Manifestation of acute appendicitis as known but paradox visceral side effect of ulcerative colitis anti-inflammatory therapy with januskinase-inhibitor Tofacitinib (Xeljanz™).

BACKGROUND: The etiopathogenesis of accompanying inflammatory phenomena and consequences of immunomodulation constitute a challenging and innovative field in the medical treatment of patients with autoimmune diseases. AIM: Based on i) clinical management experience gained from this challenging clinical case and ii) selective references of reports published in the scientific medical literature, we present an unusual counterfactual scientific case report. A patient diagnosed with ulcerative colitis undergoing januskinase (JAK)-inhibitor therapy developed acuteappendicitis as an unusual complication or as a visceral side effect of immunosuppressive/anti-inflammatory therapy. METHOD: Scientific case report. RESULTS: (case description): Medical history: A 52-year-old male presented with spasmodic pain in the right lower abdomen lasting for two days (no fever, no bowel movement changes (no stool irregularities), no vomiting). MEDICATION USED TO DATE: Steroid-resistant ulcerative colitis treated with immunosuppressive therapy (Adalimumab administered for 10 months [next generation anti-TNFα mAb], Vendolizumab for 9 months [α4ß7 integrin antagonist], Tofacitinib for 6 months); fructose intolerance, no previous abdominal surgery; medication: XeljanzTM (Tofacitinib, 5 mg 2x1; JAK-inhibitor; PFIZER PHARMA GmbH, Berlin,Germany); MutaflorTM (1x1; Ardeypharm GmbH, Herdecke, Germany). CLINICAL FINDINGS: Pressure pain in the right lower abdomen with local muscular defense (Mc-Burney's/Lanz's point positive), no peritonism, Psoas-muscle sign positive. DIAGNOSTIC MEASURES: Laboratory parameters: standard value of white blood cell count, CrP: 25 mg/l.-Transabdominal ultrasound revealed hypertrophic 'appendix vermiformis' with detectable target-phenomenon and surrounding fluid. DECISION-MAKING: Indication for laparoscopic exploration. THERAPY: Under perioperative single-shot antibiotic administration with UnacidTM, the patient underwent emergency laparoscopic appendectomy due to confirmed acute appendicitis with additional lavage and placement of local drainage. CLINICAL COURSE: The postoperative phase was uneventful (sufficient analgetic therapy, removal of local drainage on the 2nd postoperative day). The patient was discharged four days after surgery. Histopathology confirmed ulcero-phlegmonous, acute purulent appendicitis with fibrinous purulent mesenteriolitis. FURTHER MEASURES: Immunosuppressive therapy was continued. CONCLUSION: Based on the paradoxon of an acute inflammatory disease (acute appendicitis) seen in the case of a patient undergoing immunosuppressive/anti-inflammatory treatment using a JAK-Inhibitor for ulcerative colitis, we consider this case worthy of publication although this side effect has previously been described in patients with rheumatoid arthritis. This might be the manifestation of i) an immunomodulatory effect that reduced or at least altered mucosal defense, including an increased risk of opportunistic infections, presenting as a specific visceral 'side effect' of the JAK-Inhibitor and/or as a consequence; ii) an induced alternative inflammatory mechanism/proinflammatory signal transduction and - theoretically - an intestinal drainage defect in the segment of right colic artery with consecutive collection of necrotic cells and activation of inflammatory mediators.

[Traumatic injuries of the kidney and the urinary tract in blunt abdominal trauma]. / Traumatische Verletzungen der Nieren und der ableitenden Harnwege bei stumpfen Bauchtraumata.

