil, tillage system and soil water content and decreases over time after tillage. The objective of this study was to evaluate short-term (one year period) and long-term (nine year period) effects of soil tillage and nutrient sources on some physical properties of a very clayey Hapludox. Five tillage systems were evaluated: no-till (NT), chisel plow + one secondary disking (CP), primary + two (secondary) diskings (CT), CT with burning of crop residues (CTb), and CT with removal of crop residues from the field (CTr), in combination with five nutrient sources: control without nutrient application (C); mineral fertilizers, according to technical recommendations for each crop (MF); 5 Mg ha-1 yr-1 of poultry litter (wetmatter) (PL); 60 m³ ha-1 yr-1 of cattle slurry (CS) and; 40 m³ ha-1 yr-1 of swine slurry (SS). Bulk density (BD), total porosity (TP), and parameters related to the water retention curve (macroporosity, mesoporosity and microporosity) were determined after nine years and at five sampling dates during the tenth year of the experiment. Soil physical properties were tillage and time-dependent. Tilled treatments increased total porosity and macroporosity, and reduced bulk density in the surface layer (0.00-0.05 m), but this effect decreased over time after tillage operations due to natural soil reconsolidation, since no external stress was applied in this period. Changes in pore size distribution were more pronounced in larger and medium pore diameter classes. The bulk density was greatest in intermediate layers in all tillage treatments (0.05-0.10 and 0.12-0.17 m) and decreased down to the deepest layer (0.27-0.32 m), indicating a more compacted layer around 0.05-0.20 m. Nutrient sources did not significantly affect soil physical and hydraulic properties studied.

Comparison of two oral probiotic preparations in a randomized crossover trial highlights a potentially beneficial effect of Lactobacillus paracasei NCC2461 in patients with allergic rhinitis.

BACKGROUND: There is promising but conflicting evidence to recommend the addition of probiotics to foods for prevention and treatment of allergy. Based on previous studies with fermented milk containing Lactobacillus paracasei NCC2461, we aimed to compare the effect of a powder form of the latter probiotic with the effect of a blend of Lactobacillus acidophilus ATCC SD5221 and Bifidobacterium lactis ATCC SD5219 in patients with allergic rhinitis. METHODS: A double-blind, randomized, cross-over study, involving 31 adults with allergic rhinitis to grass pollen, was performed outside the grass pollen season (registration number: NCT01233154). Subjects received each product for 4-weeks in two phases separated by a wash-out period of 6 to 8 weeks. A nasal provocation test was performed before and after each 4-week product intake period, and outcome parameters (objective and subjective clinical symptoms; immune parameters) were measured during and/or 24 hours after the test. RESULTS: Out of the 31 subject enrolled, 28 completed the study. While no effect was observed on nasal congestion (primary outcome), treatment with NCC2461 significantly decreased nasal pruritus (determined by VAS), and leukocytes in nasal fluid samples, enhanced IL-5, IL-13 and IL-10 production by peripheral blood mononuclear cells in an allergen specific manner and tended to decrease IL-5 secretion in nasal fluid, in contrast to treatment with the blend of L. acidophilus and B. lactis. CONCLUSIONS: Despite short-term consumption, NCC2461 was able to reduce subjective nasal pruritus while not affecting nasal congestion in adults suffering from grass pollen allergic rhinitis. The associated decrease in nasal fluid leukocytes and IL-5 secretion, and the enhanced IL-10 secretion in an allergen specific manner may partly explain the decrease in nasal pruritus. However, somewhat unexpected systemic immune changes were also noted. These data support the study of NCC2461 consumption in a seasonal clinical trial to further demonstrate its potentially beneficial effect.

The CbrA-CbrB two-component regulatory system controls the utilization of multiple carbon and nitrogen sources in Pseudomonas aeruginosa.

