Tratamientos prostodónticos en adultos mayores realizados en un centro dental especializado entre los años 2016 y 2018 / Prosthodontic treatments in older adults performed in a specialized dental center between 2016 and 2018

RESUMEN Los Adultos Mayores (AM) son más propensos a sufrir enfermedades y comorbilidades que afectan su estado bucal, por lo que necesitan de tratamientos prostodónticos acondicionados a su estado sistémico para devolverles la función masticatoria, estética y armonía oral. No obstante, la pobre cultura de prevención y la falta de profesionales especializados en su atención dificulta en gran medida esta labor. Objetivo: Determinar los tratamientos prostodónticos en pacientes adultos mayores realizados en el Servicio de Estomatología en Pacientes Especiales del Centro Dental Docente Cayetano Heredia desde abril de 2016 hasta diciembre de 2018. Material y métodos: Se realizó un estudio observacional, descriptivo, transversal y retrospectivo en una muestra de 144 AM con 200 tratamientos realizados. Se consideraron variables demográficas como sexo, grupo etario y procedencia. Se elaboró una base de datos, y posteriormente tablas de contenido para el análisis de sus resultados. Resultados: La PPR fue el tratamiento más realizado para ambos sexos, 39,8% (n=57) para el sexo femenino y 38,6% (n=22) para el sexo masculino. De acuerdo al grupo etario, los viejos-viejos fueron los pacientes que más PPR se realizaron con 40,19% (n=43). La mayoría de los pacientes provenientes de Lima Norte se realizaron el tratamiento de PPR con 41.96% (n=47). Conclusiones: Las prótesis removibles predominaron más que las fijas, siendo la PPR la que más se realizó. También se evidencio que el sexo femenino recibió más tratamientos prostodónticos y que el lugar de procedencia que más se registro fue el de Lima Norte, posiblemente por la cercanía al centro dental.

SUMMARY Older adults are more prone to suffer diseases and comorbidities that affect their oral condition, so they need prosthodontic treatments conditioned to their systemic state to restore their masticatory, aesthetic and oral harmony function. However, the poor culture of prevention and the lack of specialized professionals in their care greatly hinders this work. Objective: To determine the prosthodontic treatments in older adults performed in the Service of Estomatología in Pacientes Especiales of the Centro Dental Docente Cayetano Heredia from april 2016 to december 2018. Material and methods: An observational, descriptive, cross-sectional, and retrospective study was carried out in a sample of 144 older adults with 200 treatments performed. Demographic variables such as sex, age group and origin wereconsidered. A database was developed, and later tables of contents for the analysis of its results. Results: PPR was the most performed treatment for both sexes, 39.8% (n = 57) for the female sex and 38.6% (n = 22) for the male sex. According to the age group, the old-old were the patients who performed the most PPR with 40.19% (n = 43). Most of the patients from Lima Norte underwent PPR treatment with 41.96% (n = 47). Conclusions: The removable prostheses predominated more than the fixed ones, being the PPR the one that was performed the most. It was also evidenced that the female sex received more prosthodontic treatments and that the place of origin that was most recorded was Lima Norte, possibly due to its proximity to the dental center.

Odontología bajo anestesia general en el paciente con epilepsia: Reporte de caso y revisión de literatura / Dentistry under general anesthesia in the patient with epilepsy. Case report and literature review

RESUMEN La atención clínica del paciente portador de epilepsia (EP) asociada a discapacidad intelectual (DI), representa un reto para el estomatólogo por su difícil manejo conductual. Estos pacientes requerirán de alternativas para poder llevar a cabo un tratamiento odontológico exitoso. La anestesia general (AG), es una alternativa ante la falla de las técnicas de manejo conductual, existencia de compromiso sistémico que lo amerite, acceso médico especializado distante al lugar de residencia o por circunstancias particulares de cada caso. Se presenta el caso de un paciente varón de 27 años, con diagnóstico de EP asociada a DI, de difícil manejo conductual atendido bajo anestesia general en el servicio de Estomatología de Pacientes Especiales de la Universidad Peruana Cayetano Heredia. Objetivo : Este artículo busca presentar una revisión de la literatura y el Tratamiento Odontológico Integral bajo anestesia general de un paciente con de Epilepsia asociada a Discapacidad Intelectual moderada. Conclusiones: Los pacientes con estas patologías de fondo son propensos a presentar deterioro del órgano bucal, por lo que requerirán prestaciones estomatológicas constantes. Por la poca colaboración de este tipo de pacientes, se debe considerar a la AG como alternativa para brindar el TOI en un solo acto operatorio.