BACKGROUND: In the context of blunt abdominal trauma, injuries to the urinary tracts often occur, especially in polytrauma patients. Urotrauma is rarely immediately life-threatening but can lead to serious complications and chronic functional limitations during treatment. Therefore early urological involvement is crucial for adequate interdisciplinary treatment. METHODS: The most important facts for the clinical routine on the consultant urological management of urogenital injuries in blunt abdominal trauma are discussed according to the European "EAU guidelines on Urological Trauma" and the German "S3 guidelines on Polytrauma/Treatment of Severely Injured Patients" as well as the relevant literature. RESULTS: Urinary tract injuries can occur even with an initially inconspicuous status and always require explicit exclusion diagnostics by means of contrast medium tomography of the entire urinary tract and, if necessary, by means of urographic and endoscopic examinations. The most common urological intervention is catheterization of the urinary tract which is often required. Less common is urological surgery, which should be coordinated interdisciplinarily with visceral and trauma surgery. More than 90% of vitally threatening kidney injuries (usually up to the American Association for the Surgery of Trauma (AAST) grades 4-5) are now treated by interventional radiology. CONCLUSION: Due to possible complex injury patterns in blunt abdominal trauma, these patients should ideally be directed to (certified) trauma centers with subspecialized or maximum care from the departments of visceral and vascular surgery, trauma surgery, interventional radiology and urology.

Prevalencia del síndrome metabólico en Argentina en los últimos 25 años: revisión sistemática de estudios observacionales poblacionales / Prevalence of metabolic syndrome in Argentina in the last 25 years: systematic review of population observational studies

Introducción y objetivo: El síndrome metabólico (SM) comprende un conjunto de factores de riesgo para las enfermedades cardiovasculares y la diabetes. Argentina cuenta con numerosos estudios epidemiológicos sobre SM y, sin embargo, no se ha realizado un análisis sistemático de la prevalencia de SM en nuestra población. Con el fin de estimar la prevalencia de SM en la República Argentina se realizó una revisión sistemática de los estudios observacionales publicados durante el período 1988-2014. Estrategia de búsqueda: Se realizó una búsqueda bibliográfica en las bases de datos MEDLINE (National Library of Medicine), SciELO (Scientific Electronic Library Online) y LILACS (Latin American and Caribbean Health Sciences Literature) sobre estudios realizados en Argentina entre enero de 1988 y diciembre de 2014. Se utilizaron los siguientes términos de búsqueda combinados en los idiomas inglés, castellano y portugués: «síndrome metabólico», «insulinorresistencia», «síndrome dismetabólico», «prevalencia», «epidemiología», «Argentina». Selección de estudios: Fueron incluidos en el análisis los estudios epidemiológicos basados en población adulta de la República Argentina con reporte de la prevalencia de SM (de acuerdo con los criterios de la OMS, ATPIII o IDF). Síntesis de resultados: En la búsqueda bibliográfica inicial se identificaron 400publicaciones. En la segunda fase de búsqueda, 296títulos y resúmenes fueron excluidos. En la tercera fase, se analizó el texto completo de 104estudios. Finalmente, se incluyeron 6 publicaciones en el análisis que reportaron la prevalencia de SM sobre un total de 10.191sujetos (39,6% varones). La edad media de la población fue de 45,2años. La prevalencia de SM (modelo de efectos aleatorios) fue del 27,5% (IC 95%: 21,3-34,1%). La prevalencia de SM fue más elevada en varones que en mujeres (29,4% vs. 27,4%, respectivamente; p=0,02). En orden de frecuencia, los componentes de SM más comunes fueron la dislipidemia (38,3%), la presión arterial elevada (33,4%), la obesidad (32,1%) y la diabetes (7,5%). Conclusiones: Nuestros datos muestran que la prevalencia de SM es alta, lo que representa un problema de salud pública muy importante en Argentina (AU)

