Molecular mechanism of renal tubular secretion of the antimalarial drug chloroquine

The antimalarial drug chloroquine is eliminated to a significant extent by renal tubular secretion. The molecular mechanism of renal chloroquine secretion remains unknown. We hypothesized that organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1), localized in the basolateral and luminal membranes of proximal tubule cells, respectively, are involved in chloroquine transport. The interaction of chloroquine with both transporters was investigated using single-transfected human embryonic kidney 293 (HEK293)-MATE1 cells in uptake experiments and single-transfected Madin-Darby canine kidney II (MDCK)-OCT2 and MDCK-MATE1 cells as well as double-transfected MDCK-OCT2-MATE1 cells grown as polarized monolayers on transwell filters. In HEK293-MATE1 cells, chloroquine competitively inhibited MATE1-mediated metformin uptake (K(i) = 2.8 μM). Cellular accumulation of chloroquine was significantly lower (P < 0.001) and transcellular chloroquine transport was significantly increased (P < 0.001) in MDCK-MATE1 and MDCK-OCT2-MATE1 cells compared to vector control cells after basal addition of chloroquine (0.1 to 10 μM). In contrast, no difference in cellular accumulation or transcellular transport of chloroquine was observed between MDCK-OCT2 and vector control cells. In line with an oppositely directed proton gradient acting as a driving force for MATE1, basal-to-apical transport of chloroquine by MDCK-OCT2-MATE1 cells increased with decreasing apical pH from 7.8 to 6.0. Transcellular transport of chloroquine by MDCK-OCT2-MATE1 cells was inhibited by cimetidine, trimethoprim, and amitriptyline. Our data demonstrate that chloroquine is a substrate and potent competitive inhibitor of MATE1, whereas OCT2 seems to play no role in chloroquine uptake. Concomitantly administered MATE1 inhibitors are likely to modify the renal secretion of chloroquine.     

Advanced characterization and refinement of poly N-butyl cyanoacrylate microbubbles for ultrasound imaging

We aimed to develop and characterize poly n-butylcyanoacrylate (PBCA) microbubbles (MBs) with a narrow size distribution. MBs were synthesized by established emulsion polymerization techniques, size-isolated by centrifugation and functionalized for molecular imaging by coating their surface with streptavidin. The physical and acoustic properties of the parent solution, different-size isolated populations and functionalized MBs were measured and compared. As expected from negative zeta potentials at pH 7, cryo scanning electron microscopy showed no aggregates. In phantoms MBs were destructible at high mechanical indices and showed a frequency-dependent attenuation and backscattering. The MBs were stable in solution for more than 14 weeks and could be lyophilized without major damage. However, for injection, small needle diameters and high injection rates are shown to be critical because both lead to MB destruction. In summary, when being handled correctly, size-isolated PBCA MBs are promising candidates for preclinical functional and molecular ultrasound imaging.     

The effects of therapeutic instrumental music performance on endurance level, self-perceived fatigue level, and self-perceived exertion of inpatients in physical rehabilitation

The present study investigated the effects of a Neurologic Music Therapy (NMT) sensory-motor rehabilitation technique, Therapeutic Instrumental Music Performance (TIMP) as compared to Traditional Occupational Therapy (TOT), on endurance, self-perceived fatigue, and self-perceived exertion of 35 hospitalized patients in physical rehabilitation. The present study attempted to examine whether an active musical experience such as TIMP with musical cueing (i.e., rhythmic auditory cueing) during physical exercises influences one's perception of pain, fatigue, and exertion. All participants were diagnosed with a neurologic disorder or had recently undergone orthopedic surgery. Investigators measured the effects of TOT and TIMP during upper extremity exercise of the less affected or stronger upper extremity. Results showed no significant difference on endurance measures between the 2 treatment conditions (TIMP and TOT). Statistically significant differences were found between TIMP and TOT when measuring their effects on perceived exertion and perceived fatigue. TIMP resulted in significantly less perception of fatigue and exertion levels than TOT. TIMP can be used foran effective sensory-motor rehabilitation technique to decrease perceived exertion and fatigue level of inpatients in physical rehabilitation.     