SUMMARY The clinical care of patients with epilepsy (EP) associated with intellectual disability (ID) represents a challenge for the stomatologist because of its difficult behavioral management. These patients will require alternatives to carry out a successful dental treatment. General anesthesia (AG), is an alternative to the failure of behavioral management techniques, existence of systemic commitment that warrants it, specialized medical access distant from the place of residence or due to particular circumstances of each case. We present the case of a 27-year-old male patient, with a diagnosis of EP associated with ID, of difficult behavioral management treated under general anesthesia in the Special Patients Stomatology service of the Peruvian University Cayetano Heredia. Objective: This article seeks to present a review of the literature and Comprehensive Dental Treatment under general anesthesia of a patient with Epilepsy associated with moderate Intellectual Disability. Conclusions: Patients with these underlying pathologies are prone to present deterioration of the oral organ, so they will require constant stomatological benefits. Due to the low collaboration of this type of patients, the AG should be considered as an alternative to provide the TOI in a single operative act.

Caries dental en niños con necesidades especiales de un colegio de bajos recursos en el Perú / Dental caries in children with special needs from a low resource school in Peru

Objetivos: Determinar la prevalencia de caries dental en los niños del centro de educación básica especial Helen Keller situado en el Callao, Perú durante el 2015. Material y Métodos: Estudio observacional, transversal sobre los datos de 30 niños del centro de educación básica especial Helen Keller. Información recogida por alumnos de la Facultad de Estomatología de la Universidad Peruana Cayetano Heredia (UPCH), en el centro educativo durante el año 2015. Se analizaron las características de los niños (edad, sexo, y diagnóstico sistémico). Para caries dental se utilizó el índice CPOD/ceod y el índice CPOS/ceos. Resultados: El 90% (n=27) de los escolares presentó caries dental. El retardo mental fue la condición más prevalente (43,3%, n=13). Se encontró un índice de CPOD de 2,9 (DE 3,8) y en dientes deciduos (ceod) de 6,0 (DE 4,0). Conclusiones: Existe una alta prevalencia de caries dental en los niños del centro de educación básica especial Helen Keller Callao, Perú en el año 2015.

Objectives: Determine dental caries prevalence of children from a basic educational center for special needs, Helen Keller school situated at Callao, Perú during 2015. Material and Methods: Cross-sectional study on a sample of 30 children from the basic educational center for special needs, Helen Keller school. The data was collected from Universidad Peruana Cayetano Heredia (UPCH) during 2015 at mentioned school. Children characteristics were analyzed (age, sex, systemic diagnosis) in frequencies, and dental caries prevalence. We analyzed dental caries per each tooth (DMFT/dmft index) and each surface (DFMS/dmfs index). Results: 90% (n=27) of scholars had dental caries. Mental retardation, was the most common condition (43.3%, n=13). We found a DMFT index of 2.0 (SD 3.8) and in deciduous teeth (dmft index) of 6.0 (SD 4.0). Conclusions: There is a considerable proportion of children that have dental caries in Basic educational center for special needs Helen Keller, Callao, Perú during 2015.

Evaluation of Skull Cortical Thickness Changes With Age and Sex From Computed Tomography Scans.

Head injuries resulting from motor vehicle crashes (MVC) are extremely common, yet the details of the mechanism of injury remain to be well characterized. Skull deformation is believed to be a contributing factor to some types of traumatic brain injury (TBI). Understanding biomechanical contributors to skull deformation would provide further insight into the mechanism of head injury resulting from blunt trauma. In particular, skull thickness is thought be a very important factor governing deformation of the skull and its propensity for fracture. Previously, age- and sex-based skull cortical thickness changes were difficult to evaluate based on the need for cadaveric skulls. In this cross-sectional study, skull thickness changes with age and sex have been evaluated at homologous locations using a validated cortical density-based algorithm to accurately quantify cortical thickness from 123 high-resolution clinical computed tomography (CT) scans. The flat bones of the skull have a sandwich structure; therefore, skull thickness was evaluated for the inner and outer tables as well the full thickness. General trends indicated an increase in the full skull thickness, mostly attributed to an increase in the thickness of the diploic layer; however, these trends were not found to be statistically significant. There was a significant relationship between cortical thinning and age for both tables of the frontal, occipital, and parietal bones ranging between a 36% and 60% decrease from ages 20 to 100 years in females, whereas males exhibited no significant changes. Understanding how cortical and full skull thickness changes with age from a wide range of subjects can have implications in improving the biofidelity of age- and sex-specific finite element models and therefore aid in the prediction and understanding of TBI from impact and blast injuries.

