Unraveling the Association Between Gait and Mortality-One Step at a Time.

BACKGROUND: Slowness of walking is one of the very first signs of aging and is considered a marker for overall health that is strongly associated with mortality risk. In this study, we sought to disentangle the clinical drivers of the association between gait and mortality. METHODS: We included 4,490 participants of the Rotterdam Study who underwent a gait assessment between 2009 and 2015 and were followed-up for mortality until 2018. Gait was assessed with an electronic walkway and summarized into the domains Rhythm, Phases, Variability, Pace, Tandem, Turning, and Base of Support. Cox models adjusted for age, sex, and height were built and consecutively adjusted for six categories of health indicators (lifestyle, musculoskeletal, cardiovascular, pulmonary, metabolic, and neurological). Analyses were repeated in comorbidity-free individuals. RESULTS: Multiple gait domains were associated with an increased risk of mortality, including Pace (hazard ratio (HR) per SD worse gait, adjusted for other domains: 1.34 [1.19-1.50]), Rhythm (HR: 1.12 [1.02-1.23]) and Phases (HR: 1.12 [1.03-1.21]). Similarly, a 0.1 m/s decrease in gait speed was associated with a 1.21 (1.15-1.27) times higher hazard of mortality (HR fully adjusted: 1.14 [1.08-1.20]). In a comorbidity-free subsample, the HR per 0.1 m/s decrease in gait speed was 1.25 (1.09-1.44). Cause-specific mortality analyses revealed an association between gait speed and multiple causes of death. CONCLUSIONS: Several gait domains were associated with mortality risk, including Pace which primarily represents gait speed. The association between gait speed and mortality persisted after an extensive adjustment for covariates, suggesting that gait is a marker for overall health.

Ethnic and Racial Disparities in HPV Vaccination Attitudes.

There are substantial racial and ethnic disparities in the vaccination rate for human papillomavirus (HPV), which helps protect against cervical cancer. Using data from the 2007 Health Information National Trends Survey, we explore differences between Whites, Blacks, Hispanics, and Asians in attitudes toward vaccinating adolescent girls for HPV. We use logistic regression models to explore whether racial/ethnic differences in attitudes toward HPV vaccinations are explained by HPV knowledge, demographic and socioeconomic status, and/or general distrust of the healthcare system. We include interactions to explore whether the effects of HPV knowledge and doctor distrust vary by racial/ethnic group. We find that greater HPV knowledge increases general willingness to vaccinate for all groups except Blacks. Our findings point to a need for additional research and design of culturally appropriate interventions that address barriers to vaccination.

Fiabilidad de los test de diagnóstico de disfunción sacroilíaca y de las pruebas exploratorias de la pelvis / Reliability of diagnostic tests of sacroiliac joint dysfunction and of the pelvic examination studies

Objetivos: El propósito de este estudio fue determinar el grado de fiabilidad interexaminadores e intertest de las pruebas de diagnóstico de disfunción sacroilíaca y de los signos exploratorios de la pelvis. Material y métodos: Dos examinadores exploraron por separado la articulación sacroilíaca en 30 sujetos universitarios (10 hombres; 20 mujeres; edad media ± desviación estándar 24,56 ± 5,2). Se realizaron 4 test de diagnóstico de disfunción sacroilíaca: test de flexión en bipedestación (TFB), test de flexión en sedestación (TFS), test de Gillet para ilíaco (TGI) y test de Gillet para sacro (TGS). Posteriormente, se completó la valoración con la exploración visual y palpatoria de la asimetría pélvica y de la dismetría de miembros inferiores. Resultados: Los índices de Kappa interexaminadores obtenidos para los test realizados -TFB, TFS, TGI, TGS- fueron de -0,082; -0,064; 0,262, y 0,170, respectivamente, y de -0,005 y -0,220 para la asimetría pélvica y para la dismetría de miembros inferiores. Para valorar la fiabilidad intertest, se emparejaron aquellas pruebas destinadas a la evaluación de la misma variable de disfunción sacroilíaca. Para el binomio TFB-TGI se obtuvieron valores de Kappa en cada examinador de -0,049 y 0,099, y en el caso de TFS-TGS, valores de 0,017 y 0,116. Conclusiones: Los resultados obtenidos muestran que no existe fiabilidad significativa entre examinadores en la exploración sacroilíaca y pélvica, así como tampoco entre los test destinados a evaluar el mismo tipo de variable de disfunción sacroilíaca

