A cross-sectional analysis of the association between polycyclic aromatic hydrocarbons and diesel particulate matter exposures and hypertension among individuals of Mexican origin residing in Houston, TX

Background. Research has shown that elevations of only 10 mmHg diastolic blood pressure (BP) and 5 mmHg systolic BP are associated with substantial (as large as 50%) increases in risks for cardiovascular disease, a leading cause of death, worldwide. Epidemiological studies have found that particulate matter (PM) increases blood pressure (BP) and many biological mechanisms which may suggest that the organic matter of PM contributes to the increase in BP. To understand components of PM which may contribute to the increase in BP, this study focuses on diesel particulate matter (DPM) and polycyclic aromatic hydrocarbons (PAHs). To our knowledge, there have been only four epidemiological studies on BP and DPM, and no epidemiological studies on BP and PAHs. ^ Objective. Our objective was to evaluate the association between prevalent hypertension and two ambient exposures: DPM and PAHs amongst the Mano a Mano cohort. ^ Methods. The Mano a Mano cohort which was established by the M.D. Anderson Cancer Center in 2001, is comprised of individuals of Mexican origin residing in Houston, TX. Using geographical information systems, we linked modeled annual estimates of PAHs and DPM at the census track level from the U.S. Environmental Protection Agency's National-Scale Air Toxics Assessment to residential addresses of cohort members. Mixed-effects logistic regression models were applied to determine associations between DPM and PAHs and hypertension while adjusting for confounders. ^ Results. Ambient levels of DPM, categorized into quartiles, were not statistically associated with hypertension and did not indicate a dose response relationship. Ambient levels of PAHs, categorized into quartiles, were not associated with hypertension, but did indicate a dose response relationship in multiple models (for example: Q2: OR = 0.98; 95% CI, 0.73–1.31, Q3: OR = 1.08; 95% CI, 0.82–1.41, Q4: OR = 1.26; 95% CI, 0.94–1.70). ^ Conclusion. This is the first assessment to analyze the relationship between ambient levels of PAHs and hypertension and it is amongst a few studies investigating the association between ambient levels of DPM and hypertension. Future analyses are warranted to explore the effects DPM and PAHs using different categorizations in order to clarify their relationships with hypertension.^

Bayesian adaptive designs in early phase clinical trials

There are two practical challenges in the phase I clinical trial conduct: lack of transparency to physicians, and the late onset toxicity. In my dissertation, Bayesian approaches are used to address these two problems in clinical trial designs. The proposed simple optimal designs cast the dose finding problem as a decision making process for dose escalation and deescalation. The proposed designs minimize the incorrect decision error rate to find the maximum tolerated dose (MTD). For the late onset toxicity problem, a Bayesian adaptive dose-finding design for drug combination is proposed. The dose-toxicity relationship is modeled using the Finney model. The unobserved delayed toxicity outcomes are treated as missing data and Bayesian data augment is employed to handle the resulting missing data. Extensive simulation studies have been conducted to examine the operating characteristics of the proposed designs and demonstrated the designs' good performances in various practical scenarios.^

A simulation study of the standard design, the rolling six design, the CRM, and the modified CRM in Phase I clinical trials

The Phase I clinical trial is considered the "first in human" study in medical research to examine the toxicity of a new agent. It determines the maximum tolerable dose (MTD) of a new agent, i.e., the highest dose in which toxicity is still acceptable. Several phase I clinical trial designs have been proposed in the past 30 years. The well known standard method, so called the 3+3 design, is widely accepted by clinicians since it is the easiest to implement and it does not need a statistical calculation. Continual reassessment method (CRM), a design uses Bayesian method, has been rising in popularity in the last two decades. Several variants of the CRM design have also been suggested in numerous statistical literatures. Rolling six is a new method introduced in pediatric oncology in 2008, which claims to shorten the trial duration as compared to the 3+3 design. The goal of the present research was to simulate clinical trials and compare these phase I clinical trial designs. Patient population was created by discrete event simulation (DES) method. The characteristics of the patients were generated by several distributions with the parameters derived from a historical phase I clinical trial data review. Patients were then selected and enrolled in clinical trials, each of which uses the 3+3 design, the rolling six, or the CRM design. Five scenarios of dose-toxicity relationship were used to compare the performance of the phase I clinical trial designs. One thousand trials were simulated per phase I clinical trial design per dose-toxicity scenario. The results showed the rolling six design was not superior to the 3+3 design in terms of trial duration. The time to trial completion was comparable between the rolling six and the 3+3 design. However, they both shorten the duration as compared to the two CRM designs. Both CRMs were superior to the 3+3 design and the rolling six in accuracy of MTD estimation. The 3+3 design and rolling six tended to assign more patients to undesired lower dose levels. The toxicities were slightly greater in the CRMs.^

Calidad ambiental electromagnética : atenuación de las radiaciones electromagnéticas en los espacios habitados