Evaluation of morphological changes in the adult skull with age and sex.

The morphology of the brain and skull are important in the evaluation of the aging human; however, little is known about how the skull may change with age. The objective of this study was to evaluate the morphological changes of the adult skull using three-dimensional geometric morphometric analysis of thousands of landmarks with the focus on anatomic regions that may be correlated with brain atrophy and head injury. Computed tomography data were collected between ages 20 and 100. Each scan was segmented using thresholding techniques. An atlas image of a 50th percentile skull was registered to each subject scan by computing a series of rigid, affine, and non-linear transformations between atlas space and subject space. Landmarks on the atlas skull were transformed to each subject and partitioned into the inner and outer cranial vault and the cranial fossae. A generalized Procrustes analysis was completed for the landmark sets. The coordinate locations describing the shape of each region were regressed with age to generate a model predicting the landmark location with age. Permutation testing was performed to assess significant changes with age. For the males, all anatomic regions reveal significant changes in shape with age except for the posterior cranial fossa. For the females, only the middle cranial fossa and anterior cranial fossa were found to change significantly in shape. Results of this study are important for understanding the adult skull and how shape changes may pertain to brain atrophy, aging, and injury.

Skull Thickness Morphing for an Age and Sex Specific FE Model of the Skull.

Skull deformation is believed to be a contributing factor in traumatic brain injury (TBI). Furthermore, skull thickness is thought to be an important factor governing deformation of the skull and its susceptibility to fracture. Although many studies have been done to understand the mechanisms of brain injury and skull fracture, the majority of the cadaveric and finite element (FE) modeling efforts are comprised of older males and 50th percentile male skulls, respectively, which do not accurately represent the population as a whole. This study employed a set of skull table thickness regressions defined at homologous landmarks on the skull which were calculated from 123 pre-existing head CT scans (ages 20-100) using a cortical density-based algorithm. A method was developed to morph the Global Human Body Models Consortium (GHBMC) 50th percentile male skull model to age and gender specific geometries based on the full thickness regressions using a Thin Plate Spline algorithm. A quantitative measure of morphing error was devised and measured using the morphed and desired full thickness values at the homologous landmark locations. This methodology can be used to create gender and age-specific FE models of the skull and will ultimately be used to understand the relationship between cortical thickness, skull deformation, and head injury.

Preliminary Development and Validation of an Atlas-Based Finite Element Brain Model.

Traumatic brain injury (TBI) is a leading cause of disability and injury-related death, accounting for nearly one third of all injury-related deaths. To prevent and understand these types of injuries, finite element models can be employed. In this study, an anatomically accurate finite element model was developed from the International Consortium for Brain Mapping (ICBM) using a voxel-based mesh generation approach. The aim of this study was to compare relative brain displacement of the atlas-based brain model (ABM) to cadaveric data. In these experiments, neutral density targets (NDTs) were implanted in the brain and their relative motion with respect to the skull was recorded. The same boundary conditions were applied to ABM and the relative displacements of the nodes nearest to the physical location of each NDT were computed. Initial simulation and validation show good agreement with experimental data. The data obtained in this study and further development of this model will help us understand the biomechanics of head injury as well as provide a tool to predict and prevent brain injury.

Estimation of skull table thickness with clinical CT and validation with microCT.