Introduction and aim: Metabolic syndrome (MS) comprises a set of risk factors for cardiovascular disease and diabetes. Argentina has numerous epidemiological studies on MS, however, there has been no systematic analysis of the prevalence of MS in our population. To estimate the prevalence of MS in the Argentine Republic, a systematic review of observational studies published during the period 1988-2014 was carried out. Search strategy: A bibliographic search was conducted in the MEDLINE (National Library of Medicine), SciELO (Scientific Electronic Library Online) and LILACS (Latin American and Caribbean Health Sciences Literature) databases on studies conducted in Argentina between January 1989 and December 2014. The following search terms were combined in English, Spanish and Portuguese: 'metabolic syndrome', 'insulin resistance', 'dysmetabolic syndrome', 'prevalence', 'epidemiology', and 'Argentina'. Selection of studies: Epidemiological studies based on the adult population of Argentina with specific report of the prevalence of MS (according to the WHO, ATP III or IDF criteria) were included in the analysis. Synthesis results: In the initial bibliographic search, 400 publications were identified. In the second phase of search, 296 titles and abstracts were excluded. In the third phase, the full text of 104 studies was analyzed. Finally, 6 publications were included in the analysis that reported the prevalence of MS in a total of 10,191 subjects (39.6% male). The average age of the population was 45.2 years. The prevalence of MS (random effects model) was 27.5% (95% CI: 21.3%-34.1%). The prevalence of MS was higher in men than in women (29.4% vs. 27.4%, respectively, P=.02). In order of frequency, the most common components of MS were dyslipidaemia (38.3%), hypertension (33.4%), obesity (32.1%) and diabetes (7.5%). Conclusions: Our data show that the prevalence of MS is high, which represents a very important public health problem in Argentina (AU)

Agonists of G-Protein-Coupled Odorant Receptors Are Predicted from Chemical Features.

Predicting the activity of chemicals for a given odorant receptor is a longstanding challenge. Here the activity of 258 chemicals on the human G-protein-coupled odorant receptor (OR)51E1, also known as prostate-specific G-protein-coupled receptor 2 (PSGR2), was virtually screened by machine learning using 4884 chemical descriptors as input. A systematic control by functional in vitro assays revealed that a support vector machine algorithm accurately predicted the activity of a screened library. It allowed us to identify two novel agonists in vitro for OR51E1. The transferability of the protocol was assessed on OR1A1, OR2W1, and MOR256-3 odorant receptors, and, in each case, novel agonists were identified with a hit rate of 39-50%. We further show how ligands' efficacy is encoded into residues within OR51E1 cavity using a molecular modeling protocol. Our approach allows widening the chemical spaces associated with odorant receptors. This machine-learning protocol based on chemical features thus represents an efficient tool for screening ligands for G-protein-coupled odorant receptors that modulate non-olfactory functions or, upon combinatorial activation, give rise to our sense of smell.

[Prevalence of metabolic syndrome in Argentina in the last 25 years: systematic review of population observational studies]. / Prevalencia del síndrome metabólico en Argentina en los últimos 25 años: revisión sistemática de estudios observacionales poblacionales.

INTRODUCTION AND AIM: Metabolic syndrome (MS) comprises a set of risk factors for cardiovascular disease and diabetes. Argentina has numerous epidemiological studies on MS, however, there has been no systematic analysis of the prevalence of MS in our population. To estimate the prevalence of MS in the Argentine Republic, a systematic review of observational studies published during the period 1988-2014 was carried out. SEARCH STRATEGY: A bibliographic search was conducted in the MEDLINE (National Library of Medicine), SciELO (Scientific Electronic Library Online) and LILACS (Latin American and Caribbean Health Sciences Literature) databases on studies conducted in Argentina between January 1989 and December 2014. The following search terms were combined in English, Spanish and Portuguese: 'metabolic syndrome', 'insulin resistance', 'dysmetabolic syndrome', 'prevalence', 'epidemiology', and 'Argentina'. SELECTION OF STUDIES: Epidemiological studies based on the adult population of Argentina with specific report of the prevalence of MS (according to the WHO, ATP III or IDF criteria) were included in the analysis. SYNTHESIS RESULTS: In the initial bibliographic search, 400 publications were identified. In the second phase of search, 296 titles and abstracts were excluded. In the third phase, the full text of 104 studies was analyzed. Finally, 6 publications were included in the analysis that reported the prevalence of MS in a total of 10,191 subjects (39.6% male). The average age of the population was 45.2 years. The prevalence of MS (random effects model) was 27.5% (95% CI: 21.3%-34.1%). The prevalence of MS was higher in men than in women (29.4% vs. 27.4%, respectively, P=.02). In order of frequency, the most common components of MS were dyslipidaemia (38.3%), hypertension (33.4%), obesity (32.1%) and diabetes (7.5%). CONCLUSIONS: Our data show that the prevalence of MS is high, which represents a very important public health problem in Argentina.