A novel two-component system, CbrA-CbrB, was discovered in Pseudomonas aeruginosa; cbrA and cbrB mutants of strain PAO were found to be unable to use several amino acids (such as arginine, histidine and proline), polyamines and agmatine as sole carbon and nitrogen sources. These mutants were also unable to use, or used poorly, many other carbon sources, including mannitol, glucose, pyruvate and citrate. A 7 kb EcoRI fragment carrying the cbrA and cbrB genes was cloned and sequenced. The cbrA and cbrB genes encode a sensor/histidine kinase (Mr 108 379, 983 residues) and a cognate response regulator (Mr 52 254, 478 residues) respectively. The amino-terminal half (490 residues) of CbrA appears to be a sensor membrane domain, as predicted by 12 possible transmembrane helices, whereas the carboxy-terminal part shares homology with the histidine kinases of the NtrB family. The CbrB response regulator shows similarity to the NtrC family members. Complementation and primer extension experiments indicated that cbrA and cbrB are transcribed from separate promoters. In cbrA or cbrB mutants, as well as in the allelic argR9901 and argR9902 mutants, the aot-argR operon was not induced by arginine, indicating an essential role for this two-component system in the expression of the ArgR-dependent catabolic pathways, including the aruCFGDB operon specifying the major aerobic arginine catabolic pathway. The histidine catabolic enzyme histidase was not expressed in cbrAB mutants, even in the presence of histidine. In contrast, proline dehydrogenase, responsible for proline utilization (Pru), was expressed in a cbrB mutant at a level comparable with that of the wild-type strain. When succinate or other C4-dicarboxylates were added to proline medium at 1 mM, the cbrB mutant was restored to a Pru+ phenotype. Such a succinate-dependent Pru+ property was almost abolished by 20 mM ammonia. In conclusion, the CbrA-CbrB system controls the expression of several catabolic pathways and, perhaps together with the NtrB-NtrC system, appears to ensure the intracellular carbon: nitrogen balance in P. aeruginosa.

Biomass production and phosphorus use of forage grasses fertilized with two phosphorus sources

A major constraint to agricultural production in acid soils of tropical regions is the low soil P availability, due to the high adsorption capacity, low P level in the source material and low efficiency of P uptake and use by most of the modern varieties grown commercially. This study was carried out to evaluate the biomass production and P use by forage grasses on two soils fertilized with two P sources of different solubility. Two experiments were carried out, one for each soil (Cambisol and Latosol), using pots filled with 4 dm³ soil in a completely randomized design and a 4 x 2 factorial scheme. The treatments consisted of a combination of four forage plants (Brachiaria decumbens, Brachiaria brizantha, Pennisetum glaucum and Sorghum bicolor) with two P sources (Triple Superphosphate - TSP and Arad Reactive Phosphate - ARP), with four replications. The forage grasses were harvested at pre-flowering, when dry matter weight and P concentrations were measured. Based on the P concentration and dry matter production, the total P accumulation was calculated. With these data, the following indices were calculated: the P uptake efficiency of roots, P use efficiency, use efficiency of available P, use efficiency of applied P and agronomic efficiency. The use of the source with higher solubility (TSP) resulted, generally, in higher total dry matter and total P accumulation in the forage grasses, in both soils. For the less reactive source (ARP), the means found in the forage grasses, for use efficiency and efficient use of available P, were always higher when grown in Latosol, indicating favorable conditions for the solubility of ARP. The total dry matter of Brachiaria brizantha was generally higher, with low P uptake, accumulation and translocation, which indicated good P use efficiency for both P sources and soils. The forage plants differed in the P use potential, due to the sources of the applied P and of the soils used. Less than 10 % of the applied P was immobilized in the forage dry matter. Highest values were observed for TSP, but this was not reflected in a higher use efficiency of P from this source.

Acute supra-therapeutic oral terbutaline administration has no ergogenic effect in non-asthmatic athletes.

This study aimed to investigate the effects on a possible improvement in aerobic and anaerobic performance of oral terbutaline (TER) at a supra-therapeutic dose in 7 healthy competitive male athletes. On day 1, ventilatory threshold, maximum oxygen uptake [Formula: see text] and corresponding power output were measured and used to determine the exercise load on days 2 and 3. On days 2 and 3, 8 mg of TER or placebo were orally administered in a double-blind process to athletes who rested for 3 h, and then performed a battery of tests including a force-velocity exercise test, running sprint and a maximal endurance cycling test at Δ50 % (50 % between VT and [Formula: see text]). Lactatemia, anaerobic parameters and endurance performance ([Formula: see text] and time until exhaustion) were raised during the corresponding tests. We found that TER administration did not improve any of the parameters of aerobic performance (p > 0.05). In addition, no change in [Formula: see text] kinetic parameters was found with TER compared to placebo (p > 0.05). Moreover, no enhancement of the force-velocity relationship was observed during sprint exercises after TER intake (p > 0.05) and, on the contrary, maximal strength decreased significantly after TER intake (p < 0.05) but maximal power remained unchanged (p > 0.05). In conclusion, oral acute administration of TER at a supra-therapeutic dose seems to be without any relevant ergogenic effect on anaerobic and aerobic performances in healthy athletes. However, all participants experienced adverse side effects such as tremors.