Brain injuries resulting from motor vehicle crashes (MVC) are extremely common yet the details of the mechanism of injury remain to be well characterized. Skull deformation is believed to be a contributing factor to some types of traumatic brain injury (TBI). Understanding biomechanical contributors to skull deformation would provide further insight into the mechanism of head injury resulting from blunt trauma. In particular, skull thickness is thought be a very important factor governing deformation of the skull and its propensity for fracture. Current computed tomography (CT) technology is limited in its ability to accurately measure cortical thickness using standard techniques. A method to evaluate cortical thickness using cortical density measured from CT data has been developed previously. This effort validates this technique for measurement of skull table thickness in clinical head CT scans using two postmortem human specimens. Bone samples were harvested from the skulls of two cadavers and scanned with microCT to evaluate the accuracy of the estimated cortical thickness measured from clinical CT. Clinical scans were collected at 0.488 and 0.625 mm in plane resolution with 0.625 mm thickness. The overall cortical thickness error was determined to be 0.078 ± 0.58 mm for cortical samples thinner than 4 mm. It was determined that 91.3% of these differences fell within the scanner resolution. Color maps of clinical CT thickness estimations are comparable to color maps of microCT thickness measurements, indicating good quantitative agreement. These data confirm that the cortical density algorithm successfully estimates skull table thickness from clinical CT scans. The application of this technique to clinical CT scans enables evaluation of cortical thickness in population-based studies.

Variation in diffusion of gases through PDMS due to plasma surface treatment and storage conditions.

Polydimethylsiloxane (PDMS) is a commonly used polymer in the fabrication of microfluidic devices due to such features as transparency, gas permeability, and ease of patterning with soft lithography. The surface characteristics of PDMS can also be easily changed with oxygen or low pressure air plasma converting it from a hydrophobic to a hydrophilic state. As part of such a transformation, surface methyl groups are removed and replaced with hydroxyl groups making the exposed surface to resemble silica, a gas impermeable substance. We have utilized Platinum(II)-tetrakis(pentaflourophenyl)porphyrin immobilized within a thin (~1.5 um thick) polystyrene matrix as an oxygen sensor, Stern-Volmer relationship, and Fick's Law of simple diffusion to measure the effects of PDMS composition, treatment, and storage on oxygen diffusion through PDMS. Results indicate that freshly oxidized PDMS showed a significantly smaller diffusion coefficient, indicating that the SiO2 layer formed on the PDMS surface created an impeding barrier. This barrier disappeared after a 3-day storage in air, but remained significant for up to 3 weeks if PDMS was maintained in contact with water. Additionally, higher density PDMS formulation (5:1 ratio) showed similar diffusion characteristics as normal (10:1 ratio) formulation, but showed 60 % smaller diffusion coefficient after plasma treatment that never recovered to pre-treatment levels even after a 3-week storage in air. Understanding how plasma surface treatments contribute to oxygen diffusion will be useful in exploiting the gas permeability of PDMS to establish defined normoxic and hypoxic oxygen conditions within microfluidic bioreactor systems.

Evaluation of the extent and distribution of diffuse axonal injury from real world motor vehicle crashes - biomed 2013.

Diffuse axonal injury (DAI) is a common traumatic brain injury (TBI) often seen as a result of motor vehicle crashes (MVC). Twelve (12) cases of DAI were selected from the Crash Injury Research and Engineering Network (CIREN) to determine the extent and distribution of injury with respect to the head contact location. Head computed tomography (CT) scans were collected for each subject and segmented using semi-automated methods to establish the volumes of DAI. The impacted area on the subject's head was approximated from evidence of a soft tissue scalp contusion on the CT scan. This was used in conjunction with subject images and identified internal vehicle contact locations to ascertain a label map of the contact location. A point cloud was developed from the contact location label map and the centroid of the point cloud was calculated as the subject's head impact location. The injury and contact location were evaluated in spherical coordinates and grouped into 0.2 by 0.2 radial increments of azimuth and elevation. The radial increments containing DAI were projected onto a meshed sphere to evaluate the radial distance from the impact location to primary location of DAI and approximate anatomical location. Of the 170 injuries observed, 123 were identified in the frontal lobe and 36 in the parietal lobe. The distribution of the DAI in relation to the change in azimuth from the contact loca y correlated with contact to the head superficial to this lobe. Results from this study provide further insight into the biomechanics of traumatic brain injury and can be used in future work as an aid to validate finite element models of the head.

Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study.