Olfactory disturbances in ageing with and without dementia: towards new diagnostic tools.

BACKGROUND: Olfactory disorders increase with age and often affect elderly people who have pre-dementia or dementia. Despite the frequent occurrence of olfactory changes at the early stages of neurodegenerative disorders such as Alzheimer's disease, olfactory disorders are rarely assessed in daily clinical practice, mainly due to a lack of standardised assessment tools. The aims of this review were to (1) summarise the existing literature on olfactory disorders in ageing populations and patients with neurodegenerative disorders; (2) present the strengths and weaknesses of current olfactory disorder assessment tools; and (3) discuss the benefits of developing specific olfactory tests for neurodegenerative diseases. METHODS: A systematic review was performed of literature published between 2000 and 2015 addressing olfactory disorders in elderly people with or without Alzheimer's disease or other related disorders to identify the main tools currently used for olfactory disorder assessment. RESULTS: Olfactory disorder assessment is a promising method for improving both the early and differential diagnosis of Alzheimer's disease. However, the current lack of consensus on which tests should be used does not permit the consistent integration of olfactory disorder assessment into clinical settings. CONCLUSION: Otolaryngologists are encouraged to use olfactory tests in older adults to help predict the development of neurodegenerative diseases. Olfactory tests should be specifically adapted to assess olfactory disorders in Alzheimer's disease patients.

Use of the triglyceride/high-density lipoprotein cholesterol ratio to identify cardiometabolic risk: impact of obesity?

There is evidence that the plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) identifies insulin resistance and increased cardiometabolic risk and outcome in apparently healthy individuals. Since use of the TG/HDL-C ratio to accomplish this task in persons over a wide range of adiposity has not been studied, the ability of previously defined sex-specific TG/HDL-C cut-points to identify increased cardiometabolic risk was evaluated in apparently healthy normal weight, overweight, and obese individuals. Data were analyzed from a population-based study of apparently healthy men (n=416) and women (n=893), subdivided into categories by body mass index (BMI, kg/m2): normal weight (BMI 20.0-24.9), overweight (BMI 25.0-29.9) and obese (BMI 30.0-34.9). The adiposity groups were further stratified on the basis of their TG/HDL-C ratio into groups defined as being either at 'high risk' versus 'low risk' of cardiometabolic disease. Multiple cardiometabolic risk factors were compared between these subgroups, as was their degree of insulin resistance assessed by fasting plasma insulin concentration and homeostasis model assessment of insulin resistance. The proportion of high-risk individuals varied with BMI category, ranging from 14% (normal weight) to 36% (obese). However, within each BMI category high-risk individuals had a significantly more adverse cardiometabolic risk profile. Finally, the adjusted OR of being insulin resistant was significantly greater in those with a high TG/HDL-C ratio in the normal (3.02), overweight (2.86), and obese (2.51) groups. Thus, irrespective of differences in BMI, the TG/HDL-C ratio identified apparently healthy persons with a more adverse cardiometabolic risk profile associated with an increased prevalence of insulin resistance.

Should the first blood pressure reading be discarded?