Objectives: The purpose of this study was to determine the degree of inter-examiner and inter-test reliability in the diagnostic tests of sacroiliac dysfunction and in the signs of pelvic exploration. Material and methods: Two examiners separately examined the sacroiliac joint in 30 university subjects (10 men, 20 women, mean age = 24.56, SD = 5.2). Four diagnostic sacroiliac dysfunction tests were performed: standing flexion test (StFT), sitting flexion test (SiFT) and Iliac Gillet test (IGT) and Sacral Gillet test (SGT). Assessment was completed with a visual examination and palpation of pelvic asymmetry and lower limb dysmetria. Results: The Kappa inter-examiner rates obtained for StFT was -0.082, for the SiFT was -0.064, for the IGT was 0.262, for the SGT was 0.170, for pelvic asymmetry was -0.005, and for lower limb dysmetria was -0.220. The tests aimed at the evaluation of the same variable of sacroiliac dysfunction were matched to evaluate the inter-test reliability. For the binomial StFT-IGT, Kappa values were obtained for each examiner of -0.049 and 0.099, and for the binomial SiFT-SGT, values of 0.017 and 0.116 were obtained. Conclusions: The results show that there is no significant reliability between examiners in the sacroiliac and pelvic examination and between the tests that evaluate the same variable of sacroiliac joint dysfunction

Actividades científicas del Servicio de Psiquiatría y Psicología Infantil y Juvenil de H. Infantil Universitario Niño Jesús / Scientific activities of Psychiatry and Child and Adolescent Psychology H. Infantil Universitario Niño Jesús

El Servicio de Psiquiatría Infantil, con más de 40 años de actividad, desarrolla varias líneas de actividad científica 8asistencial, docente y de investigación). Un tema de atención preferente son los trastornos psicosomáticos en la infancia y otro los trastornos de la alimentación (AU)

The Child Psychiatry Department, with more than 40 years of activity, develops several lines of scientific activity (care, teaching and research). A preferential care theme is psychosomatic disorders in childhood and another one is eating disorders (AU)

The changing relationship between education and marriage in the United States, 1940-2000.

In 1940, when gender specialization was high, there was a negative relationship between education and marriage for women. College-educated women were least likely to be currently married and most likely to be never married. Declines in specialization were accompanied by a transition in this relationship. By 2000, when gender specialization was low, there was a positive relationship between education and marriage for women. College-educated women were most likely to be currently married, in part because they were more likely to stay married or remarry after divorce or widowhood. This transition occurred earlier and more completely for black women than for white women. These changes suggest that the relationship between education and marriage is shaped in part by the gender-role context.

Incidencia de flebitis secundaria por catéter venoso de acceso periférico e impacto de un protocolo de manejo / Incidence of phlebitis due to peripherally inserted venous catheters: Impact of a catheter management protocol