OBJECTIVES: This study sought to evaluate the influence of single nucleotide polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose clopidogrel after percutaneous coronary intervention (PCI). BACKGROUND: There is a lack of prospective, multicenter data regarding the effect of different genetic variants on clopidogrel pharmacodynamics over time in patients undergoing PCI. METHODS: The GRAVITAS (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety) trial screened patients with platelet function testing after PCI and randomly assigned those with high on-treatment reactivity (OTR) to either high- or standard-dose clopidogrel; a cohort of patients without high OTR were also followed. DNA samples obtained from 1,028 patients were genotyped for 41 SNPs in 17 genes related to platelet reactivity. After adjusting for clinical characteristics, the associations between the SNPs and OTR using linear regression were evaluated. RESULTS: CYP2C19*2 was significantly associated with OTR at 12 to 24 h (R(2) = 0.07, p = 2.2 × 10(-15)), 30 days (R(2) = 0.10, p = 1.3 × 10(-7)), and 6 months after PCI (R(2) = 0.07, p = 1.9 × 10(-11)), whereas PON1, ABCB1 3435 C→T, and other candidate SNPs were not. Carriers of 1 and 2 reduced-function CYP2C19 alleles were significantly more likely to display persistently high OTR at 30 days and 6 months, irrespective of treatment assignment. The portion of the risk of persistently high OTR at 30 days attributable to reduced-function CYP2C19 allele carriage was 5.2% in the patients randomly assigned to high-dose clopidogrel. CONCLUSIONS: CYP2C19, but not PON1 or ABCB1, is a significant determinant of the pharmacodynamic effects of clopidogrel, both early and late after PCI. In patients with high OTR identified by platelet function testing, the CYP2C19 genotype provides limited incremental information regarding the risk of persistently high reactivity with clopidogrel 150-mg maintenance dosing. (Genotype Information and Functional Testing Study [GIFT]; NCT00992420).

Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial.

BACKGROUND: In the Gauging Responsiveness With A VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) trial, 6 months of high-dose clopidogrel did not reduce cardiovascular events compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity (OTR) after percutaneous coronary intervention, defined as OTR ≥230 P2Y12 reaction units according to the VerifyNow P2Y12 platelet function test. The aim of this analysis was to examine the relationship between outcomes and OTR over the course of the trial. METHODS AND RESULTS: OTR was measured at 12 to 24 hours and 30±7 days after percutaneous coronary intervention. Cox proportional hazards models with OTR as a time-varying covariate were used to determine the association between OTR and the primary end point of cardiovascular death, myocardial infarction, and stent thrombosis. Of the 2800 enrolled patients, 2796 (99.98%) had evaluable platelet function data. OTR <208 P2Y12 reaction units was significantly associated with a lower risk of the primary end point at 60 days (hazard ratio, 0.18; 95% confidence interval, 0.04 to 0.79; P=0.02) and at 6 months (hazard ratio, 0.43; 95% confidence interval, 0.23 to 0.82; P=0.01). After adjustment for other significant predictors of outcome, OTR <208 P2Y12 reaction units remained independently associated with the primary end point at 60 days (hazard ratio, 0.23; 95% confidence interval, 0.05 to 0.98; P=0.047) and tended to be associated at 6 months (adjusted hazard ratio, 0.54; 95% confidence interval, 0.28 to 1.04; P=0.065). CONCLUSIONS: In the GRAVITAS trial, achievement of on-clopidogrel reactivity <208 P2Y12 reaction units at 12 to 24 hours after percutaneous coronary intervention or during follow-up was associated with a lower risk for cardiovascular events. The efficacy of an individualized strategy to target a level of OTR below this threshold merits investigation. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00645918.

Is pocket mobile echocardiography the next-generation stethoscope? A cross-sectional comparison of rapidly acquired images with standard transthoracic echocardiography.