We evaluated the consequences of excluding the first of three blood pressure (BP) readings in different settings: a random population sample (POS, n=1525), a general practice office (GPO, n=942) and a specialized hypertension center (SHC, n=462). Differences between systolic and diastolic BP (SBP and DBP) estimates obtained including and excluding the first reading were compared and their correlation with ambulatory BP monitoring (ABPM) was estimated. The samples were divided into quartiles according to the difference between the third and the first SBP (3-1ΔSBP). SBP decreased through sequential readings, 3-1ΔSBP was -5.5 ± 9.7 mm Hg (P<0.001), -5.1 ± 10.4 mm Hg (P<0.001) and -6.1 ± 9.3 mm Hg (P<0.001) for POS, GPO and SHC, respectively. However, individuals included in the top quartile of 3-1ΔSBP showed their highest values on the third reading. The mean SBP estimate was significantly higher excluding the first reading (P<0.001), but the differences among both approaches were small (1.5-1.6 mm g). Moreover, the correlation between SBP values including and excluding the first reading and daytime ABPM were comparable (r = 0.69 and 0.68, respectively). Similar results were observed for DBP. In conclusion, our study does not support the notion of discarding the first BP measurement and suggests that it should be measured repeatedly, regardless the first value.

Identifying cardiovascular disease risk and outcome: use of the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio versus metabolic syndrome criteria.

BACKGROUND: Metabolic syndrome (MetS) has been shown to predict both risk and CVD events. We have identified sex-specific values for the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio associated with an unfavourable cardio-metabolic risk profile, but it is not known whether it also predicts CVD outcome. METHODS: To quantify risk for CVD outcomes associated with a high TG/HDL-C ratio and to compare this risk with that predicted using MetS, a population longitudinal prospective observational study was performed in Rauch City, Buenos Aires, Argentina. In 2003 surveys were performed on a population random sample of 926 inhabitants. In 2012, 527 women and 269 men were surveyed again in search of new CVD events. The first CVD event was the primary endpoint. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points, and with or without MetS, were estimated using Cox proportional hazard. MAIN OUTCOME: The first CVD event was the primary endpoint. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points, and with or without MetS, were estimated using Cox proportional hazard. RESULTS: The number of subjects deemed at 'high' CVD risk on the basis of an elevated TG/HDL-C ratio (30%) or having the MetS (35%) was relatively comparable. The unadjusted hazard risk was significantly increased when comparing 'high' versus 'low' risk groups no matter which criteria was used, although it was somewhat higher in those with the MetS (HR = 3.17, 95% CI:1.79-5.60 vs. 2.16, 95% CI:1.24-3.75). However, this difference essentially disappeared when adjusted for sex and age (HR = 2.09, 95% CI:1.18-3.72 vs. 2.01, 95% CI:1.14-3.50 for MetS and TG/HDL-C respectively). CONCLUSIONS: An elevated TG/HDL-C ratio appears to be just as effective as the MetS diagnosis in predicting the development of CVD.

Frequency-shift vs phase-shift characterization of in-liquid quartz crystal microbalance applications.

The improvement of sensitivity in quartz crystal microbalance (QCM) applications has been addressed in the last decades by increasing the sensor fundamental frequency, following the increment of the frequency/mass sensitivity with the square of frequency predicted by Sauerbrey. However, this sensitivity improvement has not been completely transferred in terms of resolution. The decrease of frequency stability due to the increase of the phase noise, particularly in oscillators, made impossible to reach the expected resolution. A new concept of sensor characterization at constant frequency has been recently proposed. The validation of the new concept is presented in this work. An immunosensor application for the detection of a low molecular weight contaminant, the insecticide carbaryl, has been chosen for the validation. An, in principle, improved version of a balanced-bridge oscillator is validated for its use in liquids, and applied for the frequency shift characterization of the QCM immunosensor application. The classical frequency shift characterization is compared with the new phase-shift characterization concept and system proposed.

Efficacy of cecropin A-melittin peptides on a sepsis model of infection by pan-resistant Acinetobacter baumannii.