Objetivo. Evaluar el impacto de un protocolo de manejo de catéteres sobre la incidencia de flebitis causadas por catéteres venosos de acceso periférico (FCVAP) y analizar los factores relacionados con su desarrollo en pacientes hospitalizados. Método. Desde septiembre de 2002 hasta diciembre de 2007 se incluyeron prospectivamente 3.978 episodios de canalizaciones venosas. Se implantó progresivamente un protocolo de manejo de catéteres, se determinó la incidencia de FCVAP y se analizaron las variables asociadas a su desarrollo. Resultados. La incidencia de FCVAP fue 4,8%; 4,3%; 3,6%; 2,5%; 1,3% y 1,8% desde 2002 hasta 2007 (p<0,001). Para vías periféricas, amiodarona (Odds ratio ajustada [ORA] 25,97; IC del 95%: 7,29–92,55, p=0,0001), cefotaxima (ORA 2,90; IC del 95%: 1,29–6,52, p=0,01) y el turno de colocación de la vía (ORA para turno de mañana vs. noche 0,60; IC del 95%: 0,35–1,02, p=0,063) se asociaron independientemente con FCVAP. Para las vías centrales de acceso periférico se asoció de manera independiente con FCVAP únicamente el antecedente de flebitis (ORA 3,24; IC del 95%: 1,05–9,98, p=0,04). Conclusiones. La aplicación de un protocolo de actuación disminuye la incidencia de FCVAP en pacientes hospitalizados. El antecedente de flebitis en las vías centrales de acceso periférico y la amiodarona o cefotaxima por vías de acceso periférico aumentan el riesgo de FCVAP. La colocación de vías periféricas en turnos de mañana se asocia con menor incidencia de FCVAP que en el turno de noche(AU)

Objective. To assess the impact on the incidence of PPIVC by implementing a catheter management protocol and to determine risk factors for PPIVC development in hospitalized patients. Method. A total of 3978 episodes of venous catheterization were prospectively included from September 2002 to December 2007. A catheter management protocol was implemented during this period of time. The incidence and variables associated to the occurrence of PPIVC were determined. Results. The incidence of PPIVC from 2002 to 2007 was 4.8%, 4.3%, 3.6%, 2.5%, 1.3% and 1.8% (p<0.001). Perfusion of amiodarone [adjusted OR (AOR) 25.97; 95% CI=7.29–92.55, p=0.0001] and cefotaxime (AOR 2.90; 95% CI=1.29–6.52, p=0.01) and the shift when the catheters were placed (AOR for morning vs. night shift 0.60; 95% CI=0.35–1.02, p=0.063) were independently associated to the development of PPIVC. A history of phlebitis was the only factor independently associated to phlebitis due to peripherally inserted central venous catheters (AOR 3.24; CI at 95% CI= 1.05–9.98, p=0.04). Conclusions. A catheter management protocol decreases the incidence of PPIVC in hospitalized patients. The risk of PPIVC increases for peripherally inserted central venous catheters when the patients have a history of phlebitis and for peripheral venous catheters when amiodarone or cefotaxime are infused. Catheterization of peripheral veins performed during morning shifts is associated with a lower incidence of PPIVC when compared with night shift catheterizations(AU)

[Incidence of phlebitis due to peripherally inserted venous catheters: impact of a catheter management protocol]. / Incidencia de flebitis secundaria por catéter venoso de acceso periférico e impacto de un protocolo de manejo.

OBJECTIVE: To assess the impact on the incidence of PPIVC by implementing a catheter management protocol and to determine risk factors for PPIVC development in hospitalized patients. METHOD: A total of 3978 episodes of venous catheterization were prospectively included from September 2002 to December 2007. A catheter management protocol was implemented during this period of time. The incidence and variables associated to the occurrence of PPIVC were determined. RESULTS: The incidence of PPIVC from 2002 to 2007 was 4.8%, 4.3%, 3.6%, 2.5%, 1.3% and 1.8% (p<0.001). Perfusion of amiodarone [adjusted OR (AOR) 25.97; 95% CI=7.29-92.55, p=0.0001] and cefotaxime (AOR 2.90; 95% CI=1.29-6.52, p=0.01) and the shift when the catheters were placed (AOR for morning vs. night shift 0.60; 95% CI=0.35-1.02, p=0.063) were independently associated to the development of PPIVC. A history of phlebitis was the only factor independently associated to phlebitis due to peripherally inserted central venous catheters (AOR 3.24; CI at 95% CI= 1.05-9.98, p=0.04). CONCLUSIONS: A catheter management protocol decreases the incidence of PPIVC in hospitalized patients. The risk of PPIVC increases for peripherally inserted central venous catheters when the patients have a history of phlebitis and for peripheral venous catheters when amiodarone or cefotaxime are infused. Catheterization of peripheral veins performed during morning shifts is associated with a lower incidence of PPIVC when compared with night shift catheterizations.