BACKGROUND: A pocket mobile echocardiography (PME) device is commercially available for clinical use, but public data documenting its accuracy compared with standard transthoracic echocardiography (TTE) are not available. OBJECTIVE: To compare the accuracy of rapidly acquired PME images with those acquired by standard TTE. DESIGN: Cross-sectional study. At the time of referral for TTE, ultrasonographers acquired PME images first in 5 minutes or less. Ultrasonographers were not blinded to the clinical indication for imaging or to the PME image results when obtaining standard TTE images. Two experienced echocardiographers and 2 cardiology fellows who were blinded to the indication for the study and TTE results but not to the device source interpreted the PME images. SETTING: Scripps Clinic Torrey Pines and Scripps Green Hospital, La Jolla, California. PATIENTS: Convenience sample of 97 patients consecutively referred for echocardiography. MEASUREMENTS: Visualizability and accuracy (the sum of proportions of true-positive and true-negative readings and observer variability) for ejection fraction, wall-motion abnormalities, left ventricular end-diastolic dimension, inferior vena cava size, aortic and mitral valve pathology, and pericardial effusion. RESULTS: Physician-readers could visualize some but not all echocardiographic measurements obtained with the PME device in every patient (highest proportions were for ejection fraction and left ventricular end-diastolic dimension [95% each]; the lowest proportion was for inferior vena cava size [75%]). Accuracy also varied by measurement (aortic valve was 96% [highest] and inferior vena cava size was 78% [lowest]) and decreased when nonvisualizability was accounted for (aortic valve was 91% and inferior vena cava size was 58%). Observer agreement was fair to moderate for some measurements among less-experienced readers. LIMITATION: The study was conducted at a single setting, there was no formal estimate of accuracy given the small convenience sample of patients, and few abnormal echocardiographic measurements occurred. CONCLUSION: The rapid acquisition of images by skilled ultrasonographers who use PME yields accurate assessments of ejection fraction and some but not all cardiac structures in many patients. Further testing of the device in larger patient cohorts with diverse cardiac abnormalities and with untrained clinicians obtaining and interpreting images is required before wide dissemination of its use can be recommended. PRIMARY FUNDING SOURCE: National Institutes of Health.

The n-of-1 clinical trial: the ultimate strategy for individualizing medicine?

N-of-1 or single subject clinical trials consider an individual patient as the sole unit of observation in a study investigating the efficacy or side-effect profiles of different interventions. The ultimate goal of an n-of-1 trial is to determine the optimal or best intervention for an individual patient using objective data-driven criteria. Such trials can leverage study design and statistical techniques associated with standard population-based clinical trials, including randomization, washout and crossover periods, as well as placebo controls. Despite their obvious appeal and wide use in educational settings, n-of-1 trials have been used sparingly in medical and general clinical settings. We briefly review the history, motivation and design of n-of-1 trials and emphasize the great utility of modern wireless medical monitoring devices in their execution. We ultimately argue that n-of-1 trials demand serious attention among the health research and clinical care communities given the contemporary focus on individualized medicine.

The effects of globin on microarray-based gene expression analysis of mouse blood.

The use of mouse blood as a model for human blood is often considered in the development of clinically relevant, gene expression-based disease biomarkers. However, the ability to derive biologically meaningful insights from microarray-based gene expression patterns in mouse whole blood, as in human whole blood, is hindered by high levels of globin mRNA. In order to characterize the effects of globin reduction on gene expression of peripheral mouse blood, we performed gene set enrichment analysis on genes identified as expressed in blood via microarray-based genome-wide transcriptome analysis. Depletion of globin mRNA enhanced the quality of microarray data as shown by improved gene expression detection and increased sensitivity. Compared to genes expressed in whole blood, genes detected as expressed in blood following globin reduction were enriched for low abundance transcripts implicated in many biological pathways, including development, g-protein signaling, and immune response. Broadly, globin reduction resulted in improved detection of expressed genes that serve as molecular binding proteins and enzymes in cellular metabolism, intracellular transport/localization, transcription, and translation, as well as genes that potentially could act as biomarkers for diseases such as schizophrenia. These significantly enriched pathways overlap considerably with those identified in globin-reduced human blood suggesting that globin-reduced mouse blood gene expression studies may be useful for identifying genes relevant to human disease. Overall, the results of this investigation provide a better understanding of the impact of reducing globin transcripts in mouse blood and highlight the potential of microarray-based, globin-reduced, mouse blood gene expression studies in biomarker development.

The relative importance of genetics and environment on mammographic density.

BACKGROUND: Although several environmental factors predict mammographic density, estimates of its heritability have been quite high. We investigated whether part of the presumed heritability might be attributed to differential sharing of modifiable risk factors in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: We measured percent and absolute mammographic density using mammograms from 257 MZ and 296 DZ twin pairs. The correlation of intrapair mammographic density was compared according to zygosity across strata of modifiable risk factors. Portions of variance attributable to additive genetic factors, shared environment, and individual environment were calculated using a variance component methodology in the entire set, and within twin pairs stratified by environmental trait similarity. RESULTS: Both percent density and absolute mammographic density were more highly correlated between MZ twins than DZ twins, but the correlations varied across strata. Body mass index (BMI) and parity strongly predicted differences in mammographic density within MZ twin pairs. After adjusting for covariates, 53% of the total variance in percent density and 59% of that in absolute density seemed attributable to genetic effects, but these estimates varied greatly by stratum. For twins dissimilar on BMI (difference >2.5 kg/m(2)), the additive genetic component of absolute density was estimated at only 20% (+/-19%), and the common and individual environment at 21% (+/-14%) and 49%, respectively (P value for heterogeneity across BMI = 0.0001). CONCLUSION: Our results confirm that the genome is an important determinant of mammographic density but suggest that an unknown portion of the mammographic density effect attributed to the genome may be due to shared modifiable environmental factors.