Radiopaque iodinated copolymeric nanoparticles for X-ray imaging applications

Recently we described iodinated homopolymeric radiopaque nanoparticles of 28.9 ± 6.3 nm dry diameter synthesized by emulsion polymerization of 2-methacryloyloxyethyl(2,3,5-triiodobenzoate) (MAOETIB). The nanoparticle aqueous dispersion, however, was not stable and tended to agglomerate, particularly at weight concentration of dispersed nanoparticles above 0.3%. The agglomeration rate increases as the concentration of nanoparticles in aqueous phase rises and prevents the potential in vivo use as contrast agent for medical X-ray imaging. Here we describe efforts to overcome this limitation by synthesis of iodinated copolymeric nanoparticles of 25.5 ± 4.2 nm dry diameter, by emulsion copolymerization of the monomer, MAOETIB, with a low concentration of glycidyl methacrylate (GMA). The surface of resulting copolymeric nanoparticles is far more hydrophilic than that of polyMAOETIB (PMAOETIB) nanoparticles. Therefore, P(MAOETIB-GMA) nanoparticles are significantly more stable against agglomeration in aqueous continuous phase. After intravenous injection of P(MAOETIB-GMA) nanoparticles in rats and mice (including those with a liver cancer model) CT-imaging revealed a significant enhanced visibility of the blood pool for 30 min after injection. Later, lymph nodes, liver and spleen strongly enhanced due to nanoparticle uptake by the reticuloendothelial system. This favorably enabled the differentiation of cancerous from healthy liver tissue and suggests our particles for tumor imaging in liver and lymph nodes.     

Challenging issues in surgical critical care, trauma, and acute care surgery: a report from the Critical Care Committee of the American Association for the Surgery of Trauma

Critical care workforce analyses estimate a 35% shortage of intensivists by 2020 as a result of the aging population and the growing demand for greater utilization of intensivists. Surgical critical care in the U.S. is particularly challenged by a significant shortfall of surgical intensivists, with only 2586 surgeons currently certified in surgical critical care by the American Board of Surgery, and even fewer surgeons (1204) recertified in surgical critical care as of 2009. Surgical critical care fellows (160 in 2009) represent only 7.6% of all critical care trainees (2109 in 2009), with the largest number of critical care fellowship positions in internal medicine (1472, 69.8%). Traditional trauma fellowships have now transitioned into Surgical Critical Care or Acute Care Surgery (trauma, surgical critical care, emergency surgery) fellowships. Since adult critical care services are a large, expensive part of U.S. healthcare and workforce shortages continue to impact our healthcare system, recommendations for regionalization of critical care services in the U.S. is considered. The Critical Care Committee of the AAST has compiled national data regarding these important issues that face us in surgical critical care, trauma and acute care surgery, and discuss potential solutions for these issues.     

Discrimination and Mental Health�CRelated Service Use in a National Study of Asian Americans

