In vivo serotonin 1A receptor hippocampal binding potential in depression and reported childhood adversity

Abstract Background Reported childhood adversity (CA) is associated with development of depression in adulthood and predicts a more severe course of illness. Although elevated serotonin 1A receptor (5-HT1AR) binding potential, especially in the raphe nuclei, has been shown to be a trait associated with major depression, we did not replicate this finding in an independent sample using the partial agonist positron emission tomography tracer [11C]CUMI-101. Evidence suggests that CA can induce long-lasting changes in expression of 5-HT1AR, and thus, a history of CA may explain the disparate findings. Methods Following up on our initial report, 28 unmedicated participants in a current depressive episode (bipolar n = 16, unipolar n = 12) and 19 non-depressed healthy volunteers (HVs) underwent [11C]CUMI-101 imaging to quantify 5-HT1AR binding potential. Participants in a depressive episode were stratified into mild/moderate and severe CA groups via the Childhood Trauma Questionnaire. We hypothesized higher hippocampal and raphe nuclei 5-HT1AR with severe CA compared with mild/moderate CA and HVs. Results There was a group-by-region effect (p = 0.011) when considering HV, depressive episode mild/moderate CA, and depressive episode severe CA groups, driven by significantly higher hippocampal 5-HT1AR binding potential in participants in a depressive episode with severe CA relative to HVs (p = 0.019). Contrary to our hypothesis, no significant binding potential differences were detected in the raphe nuclei (p -value s > 0.05). Conclusions With replication in larger samples, elevated hippocampal 5-HT1AR binding potential may serve as a promising biomarker through which to investigate the neurobiological link between CA and depression

Análisis de la utilización de antihistamínicos sistémicos según criterios de calidad

Objetivos: El objetivo primario del presente trabajo es analizar el uso racional de los antihistamínicos H1 en nuestro entorno. Para ello, se pretende valorar la utilización bajo prescripción médica de antihistamínicos H1 sistémicos en pacientes con alergias, analizando si la selección se adecua a las guías clínicas, los fármacos asociados y la percepción de efectividad del tratamiento con distintos antihistamínicos, así como a los indicadores de calidad de prescripción. Métodos: Estudio observacional y transversal de 94 encuestas realizadas a pacientes (EP) de diferentes ámbitos asistenciales en tratamiento con antihistamínicos H1 sistémicos, que se complementa con el análisis de ventas de antihistamínicos en farmacias (VFC) mediante un estudio observacional y retrospectivo de las dispensaciones en 4 farmacias comunitarias de la Comunidad Valenciana (datos de 2010). Resultados: Ebastina es el fármaco más prescrito (34% VFC y 27% EP), destacando la venta de preparados bucodispersables (flas) que suponen la mitad del gasto en este fármaco. Cetirizina es el segundo fármaco en cuota de mercado (16% VFC y 18% EP). Los nuevos derivados, desloratadina y levocetirizina, representan el 14 y el 12% de las VFC, y el 10 y el 17% de las EP, respectivamente, valores superiores al fármaco de primera elección, loratadina (7% VFC y 4% EP). El indicador de prescripción de loratadina + cetirizina (fármacos recomendados por diversas guías terapéuticas) es de 0,2, valor inferior al mínimo deseable (0,4) según criterios de calidad. Conclusiones: La prescripción de antihistamínicos sistémicos no sigue criterios de selección racional. La escasa utilización de loratadina y cetirizina incrementa el gasto farmacéutico, ya que su coste medio por envase (3,20 euros) es inferior al del resto de antihistamínicos (10,20 euros). Existe un campo de mejora para controlar el gasto farmacéutico mediante la promoción del uso de los antihistamínicos más eficientes

Análisis de la utilización de antihistamínicos sistémicos según criterios de calidad

Objetivos: El objetivo primario del presente trabajo es analizar el uso racional de los antihistamínicos H1 en nuestro entorno. Para ello, se pretende valorar la utilización bajo prescripción médica de antihistamínicos H1 sistémicos en pacientes con alergias, analizando si la selección se adecua a las guías clínicas, los fármacos asociados y la percepción de efectividad del tratamiento con distintos antihistamínicos, así como a los indicadores de calidad de prescripción. Métodos: Estudio observacional y transversal de 94 encuestas realizadas a pacientes (EP) de diferentes ámbitos asistenciales en tratamiento con antihistamínicos H1 sistémicos, que se complementa con el análisis de ventas de antihistamínicos en farmacias (VFC) mediante un estudio observacional y retrospectivo de las dispensaciones en 4 farmacias comunitarias de la Comunidad Valenciana (datos de 2010). Resultados: Ebastina es el fármaco más prescrito (34% VFC y 27% EP), destacando la venta de preparados bucodispersables (flas) que suponen la mitad del gasto en este fármaco. Cetirizina es el segundo fármaco en cuota de mercado (16% VFC y 18% EP). Los nuevos derivados, desloratadina y levocetirizina, representan el 14 y el 12% de las VFC, y el 10 y el 17% de las EP, respectivamente, valores superiores al fármaco de primera elección, loratadina (7% VFC y 4% EP). El indicador de prescripción de loratadina + cetirizina (fármacos recomendados por diversas guías terapéuticas) es de 0,2, valor inferior al mínimo deseable (0,4) según criterios de calidad. Conclusiones: La prescripción de antihistamínicos sistémicos no sigue criterios de selección racional. La escasa utilización de loratadina y cetirizina incrementa el gasto farmacéutico, ya que su coste medio por envase (3,20 euros) es inferior al del resto de antihistamínicos (10,20 euros). Existe un campo de mejora para controlar el gasto farmacéutico mediante la promoción del uso de los antihistamínicos más eficientes