Renal artery calcium is independently associated with hypertension.

OBJECTIVES: We tested the hypothesis that renal artery calcium (RAC), a marker of atherosclerotic plaque burden, is also significantly associated with higher blood pressure levels and a diagnosis of hypertension. BACKGROUND: In the nonrenal systemic vasculature, atherosclerotic plaque burden has been shown to be significantly associated with hypertension. METHODS: A total of 1,435 consecutive patients were evaluated at a university-affiliated disease prevention center for the extent of calcified atherosclerosis in the systemic vasculature. RESULTS: The overall prevalence of calcium in either renal artery was 17.1%, with men having a significantly higher prevalence (19.0%, 153 of 804) than women (14.7%, 93 of 631) (p = 0.03). After adjustment for age and gender, subjects with a RAC score >0 had a significantly higher prevalence of hypertension (41.2 vs. 29.5, p < 0.01). In a logistic model that adjusted for age, gender, body mass index, percent body fat, diabetes, smoking, dyslipidemia, and the extent of calcified atherosclerosis in the nonrenal vasculature, those with any RAC had a significantly higher odds ratio (1.61, p = 0.01) for hypertension than those with no RAC. CONCLUSIONS: The results of this study suggest that the presence of RAC is associated with higher odds for prevalent hypertension, independent of CVD risk factors and the extent of calcified atherosclerosis in the nonrenal vasculature.

Heredity of endothelin secretion: human twin studies reveal the influence of polymorphism at the chromogranin A locus, a novel determinant of endothelial function.

BACKGROUND: Endothelial dysfunction predisposes to vascular injury in association with hypertension. Endothelin (ET-1) is a potent vasoactive peptide that is synthesized and released by the vascular endothelium and is a marker of endothelial function. Chromogranin A (CHGA) regulates the storage and release of catecholamines and may have direct actions on the microvasculature. CHGA, a candidate gene for intermediate phenotypes that contribute to hypertension, shows a pattern of single nucleotide polymorphism variations that alter the expression and function of this gene both in vivo and in vitro. METHODS AND RESULTS: In a study of twins (n=238 pairs), plasma ET-1 was 58+/-5% (P<0.0001) heritable. Plasma ET-1 was both correlated and associated with chromogranin fragment levels, and the 2 were influenced by shared genetic determination (pleiotropy [rhoG]; for the CHGA precursor, rhoG=0.318+/-0.105; P=0.0032). We therefore hypothesized that variation in the CHGA gene may influence ET-1 secretion. Carriers of the CHGA promoter -988G, -462A, and -89A minor alleles showed significantly higher mean plasma ET-1 than their major allele homozygote counterparts (P=0.02, P=0.006, P=0.03, respectively). Analysis of a linkage disequilibrium block that spans these 3 single nucleotide polymorphisms showed a significant association between the GATACA haplotype and plasma ET-1 (P=0.0075). In cultured human umbilical vein endothelial cells, CHGA caused dose-dependent secretion of ET-1 over a brief (<1 hour) time course at relatively low concentrations of CHGA (10 to 100 nmol/L) with a threshold concentration (10 nmol/L) in the range found circulating in humans in vivo. CONCLUSIONS: These results suggest that common, heritable variation in expression of the human CHGA gene influences endothelial ET-1 secretion in vivo, explained by a CHGA stimulus/ET-1 secretion coupling in endothelial cells in vitro. The findings document a previously unsuspected interaction between the sympathochromaffin system and the endothelium and suggest novel genetic and cell biological approaches to the prediction, diagnosis, and mechanism of endothelial dysfunction in human disease.

C-reactive protein, an 'intermediate phenotype' for inflammation: human twin studies reveal heritability, association with blood pressure and the metabolic syndrome, and the influence of common polymorphism at catecholaminergic/beta-adrenergic pathway loci.