Emigration and Schooling among Second-Generation Mexican-American Children.

In this Research Note, we investigate the prevalence and patterns of second-generation Mexican-American children's migration to and return from Mexico during childhood and consider the consequences of this migration for their schooling. Around one in ten second-generation Mexican-American children live in Mexico for some of their childhood. Strong patterns of return to the U.S. through childhood argue for their being considered as part of the Mexican-American second generation even when in Mexico. Their rates of school enrollment in Mexico are much lower than for second-generation Mexican-American children remaining in the U.S. and cannot be explained by their weakly negative selection into emigration. We conclude that country of residence is a far more important determinant of schooling outcome than is migrant status in that country.

Less help for mother: the decline in coresidential female support for the mothers of young children, 1880-2000.

Research on changes in women's parenting has focused primarily on their increased likelihood of combining parenthood with paid employment, exploring the pressures that result from this "second shift" or "double burden." This article complements this approach by focusing instead on the likely reduction in the help that mothers of small children have received as declines both in fertility and the coresidence of nonnuclear adults have reduced the number of other women in the household. Using national census data for the period 1880 to 2000, we show a substantial decline in the presence and availability of other females in the household, as fewer are coresident and more of those who are coresident are employed or in school. Although all mothers experience this decline, it is most acute for mothers working for pay in nonagricultural activities.

Slow release of two antibiotics of veterinary interest from PVA hydrogels.

Two antibiotics, tylosin tartrate and oxytetracycline hydrochloride, were entrapped in poly(vinyl alcohol) (PVA) hydrogels (MW 31,000-50,000) by a cryogen procedure obtaining a controlled release system suitable for veterinary application. It was found that at a low drug matrix loading (10 mg/ml), the in vitro release rate of both antibiotics could be reduced by a previous freeze drying of the gel, while no reduction in drug rate took place in heavily loaded matrices (300 mg/ml). When PVA hydrogels containing tylosin were administered to rats per os the drug could not be detected in the blood, but it was found in organs,: liver, kidneys, and muscles, for up to 120 h. On the other hand, when the same amount of drug was administered orally as powder, no appreciable organ accumulation was detected, while the drug was found in faeces and urine. These data show that PVA hydrogels can be a suitable slow release system for tylosin administration. Oxytetracycline could also be quantitatively entrapped and released from PVA hydrogels, but once administered per os to rats, it was not detected in blood or organs.

Collection, storage, and filtration of in vivo study samples using 96-well filter plates to facilitate automated sample preparation and LC/MS/MS analysis.

The benefits of high-throughput bioanalysis within the pharmaceutical industry are well established. One of the most significant bottlenecks in bioanalysis is transferring in vivo-generated study samples from their collection tubes during sample preparation and extraction. In most cases, the plasma samples must be stored frozen prior to analysis, and the freeze/thaw (F/T) process introduces thrombin clots that are capable of plugging pipets and automated liquid-transfer systems. A new approach to dealing with this problem involves the use of Ansys Captiva 96-well 20-microm polypropylene filter plates to collect, store frozen, and filter plasma samples prior to bioanalysis. The samples are collected from the test subjects, and the corresponding plasma samples are placed directly into the wells of the filter plate. Two Duoseal (patent pending) covers are used to seal the top and bottom of the plate, and the plate is stored at down to -70 degrees C. Prior to sample analysis, the seals are removed and the plate is placed in a 96-well SPE manifold. As the plasma thaws, it passes (by gravity or mild vacuum) through the polypropylene filter into a 96-well collection plate. A multichannel pipet or automated liquid-transfer system is used to transfer sample aliquots without fear of plugging. A significant advantage of this approach is that, unlike other methods, issues related to incomplete pipetting are virtually eliminated. The entire process is rapid since thawing and filtering take place simultaneously, and if a second F/T cycle is required for reanalysis, it is not necessary to refilter the samples (additional clotting was not observed after three F/T cycles). This technique was tested using monkey, rat, and dog plasma and sodium heparin and EDTA anticoagulants. To assess the possibility of nonspecific binding to the polypropylene filter, a variety of drug candidates from diverse drug classes were studied. Validation data generated for two Lilly compounds from distinct classes, before and after filtering, are presented in this paper as practical examples of this technique. While LC/MS/MS is the primary method of bioanalysis in our laboratory, the technique presented in this paper is applicable to other forms of detection as well.