Pan-resistant Acinetobacter baumannii have prompted the search for therapeutic alternatives. We evaluate the efficacy of four cecropin A-melittin hybrid peptides (CA-M) in vivo. Toxicity was determined in mouse erythrocytes and in mice (lethal dose parameters were LD(0), LD(50), LD(100)). Protective dose 50 (PD(50)) was determined by inoculating groups of ten mice with the minimal lethal dose of A. baumannii (BMLD) and treating with doses of each CA-M from 0.5 mg/kg to LD(0). The activity of CA-Ms against A. baumannii was assessed in a peritoneal sepsis model. Mice were sacrificed at 0 and 1, 3, 5, and 7-h post-treatment. Spleen and peritoneal fluid bacterial concentrations were measured. CA(1-8)M(1-18) was the less haemolytic on mouse erythrocytes. LD(0) (mg/kg) was 32 for CA(1-8)M(1-18), CA(1-7)M(2-9), and Oct-CA(1-7)M(2-9), and 16 for CA(1-7)M(5-9). PD(50) was not achieved with non-toxic doses (≤ LD(0)). In the sepsis model, all CA-Ms were bacteriostatic in spleen, and decreased bacterial concentration (p < 0.05) in peritoneal fluid, at 1-h post-treatment; at later times, bacterial regrowth was observed in peritoneal fluid. CA-Ms showed local short-term efficacy in the peritoneal sepsis model caused by pan-resistant Acinetobacter baumannii.

A piezoelectric immunosensor for the determination of pesticide residues and metabolites in fruit juices.

A quartz crystal microbalance (QCM) immunosensor was developed for the determination of the insecticide carbaryl and 3,5,6-trichloro-2-pyridinol (TCP), the main metabolite of the insecticide chlorpyrifos and of the herbicide triclopyr. The detection was based on a competitive conjugate-immobilized immunoassay format using monoclonal antibodies (MAbs). Hapten conjugates were covalently immobilized, via thioctic acid self-assembled monolayer (SAM), onto the gold electrode sensitive surface of the quartz crystal. This covalent immobilization allowed the reusability of the modified electrode surface for at least one hundred and fifty assays without significant loss of sensitivity. The piezoimmunosensor showed detection limits (analyte concentrations producing 10% inhibition of the maximum signal) of 11 and 7 microg l(-1) for carbaryl and TCP, respectively. The sensitivity attained (I(50) value) was around 30 microg l(-1) for both compounds. Linear working ranges were 15-53 microg l(-1) for carbaryl and 13-83 microg l(-1) for TCP. Each complete assay cycle took 20 min. The good sensitivity, specificity, and reusability achieved, together with the short response time, allowed the application of this immunosensor to the determination of carbaryl and TCP in fruits and vegetables at European regulatory levels, with high precision and accuracy.

Synthesis and SAR of bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors.

Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.

[Abnormal antioxidant system in inborn errors of intermediary metabolism]. / Alteraciones del sistema antioxidante en errores cong nitos del metabolismo intermediario.

INTRODUCTION: Oxidative stress may be implied in the pathogenic mechanisms of inborn errors of intermediary metabolism (IEIM). OBJECTIVE: The evaluation of the antioxidant status in IEIM by the measurement of erythrocyte antioxidant enzyme activities, superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase and catalase. PATIENTS AND METHODS: 34 patients with IEIM: 1) eleven with organic acidurias on protein restricted diet; 2) nine without special diet; 3) five patients with aminoacidopathies on protein restriction; 4) three patients with galactosemia and six with aminoacidopathies on protein free diet. Erythrocyte antioxidant enzymes were measured by spectrometric procedures adapted to the Cobas Fara II analyser. RESULTS: SOD activity was significantly higher in groups 2 and 4 (p= 0.009, p= 0.001, respectively), and significantly lower in group 3 (p= 0.001) compared with age matched controls. SOD activity was significantly higher in the patients with IEIM on protein free diet (groups 2 and 4) compared with those on protein restricted diet (groups 1 and 3; p= 0.002) or with controls (p= 0.003). GPx activity was found significantly lower in group 1 patients (p= 0.004), and higher in group 2 (p= 0.029) compared with controls. CONCLUSIONS: 35% of the patients with IEIM had SOD activity above the control range, most of them with organic acidurias or homocystinuria, suggesting an induction of enzyme protein synthesis owing to an excess of free radical generation. The lower activities observed in patients on natural protein restriction may likely be due to a deficient bioavailability of antioxidant cofactors.