Adhésion thérapeutique en oncologie : persistance, qualité d'exécution et satisfaction des patients sous traitement oral et MEMS®

Introduction: en oncologie apparaissent sur le marché depuis quelques années de nouveaux traitements en formulation orale facilitant l'administration et améliorant la qualité de vie du patient mais augmentant le risque de non adhésion et d'erreurs de posologie. L'observation par MEMS® (Medication Event Monitoring System) permet le suivi et l'encadrement du traitement oral et par le biais d'entretiens semi structurés menés par le pharmacien, ouvre la discussion sur les problèmes révélés par cette prise en charge. Méthode: étude non randomisée prospective uni centrique regroupant 50 patients inclus dans 3 groupes de traitements oncologiques oraux courants (capecitabine, letrozole/exemestane, imatinib/sunitinib) bénéficiant d'un suivi oncologique classique et équipés d'un MEMS® pour un an maximum. La persistance et la qualité d'exécution sont les deux paramètres mesurés grâce aux données récoltées électroniquement. Les entretiens sont dédiés à la prévention de la non adhésion et à la gestion des effets secondaires médicamenteux. La satisfaction est évaluée par un questionnaire à la fin du suivi. Résultats: à ce jour 38 patients ont été inclus dans l'étude. Les données complètes sont disponibles pour les 19 premiers patients dont 10 sous capecitabine et 9 sous letrozole/exemestane. Dans ce collectif l'âge médian est de 66 ans avec une majorité de femmes (11:8). La persistance à 10 jours est de 85% et la qualité d'exécution de 99%. Les toxicités observées supérieures à grade 1 sont 1 syndrome mains-pieds (G3) et 1 syndrome coronarien aigu (G3). Le questionnaire de fin de suivi relève une satisfaction de 85% des patients pour les entretiens proposés (57% utiles, 28% très utiles, 15% inutiles) et le succès quant à l'intégration du MEMS® dans leur quotidien (57% très facile, 43% facile). Conclusion: la persistance et la qualité d'exécution observées dans notre collectif sont excellentes. La satisfaction retrouvée auprès des patients reflète le besoin d'un soutien complémentaire face à la complexité de la maladie oncologique. La gestion pluridisciplinaire profite tant aux patients qu'au binôme médecin-pharmacien par l'amélioration de la communication globale entre les divers acteurs et par l'identification précoce des risques de non adhésion. La poursuite de cette étude et l'analyse des futures données permettra de mesurer le réel impact de notre intervention et de justifier le bénéfice pour des patients sous traitement similaire.

Dynamic compact thermal models with multiple power sources: application to an ultrathin chip stacking technology

Whereas numerical modeling using finite-element methods (FEM) can provide transient temperature distribution in the component with enough accuracy, it is of the most importance the development of compact dynamic thermal models that can be used for electrothermal simulation. While in most cases single power sources are considered, here we focus on the simultaneous presence of multiple sources. The thermal model will be in the form of a thermal impedance matrix containing the thermal impedance transfer functions between two arbitrary ports. Eachindividual transfer function element ( ) is obtained from the analysis of the thermal temperature transient at node ¿ ¿ after a power step at node ¿ .¿ Different options for multiexponential transient analysis are detailed and compared. Among the options explored, small thermal models can be obtained by constrained nonlinear least squares (NLSQ) methods if the order is selected properly using validation signals. The methods are applied to the extraction of dynamic compact thermal models for a new ultrathin chip stack technology (UTCS).