Determination of olanzapine in human blood by liquid chromatography-tandem mass spectrometry.

A liquid chromatographic-tandem mass spectrometric (LC-MS-MS) assay was developed and validated to quantitatively determine olanzapine (OLZ) concentrations in human blood. Liquid-liquid extraction, using n-butanol:cyclohexane (3:47, v/v), was used to isolate OLZ and its internal standard, LY170158, from the biological matrix. Chromatographic resolution of OLZ from endogenous interferences and known metabolites was accomplished with a MetaChem Monochrom HPLC column (4.6 x 150 mm, d(p) 5 microm). Detection occurred using a Perkin-Elmer Sciex API III Plus triple quadrupole mass spectrometer using positive ion APCI and multiple reaction monitoring (MRM). The linear dynamic range was from 5 to 500 ng ml(-1) based on a 0.25-ml aliquot of human blood. The inter-day precision (%RSD) and accuracy (%RE) ranged from 3.65 to 10.64 and from -2.14 to 3.07, respectively. Modifications to an existing assay for the determination of OLZ in human plasma were necessary. A different structural analog was used as the internal standard due to instability observed for the original analog when using human blood as the matrix. A second modification was the addition of the anti-oxidant sodium ascorbate to inhibit degradation of OLZ in human blood, as has been noted by other investigators. Upon fortification of human blood with sodium ascorbate (final concentration, 0.33 mM), OLZ was found to be stable for at least 1 week at -70 degrees C as well as through two freeze-thaw cycles. This assay, which will be used to investigate the distribution of OLZ in human blood, grants insight into the proper sample handling conditions needed to perform valid determinations of OLZ in human blood.

Clinical characteristics and outcome of a cohort of 101 patients with hepatocellular carcinoma.

AIM: To conduct a cohort study of 101 patients with hepatocellular carcinoma (HCC) presenting to a tertiary care medical referral center in Germany between 1997 and 1999. METHODS AND RESULTS: Data were retrospectively analyzed by chart review. In 95 cases (72 males and 23 females) sufficient data were available for analysis. Twenty five (29%) of 85 patients were HBsAg or anti HBc positive, 21/85 (25%) were anti HCV positive, and 6/85 (7%) were positive for both HBV and HCV-markers. Age was significantly lower in HBV positive patients than in the other two groups. Thirty one (34%) of 90 patients had histories of alcohol abuse. In 79/94 (84%) patients, cirrhosis was diagnosed. Of these cirrhotic patients, 29/79 (37%) belonged to Child Pugh's group (CHILD) A, 32/79 (40%) to CHILD B, and 18/79 (23%) to CHILD C. AFP was elevated in 61/91 (67%) patients. A single tumor nodule was found in 38/94 (40%), more than one nodule in 31/94 (34%), and 25/94 (26%) had a diffusely infiltrating tumor, i.e. the tumor margins could not be seen on imaging procedures. Portal vein thrombosis was present in 19/94 (20%). Imaging data consistent with lymph node metastases were found in 10/92 (11%), while distant metastases were found in 8/93 (9%). According to Okuda 28/94 (30%) were grouped to stage I, 53/94 (56%) were grouped to stage II, and 13/94 (14%) were grouped to stage II. Survival data were available for 83 patients. The Kaplan-Meier estimate for median survival was 8 4 months. Factors influencing survival were the Okuda score, the presence of portal vein thrombosis, and the presence of ascites. The presence of non complicated liver cirrhosis by itself, distant metastases, or infection with hepatitis viruses did not influence survival. AFP positivity by itself did not influence survival, though patients with an AFP value greater than 100 microg/L did experience shortened survival. Treatment besides tamoxifen or supportive care was associated with prolonged survival. The influence of therapy on survival was most pronounced in Okuda stage II patients. There was longer survival in those Okuda stage II patients who were treated with percutaneous ethanol injection. CONCLUSION: Even in a low incidence area such as Germany, the majority of HCC is caused by viral hepatitis and therefore potentially preventable. Reflecting the high proportion of advanced stage tumors in our patients, the median survival was poor. Patients who received active therapy had a longer survival.