BACKGROUND: C-reactive protein (CRP) both reflects and participates in inflammation, and its circulating concentration marks cardiovascular risk. Here we sought to understand the role of heredity in determining CRP secretion. METHODS: CRP, as well as multiple facets of the metabolic syndrome, were measured in a series of 229 twins, both monozygotic (MZ) and dizygotic (DZ), to estimate trait heritability (h2). Single nucleotide polymorphism (SNP) genotyping was done at adrenergic pathway loci. Haplotypes were inferred from genotypes by likelihood methods. Association of CRP with hypertension and the metabolic syndrome was studied in a larger series of 732 individuals, including 79 with hypertension. RESULTS: MZ and DZ twin variance components indicated substantial h2 for CRP, at approximately 56 +/- 7% (P < 0.001). CRP was significantly associated (P < 0.05) with multiple features of the metabolic syndrome in twins, including body mass index (BMI), blood pressure (BP), leptin and lipids. In established hypertension, elevated CRP was associated with increased BP, BMI, insulin, HOMA (index of insulin resistance), leptin, triglycerides and norepinephrine. Twin correlations indicated pleiotropy (shared genetic determination) for CRP with BMI (P = 0.0002), leptin (P < 0.001), triglycerides (P = 0.002) and systolic blood pressure (SBP) (P = 0.042). Approximately 9800 genotypes (43 genetic variants at 17 loci) were scored within catecholaminergic pathways: biosynthetic, receptor and signal transduction. Plasma CRP concentration in twins was predicted by polymorphisms at three loci in physiological series within the catecholamine biosynthetic/beta-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (beta1-adrenergic receptor) and ADRB2 (beta2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to approximately 6.6% of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted approximately 2.8% of CRP, while ADRB2 promoter variants T-47C and T-20C also contributed. Particular haplotypes and diplotypes at TH and ADRB1 also predicted CRP, though typically no better than single SNPs alone. Epistasis (gene-by-gene interaction) was demonstrated for particular combinations of TH and ADRB2 alleles, consistent with their actions in a pathway in series. In an illustration of pleiotropy, not only CRP but also plasma triglycerides were predicted by polymorphisms at TH (P = 0.0053) and ADRB2 (P = 0.027). CONCLUSIONS: CRP secretion is substantially heritable in humans, demonstrating pleiotropy (shared genetic determination) with other features of the metabolic syndrome, such as BMI, triglycerides or BP. Multiple, common genetic variants in the catecholaminergic/beta-adrenergic pathway contribute to CRP, and these variants (especially at TH and ADRB2) seem to interact (epistasis) to influence the trait. The results uncover novel pathophysiological links between the adrenergic system and inflammation, and suggest new strategies to probe the role and actions of inflammation within this setting.

Catecholamine storage vesicles and the metabolic syndrome: The role of the chromogranin A fragment pancreastatin.

Chromogranins or secretogranins (granins), present in secretory granules of virtually all neuroendocrine cells and neurones, are structurally related proteins encoded by different genetic loci: chromogranins A and B, and secretogranins II through VI. Compelling evidence supports both intracellular and extracellular functions for this protein family. Within the cells of origin, a granulogenic or sorting role in the regulated pathway of hormone or neurotransmitter secretion has been documented, especially for chromogranin A (CHGA). Granins also function as pro-hormones, giving rise by proteolytic processing to an array of peptide fragments for which diverse autocrine, paracrine, and endocrine activities have been demonstrated. CHGA measurements yield insight into the pathogenesis of such human diseases as essential hypertension, in which deficiency of the catecholamine release-inhibitory CHGA fragment catestatin may trigger sympathoadrenal overactivity as an aetiologic culprit in the syndrome. The CHGA dysglycaemic fragment pancreastatin is functional in humans in vivo, affecting both carbohydrate (glucose) and lipid (fatty acid) metabolism. Pancreastatin is cleaved from CHGA in hormone storage granules in vivo, and its plasma concentration varies in human disease. The pancreastatin region of CHGA gives rise to three naturally occurring human variants, one of which (Gly297Ser) occurs in the functionally important carboxy-terminus of the peptide, and substantially increases the peptide's potency to inhibit cellular glucose uptake. These observations establish a role for pancreastatin in human intermediary metabolism and disease, and suggest that qualitative hereditary alterations in pancreastatin's primary structure may give rise to interindividual differences in glucose disposition.