Aggregate stability as affected by short and long-term tillage systems and nutrient sources of a hapludox in southern Brazil

The ability of a soil to keep its structure under the erosive action of water is usually high in natural conditions and decreases under frequent and intensive cultivation. The effect of five tillage systems (NT = no-till; CP = chisel plowing and one secondary disking; CT = primary and two secondary distings; CTb = CT with crop residue burning; and CTr = CT with removal of crop residues from the field), combined with five nutrient sources (C = control, no nutrient application; MF = mineral fertilizers according to technical recommendations for each crop; PL = 5 Mg ha-1 y-1 fresh matter of poultry litter; CM = 60 m³ ha-1 y-1 slurry cattle manure; and SM = 40 m³ ha-1 y-1 slurry swine manure) on wet-aggregate stability was determined after nine years (four sampled soil layers) and on five sampling dates in the 10th year (two sampled soil layers) of the experiment. The size distribution of the air-dried aggregates was strongly affected by soil bulk density, and greater values of geometric mean diameter (GMD AD) found in some soil tillage or layer may be partly due to the higher compaction degree. After nine years, the GMD AD on the surface was greater in NT and CP compared to conventional tillage systems (CT, CTb and CTr), due to the higher organic matter content, as well as less soil mobilization. Aggregate stability in water, on the other hand, was affected by the low variation in previous gravimetric moisture of aggregates, which contributed to a high coefficient of variation of this attribute. The geometric mean diameter of water-stable aggregates (GMD WS) was highest in the 0.00-0.05 m layer in the NT system, in the layers 0.05-0.10 and 0.12-0.17 m in the CT, and values were intermediate in CP. The stability index (SI) in the surface layers was greater in treatments where crop residues were kept in the field (NT, CP and CT), which is associated with soil organic matter content. No differences were found in the layer 0.27-0.32 m. The effect of nutrient sources on GMD AD and GMD WS was small and did not affect SI.

15N uptake fom manure and fertilizer sources by three consecutive crops under controlled conditions

There are several regions of the world where soil N analysis and/or N budgets are not used to determine how much N to apply, resulting in higher than needed N inputs, especially when manure is used. One such region is the North Central "La Comarca Lagunera", one of the most important dairy production areas of Mexico. We conducted a unique controlled greenhouse study using 15N fertilizer and 15N isotopic-labeled manure that was labeled under local conditions to monitor N cycling and recovery under higher N inputs. The manure-N treatment was applied only once and was incorporated in the soil before planting the first forage crop at an equivalent rate of 30, 60 and 120 Mg ha-1 dry manure. The 15N treatments were equivalent to 120 and 240 kg ha-1 (NH4)2SO4-N for each crop. The total N fertilizer for each N fertilized treatment were 360, and 720 kg ha-1 N. We found very low N recoveries: about 9 % from the manure N inputs, lower than the 22 to 25 % from the fertilizer N inputs. The manure N recovered belowground in soil and roots ranged from 82 to 88 %. The low recoveries of N by the aboveground and low soil inorganic nitrate (NO3-N) and ammonium (NH4-N) content after the third harvested suggested that most of the 15N recovered belowground was in the soil organic form. The losses from manure N inputs ranged from 3 to 11 %, lower than the 34 to 39 % lost from fertilizer N sources. Our study shows that excessive applications of manure or fertilizer N that are traditionally used in this region will not increase the rate of N uptake by aboveground compartment but will increase the potential for N losses to the environment.

Response of irrigated wheat cultivars to different nitrogen rates and sources

High wheat yields require good N fertilization management. The objective of this study was to evaluate the effects of different N applications at sowing using Entec (N source with nitrification inhibitor) and urea (traditional N source) at covering, on four wheat cultivars. The experiment was conducted in a randomized block design in a factorial scheme, with four replications, at the Experimental Station of the Faculdade de Engenharia de Ilha Solteira - UNESP, on a dystrophic, epi-eutrophic alic Red Latosol with loamy texture, formerly under savannah vegetation. Four N rates (0, 60, 120, and 180 kg ha-1) were tested, applied at sowing in the case of Entec and top-dressed 40 days after plant emergence in the case of urea, and the four wheat cultivars E 21, E 22, E 42, and IAC 370. The yield of the wheat cultivars E 21 and E 42 was highest. Plant height and lodging index of cultivar E 22 were greatest, with consequently lowest grain yield. There was no significant difference between Entec (applied at sowing) and urea (top-dressed) in terms of grain yield and yield components. Nevertheless, urea resulted in a higher N leaf content, and Entec in a larger number of undeveloped spikelets. High nitrogen rates influenced the hectoliter mass negatively, affecting wheat grain quality. Grain yield increased under N rates of up to 82 kg ha-1 N, through Entec applied at sowing or top-dressed urea.