Challenges in Using Cultured Primary Rodent Hepatocytes or Cell Lines to Study Hepatic HDL Receptor SR-BI Regulation by Its Cytoplasmic Adaptor PDZK1

Background: PDZK1 is a four PDZ-domain containing cytoplasmic protein that binds to a variety of membrane proteins via their C-termini and can influence the abundance, localization and/or function of its target proteins. One of these targets in hepatocytes in vivo is the HDL receptor SR-BI. Normal hepatic expression of SR-BI protein requires PDZK1 - <5% of normal hepatic SR-BI is seen in the livers of PDZK1 knockout mice. Progress has been made in identifying features of PDZK1 required to control hepatic SR-BI in vivo using hepatic expression of wild-type and mutant forms of PDZK1 in wild-type and PDZK1 KO transgenic mice. Such in vivo studies are time consuming and expensive, and cannot readily be used to explore many features of the underlying molecular and cellular mechanisms. Methodology/Principal Findings: Here we have explored the potential to use either primary rodent hepatocytes in culture using 2D collagen gels with newly developed optimized conditions or PDZK1/SR-BI co-transfected cultured cell lines (COS, HEK293) for such studies. SR-BI and PDZK1 protein and mRNA expression levels fell rapidly in primary hepatocyte cultures, indicating this system does not adequately mimic hepatocytes in vivo for analysis of the PDZK1 dependence of SR-BI. Although PDZK1 did alter SR-BI protein expression in the cell lines, its influence was independent of SR-BI’s C-terminus, and thus is not likely to occur via the same mechanism as that which occurs in hepatocytes in vivo. Conclusions/Significance: Caution must be exercised in using primary hepatocytes or cultured cell lines when studying the mechanism underlying the regulation of hepatic SR-BI by PDZK1. It may be possible to use SR-BI and PDZK1 expression as sensitive markers for the in vivo-like state of hepatocytes to further improve primary hepatocyte cell culture conditions.National Institutes of Health (U.S.) (Grant HL052212)National Institutes of Health (U.S.) (Grant HL066105)National Institutes of Health (U.S.) (Grant ES015241)National Institutes of Health (U.S.) (Grant GM068762

IFNγ Response to Mycobacterium tuberculosis, Risk of Infection and Disease in Household Contacts of Tuberculosis Patients in Colombia

OBJECTIVES: Household contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNgamma produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNgamma levels in HHCs correlate with tuberculosis development. METHODS: A cohort of 2060 HHCs was followed for 2-3 years after exposure to a tuberculosis case. Besides TST, IFNgamma responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination. RESULTS: Using TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNgamma response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNgamma responders to CFP-10 (HR 1.82 95% CI 0.79-4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNgamma producers was observed (trend Log rank p = 0.007). DISCUSSION: CFP-10-induced IFNgamma production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis incidence amongst children supports administration of chemoprophylaxis to child contacts regardless of BCG vaccination

HIF-α Effects on c-Myc Distinguish Two Subtypes of Sporadic VHL-Deficient Clear Cell Renal Carcinoma

VHL tumor suppressor loss results in hypoxia inducible factor-alpha (HIF-α) stabilization, and occurs in 70% of sporadic clear cell renal carcinomas (ccRCCs). To determine whether opposing influences of HIF-1α and HIF-2α on c-Myc activity regulate human ccRCC progression, we analyzed VHL genotype and HIF-α expression in 160 primary tumors, which segregated into three groups with distinct molecular characteristics. Interestingly, ccRCCs with intact VHL, as well as pVHL-deficient, HIF-1α/HIF-2α expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling. In contrast, pVHL-deficient ccRCCs expressing only HIF-2α displayed elevated c-Myc activity, resulting in enhanced proliferation and resistance to replication stress. These reproducible distinctions in ccRCC behavior delineate HIF-α effects on c-Myc in vivo and suggest molecular criteria for selecting targeted therapies

Test-retest variability of high resolution positron emission tomography (PET) imaging of cortical serotonin (5HT2A) receptors in older, healthy adults

<p>Abstract</p> <p>Background</p> <p>Position emission tomography (PET) imaging using [¹⁸F]-setoperone to quantify cortical 5-HT_2Areceptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT_2Areceptor (5HT_2AR) binding potential. The purpose of this study was to assess the test-retest variability of [¹⁸F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT_2AR availability in subjects greater than 60 years old. Methods: Six healthy subjects (age range = 65–78 years) completed two [¹⁸F]-setoperone PET scans on two separate occasions 5–16 weeks apart.</p> <p>Results</p> <p>The average difference in the binding potential (BP_ND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions.</p> <p>Conclusion</p> <p>We conclude that the test-retest variability of [¹⁸F]-setoperone PET in elderly subjects is comparable to that of [¹⁸F]-setoperone and other 5HT_2AR radiotracers in younger subject samples.</p