Alteraciones del sistema antioxidante en errores congénitos del metabolismo intermediario / Abnormal antioxidant system in inborn errors of intermediary metabolism

Introducción. El estrés oxidativo puede implicarse en los mecanismos de patogenia de los errores congénitos del metabolismo intermediario (ECMI). Objetivo. Para evaluar el estado antioxidante en estas enfermedades analizamos las actividades eritrocitarias de las enzimas antioxidantes, superóxido dismutasa (SOD), glutatión peroxidasa (GPx), glutatión reductasa y catalasa, en 34 pacientes con ECMI. Pacientes y métodos. Distribuimos a los pacientes en cuatro grupos: 1. Once con acidurias orgánicas, tratados con dietas restringidas en proteínas naturales; 2. Nueve sin dieta especial; 3.Cinco pacientes con aminoacidopatías, en tratamiento con restricción proteica; y 4. Tres pacientes con galactosemia y seis con aminoacidopatías, con dieta proteica libre. Las enzimas antioxidantes eritrocitarias se analizaron por procedimientos espectrométricos adaptados al analizador Cobas Fara II. Resultados. La actividad SOD fue significativamente más elevada en los grupos 2 y 4 (p= 0,009, p= 0,001) y más disminuida en el grupo 3 (p= 0,001), comparada con los controles. La actividad SOD se halló significativamente más elevada en los pacientes tratados con dieta proteica libre (grupos 2 y 4), comparados con los tratados con restricción proteica (grupos 1 y 3; p= 0,002) o los controles (p= 0,003). Conclusión. El 35 por ciento de los pacientes con ECMI mostraron una actividad SOD superior al intervalo control, la mayoría de ellos con acidurias orgánicas u homocistinuria, lo que sugiere una inducción de la síntesis de la proteína enzimática debido a un exceso de producción de radicales libres. Las bajas actividades enzimáticas observadas en pacientes con restricción proteica podrían atribuirse a una biodisponibilidad deficiente de cofactores antioxidantes (AU)

Anthranilate sulfonamide hydroxamate TACE inhibitors. Part 2: SAR of the acetylenic P1' group.

The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.

The discovery of anthranilic acid-based MMP inhibitors. Part 3: incorporation of basic amines.

Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.

The discovery of anthranilic acid-based MMP inhibitors. Part 2: SAR of the 5-position and P1(1) groups.

A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p.

Determination of amphetamine in dog plasma by gas chromatography with mass selective detection.

This paper describes the validation of an analytical method for the determination of amphetamine in beagle dog plasma by gas chromatography coupled to mass spectrometry (GC-MS). d-Amphetamine-d(6) was used as the internal standard. The method consisted of a rapid single-step liquid-liquid extraction and derivatization of amphetamine with 2,2,2-trichloroethyl chloroformate, followed by sensitive GC-MS detection. This is the first report utilizing the combination of trichloroethyl chloroformate as a derivatization reagent and a deuterated amphetamine analog as an IS for the quantification of amphetamine in plasma. The method was validated in terms of specificity, curve fit, precision, accuracy, recovery and stability, and was acceptable according to FDA draft guidelines for validation of bioanalytical methods. The limit of detection was 0.65 ng/mL. The calibration range was 5-150 ng/mL. The validated method was successfully employed for the quantitation of amphetamine in dog plasma samples for pharmacokinetic profiling.