Conducta sexual de riesgo en drogodependencias / Risky sexual behavior in drug abuse

Introducción: La alteración del comportamiento, una afectividad negativa y el abuso sexual y/o físico en la infancia están relacionados con el abuso de sustancias y la conducta sexual de riesgo. Material y métodos: Analizamos la conducta sexual de un grupo de drogodependientes (n = 61) y correlacionamos con las características de personalidad. Se aplicaron análisis de variancia (ANOVA), test de la *2 y regresión lineal como procedimientos estadísticos. Resultados: Los rasgos de personalidad paranoide, esquizotípico y antisocial se correlacionaron con un inicio precoz de la conducta sexual. Hemos encontrado diferencias significativas entre la edad de inicio de la primera experiencia sexual y el subtipo de drogodependencia (F = 3,801; p < 0,05). Conclusión: Hay una relación entre el uso de sustancias tóxicas, la conducta sexual de riesgo y las características de la personalidad del individuo. Los resultados apuntan a que, entre la población drogodependiente, los rasgos de personalidad pueden ser un factor de riesgo y desencadenar el desarrollo del abuso de sustancias y la conducta sexual de riesgo (AU)

Tratamiento de la colédocolitiasis con globos extractores endoscópicos / Common bile duct stone straction with retrieval ballons

La colédocolitiasis tiene una incidencia del 10 al 20 por ciento en quienes padecen colelitiasis. Existen varias técnicas endoscópicas y quirúrgicas para su tratamiento. Utilizar globos extractores ha reportado buenos resultados con mínima morbilidad y mortalidad. Se describen los resultados del tratamiento de la colédocolitiasis con globos extractores endoscópicos. Se realizó un estudio prospectivo, clínico y longitudinal, que incluyó a todos los pacientes con colédocolitiasis, a los que se les realizó esfinterotomía endoscópica y exploración de la vía biliar común con globos. Se estudió sexo, edad, tamaño de los cálculos, resultados en la extracción y complicaciones. De Enero de 1997 a junio de 1998 diagnosticamos 52 casos de colédocolitiasis, 29 (56 por ciento) del sexo femenino, 23 (44 por ciento) del sexo masculino, con edad media de 59.9 por ciento años. 27 (51 por ciento) de los casos fueron sólo diagnósticados y trasladados a su unidad de referencia para recibir tratamiento. 25 (49 por ciento) se sometieron a esfinterotomía. De los cuales tres (12 por ciento) se resolvieron por cirugía, seis (24 por ciento) se resolvieron con esfinterotomía simple, cuatro (16 por ciento) se perdieron al seguimiento y 12 (48 por ciento) se resolvieron con la ayuda del globo. El diámetro de los litos extraídos con globo fue de 5 hasta 15mm. En un caso (lito de 20mm) no fue posible extraerlo. No hubo complicaciones relacionadas al uso del globo. El uso de globos extractores endoscópicos es eficaz en la extracción de litos menores de 15mm y con nula morbimortalidad en relación a su uso

Determination of LY295501 in human plasma by reverse phase HPLC with UV detection.

A high performance liquid chromatographic (HPLC) assay was developed and validated for the quantitative determination of LY295501 in human plasma. A structural analog, LY186641, was selected as the internal standard. The samples were processed by protein precipitation with acetonitrile followed by concentration of the supernatants and reconstitution. Chromatographic resolution of LY295501 from endogenous plasma components was accomplished with a Waters Novapak C18 HPLC column (3.9 x 150 mm, d(p) 4 mm). Detection was by absorbance at 260 nm. The linear dynamic range was from 5 to 400 microg ml(-1) of human plasma using a 0.25 ml aliquot. The inter-day precision (%RSD) and accuracy (%RE) in plasma ranged from 2.4 to 4.7, and -4.9 to 1.4, respectively. This assay is both simple and rapid, and has been used to successfully analyze over 1500 samples from human clinical trials.