Objectives. We examined the association between perceived discrimination and use of mental health services among a national sample of Asian Americans.Methods. Our data came from the National Latino and Asian American Study, the first national survey of Asian Americans. Our sample included 600 Chinese, 508 Filipinos, 520 Vietnamese, and 467 other Asians (n=2095). We used logistic regression to examine the association between discrimination and formal and informal service use and the interactive effect of discrimination and English language proficiency.Results. Perceived discrimination was associated with more use of informal services, but not with less use of formal services. Additionally, higher levels of perceived discrimination combined with lower English proficiency were associated with more use of informal services.Conclusions. The effect of perceived discrimination and language proficiency on service use indicates a need for more bilingual services and more collaborations between formal service systems and community resources.Asian Americans are one of the fastest-growing racial groups in the United States and also one of the most understudied.¹ Recent data from the National Latino and Asian American Study (NLAAS), the first national study of Asian Americans, show that they have a sizeable burden of mental illness, with a 17.30% overall lifetime rate of any psychiatric disorder and a 9.19% 12-month rate.² At the same time, low utilization rates of mental health services by Asian Americans are well documented.^3–7 Nationally, Asian Americans/Pacific Islanders are one third as likely as Whites to use available mental health services.³ Low use rates have been reported for emergency and inpatient services^4–6 as well as outpatient services.^4,7,8In the United States over a 12-month period, only 3.1% of Asian Americans use specialty mental health services, compared with 5.59% of African Americans, 5.94% of Caribbean Blacks, 4.44% of Mexicans, 5.55% of Cubans, and 8.8% of the general population.^9–11 In a study by Abe-Kim et al., only 8.6% of Asian Americans sought any mental health services compared with 17.9% of the general population.¹² Kimerling and Baumrind found that Asian American women were less likely than White women to report perceived need for mental health services, even when accounting for frequency of mental distress. Among women who did perceive a need to seek mental health services, Asian American women were less likely to use services even when health insurance was controlled.¹³Despite low use rates for formal services, research has established that Asian Americans are more likely to use informal support systems for help with mental health issues as to use formal services. Data from the Chinese American Epidemiology Study (CAPES) found that of Chinese Americans experiencing mental health problems in the past 6 months, fewer than 6% saw mental health professionals, 4% saw medical doctors, and 8% saw a minister or priest.¹⁴ A study using data from the Filipino American Community Epidemiological Study (FACES) found that of the 25% of Filipino Americans who used any type of care in the past 12 months, 17% went to the lay system (a friend or relative), 7% used medical doctors, 4% saw a clergy member or indigenous healer, and only 3% saw a mental health specialist.¹⁵ In a study using data from the CAPES, negative attitudes toward formal mental health services were correlated with more informal service use.¹⁶Discrimination is a major stressor experienced by American ethnic groups.¹⁷ Experiences with discrimination shape one''s appraisal of the world and hinder the ability to control one''s environment, thus reinforcing secondary social status and internalizing negative stereotypes.^18–20 There are many well-documented examples of policies and practices that have systematically discriminated against Asian Americans throughout US history.^21,22 Contemporary forms of discrimination include the model minority stereotype (which highlights the aggregation of success indicators while masking the challenges of immigrant populations), hate crimes, racial profiling, and employment discrimination.^23–28 Increasingly, researchers have demonstrated an association between racial discrimination and mental disorders among Asian Americans.^29–38Discrimination also may be a barrier to help seeking among Asian Americans. Indeed, research has found that perceived discrimination is significantly correlated with underuse of mental health care among Asian Americans.³⁹ Further, it is possible that discrimination may interact with other barriers to treatment. For example, Spencer and Chen found that discrimination based on speaking a different language or speaking with an accent was associated with use of more informal services among Chinese Americans.¹⁶ Uba cites racial and cultural biases—such as culturally inappropriate services, differential receipt of services, a history of institutional discrimination, and a suspicion of the service delivery system—as critical barriers to service use for Asian Americans.⁴⁰Other immigrant-related factors are important correlates of service use. For example, rates of use were found to vary by generation: US-born, third-generation or later Asian Americans had higher rates of use of specialty mental health services than did first- or second-generation individuals.¹² Other studies that have examined correlates of service use among Asian Americans have identified cultural factors, such as shame and loss of face^41–44; lack of ethnic match between provider and client, bilingual providers, knowledge of available services, and insurance coverage; socioeconomic factors; and neighborhood poverty.^{12,25,45–49} Language is a particularly important correlate of service use for Asian Americans: those who have poor English skills may be less likely to use mental health services. For example, a study of East Asian immigrants found that English fluency was positively related to willingness to use psychological services.⁵⁰We examined the association between perceived discrimination and service use, controlling for demographic characteristics, poverty status, immigration status, and barriers to services related to access and attitudes, in a national representative sample of Asian Americans using data from the NLAAS. Specifically, we examined rates of formal and informal service use. We hypothesized that discrimination would be associated with less use of formal services and more use of informal services. We also hypothesized that individuals with low English proficiency in addition to higher rates of self-reported discrimination would be less likely to use formal services and more likely to use informal services for mental health problems.