Determination of olanzapine in human plasma and serum by liquid chromatography/tandem mass spectrometry.

A liquid chromatographic/tandem mass spectrometric (LC/MS/MS) assay was developed for the quantitative determination of olanzapine (LY170053, OLZ) in human plasma and serum. Bond Elut C2 solid-phase extraction cartridges (single cartridge or 96-well format), in conjunction with a positive pressure manifold, were used to extract OLZ and its internal standard, LY170222, from the biological matrix. Chromatographic resolution of OLZ from endogenous plasma interferences and its metabolites was accomplished with a MetaChem monochrom HPLC (4.6 x 150 mm, dp 5 microns). Detection was effected with a Perkin-Elmer SCIEX API III Plus mass spectrometer using positive ion atmospheric pressure chemical ionization and a multiple reaction monitoring protocol. The linear dynamic range was from 250 pg ml-1 to 50 ng ml-1 of human plasma/serum using a 0.5 ml aliquot. The inter-day precision (relative standard deviation) and accuracy (relative error) in plasma ranged from 6.26 to 7.66% and from -3.54 to 7.52%, respectively. The intra-day precision and accuracy in serum ranged from 3.46 to 8.76% and from -8.06 to 12.46%, respectively. This assay is sensitive and selective, and will be used to support both human clinical and toxicological analyses. Furthermore, using the 96-well solid-phase extraction format, sample preparation can be easily automated.

Determination of LY355703 in dog and mouse plasma by positive ion liquid chromatography/tandem mass spectrometry with atmospheric pressure chemical ionization.

A liquid chromatographic/mass spectrometric assay was developed for the determination of LY355703, a potent anti-tumor drug, in mouse and dog plasma. Empore (3M) C18 solid-phase extraction cartridges were used for sample preparation in conjunction with a positive pressure manifold. Chromatographic separation was obtained with a cyano high-performance liquid chromatographic column and detection was conducted using atmospheric pressure chemical ionization tandem mass spectrometry in the selected reaction monitoring mode. A structural analog, compound LY354504, was used as the internal standard. The assay was validated for the determination of LY355703 in mouse (ICR and NuNu) and dog (beagle) plasma. The lower and upper limits of quantitation were 2.1 and 527 ng ml-1, respectively, using a 0.1 ml plasma aliquot. The signal-to-noise ratio of a typical 2.1 ng ml-1 standard was approximately 40:1. The inter-day precision (relative standard deviation) and accuracy (relative error) derived from the analysis of validation samples at five concentrations ranged from 2.7 to 7.6% and from 4.8 to 4.5%, respectively. Throughput is approximately one sample every 3 min. This assay is simple, sensitive, accurate, precise and is being used to support toxicokinetic studies in dog and mouse.

An automated multidimensional screening approach for rapid method development in high performance liquid chromatography.

Despite enormous advancements in the area of high performance liquid chromatography (HPLC) in recent years, method development remains a major challenge. This is primarily due to the unknown nature of the matrix material which sometimes is difficult to characterize (e.g. biological matrices). To improve the efficiency of method development a multidimensional screening approach was presented. This approach was based on two major steps: (1) a matrix spiked with drug was eluted from a large number of columns, each under different mobile phase compositions, to provide the preliminary selectivity-separation information; (2) this information was then used to compose column switching pairs (each pair consisted of a preparatory column followed by an analytical column) and the elution profile was evaluated to determine the suitable clean up and quantitation conditions. An example was provided using ethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate (EEDA), an X-ray enhancement agent, in human plasma. Since the HPLC system was fully automated the data generation time, and consequently the method development time, can be significantly reduced.