La perspectiva del arquitecto en calidad ambiental, y salud en un contexto sostenible, se amplía al considerar las radiaciones electromagnéticas no ionizantes en el diseño arquitectónico. En ese sentido, además del confort higrotérmico, acústico, lumínico y de la calidad del aire, se podría considerar el confort electromagnético de un lugar. Dado que existe gran controversia en cuales han de ser los límites de exposición a radiaciones electromagnéticas no ionizantes, establezco como punto de referencia los valores límite más restrictivos, que son los recomendados por la norma SBM-2008, desarrollada por el Institut für Baubiologie & Oekologie Neubeuern (IBN)1. Se plantean como hipótesis que podemos modificar el entorno electromagnético con materiales de construcción y geometría; y que determinados trazados geométricos tienen la capacidad de reducir el impacto de los campos electromagnéticos sobre los organismos vivos. El objetivo consiste en demostrar experimentalmente que podemos trabajar sobre la calidad ambiental electromagnética de un espacio, a través de la elección de materiales de construcción y trazados geométricos, intentando demostrar que existe una relación causa - efecto entre ambos. La metodología plantea tres aproximaciones experimentales, cada una con un tipo de radiación electromagnética, pues se pretende abarcar las situaciones que comúnmente se pueden presentar en un entorno habitado, ya sea urbano o rural. La primera aproximación trata sobre las alteraciones del campo geomagnético natural (nT / m) provocadas por los materiales de construcción. Utilizo el geomagnetómetro BPM 2010, para realizar un ensayo con cuatro tipos de materiales de distinta procedencia: origen vegetal muy poco procesado (corcho aglomerado negro) y más procesado (OSB), origen derivado del petróleo (tablero rígido de poliuretano) y de origen mineral metálico (chapa minionda). De la lectura de los datos se observa relación causa-efecto entre los materiales de construcción estudiados y las modificaciones que pueden ejercer sobre el campo magnético de un lugar. A continuación se estudia el entorno de radiación electromagnética artificial a baja frecuencia (3 Hz a 3 kHz) y a alta frecuencia, (800 MHz a 10 GHz) en vivienda y en oficina utilizando unas geometrías concretas: las tarjetas de corrección de radiaciones. Estas tarjetas se ubican en paramentos verticales y horizontales de un espacio sometido a radiación propia de un entorno urbano. Se concluye que en una habitación inciden múltiples variables simultáneas muy difíciles de trabajar por separado y que aparentemente no se pueden identificar cambios significativos en las mediciones con y sin las tarjetas de corrección de radiaciones. A continuación estudio el entorno de radiación electromagnética artificial a baja frecuencia asociada a la red de distribución eléctrica. Para poder ver cómo este entorno electromagnético lo podemos modificar, utilizo las tarjetas de corrección de radiaciones ubicadas en relación directa con organismos vivos, por un lado germinados de semillas de haba mungo sometidas a campos electromagnéticos complejos a alta y baja frecuencia, propios de una oficina; y por otro lado germinados de semillas de haba mungo, sometidas a campos electromagnéticos puros a 50 Hz, sin influencias de radiación a alta frecuencia. Se concluye que se observa relación causa - efecto entre los trazados geométricos estudiados y su capacidad para reducir el impacto de los campos electromagnéticos a altas y bajas frecuencias sobre las semillas de haba mungo. También utilizo las tarjetas de corrección de radiaciones en un ensayo normalizado en el laboratorio de bioelectromagnetismo del Hospital Universitario Ramón y Cajal, con células de neuroblastoma humano. Se concluye que se observa relación causa - efecto entre los trazados geométricos estudiados y su capacidad para reducir el impacto de los campos electromagnéticos de 50 Hz Y 100 μT sobre células de neuroblastoma humano y además disminuyen la velocidad de proliferación celular respecto del grupo de células de control. Finalmente se estudia el entorno de radiación electromagnética artificial a alta frecuencia, asociado a comunicaciones inalámbricas. Para ello realizo simulaciones con el software CST Studio, sobre las tarjetas de corrección de radiaciones a alta frecuencia. A la luz de los datos se observa relación causa - efecto entre el trazado geométrico estudiado y su capacidad para reducir radiaciones electromagnéticas de alta frecuencia. Se comprueba además que, las tarjetas de corrección de radiaciones disminuyen la intensidad de la radiación acercándose a los límites de exposición establecidos por el instituto de la biología de la construcción alemán, que podrían estar señalando los estándares de biocompatibilidad. ABSTRACT The perspective of the architect in environmental quality, and health in a sustainable context is extended to consider non-ionizing electromagnetic radiation in architectural design. In that sense, besides the hygrothermal, acoustic, lighting and air quality comfort, the electromagnetic comfort of an indoor space could be considered. There is still great controversy about which should be the limits of exposure to nonionizing electromagnetic radiation, as a benchmark, the more restrictive limits are considered, by the SBM- 2008 standard, developed by the Institut für Baubiologie & Oekologie Neubeuern (IBN). The hypotheses that arise are the following: the electromagnetic environment can be modified by using certain construction materials and geometry; and certain geometric design have the ability to reduce the impact of electromagnetic fields on living organisms. The aim is to demonstrate experimentally that we can work on electromagnetic environmental quality of a indoor space, by using certain construction materials and geometric design, trying to demonstrate a cause - effect relationship between them. The methodology raises three experimental approaches, each with a type of radiation, it is intend to cover situations commonly may occur in an inhabited environment, whether urban or rural. The first approach discusses the alteration of the natural magnetic field (nT / m) caused by the building materials. Geomagnetometre BPM 2010 is used for conducting a test with four types of materials from different sources: vegetable origin less processing (black agglomerate cork) and vegetable origin more processed (OSB), petroleum origin (rigid polyurethane board) and metallic origin (miniwave plate). It is observed across the data information that exist cause-effect relationship between the construction materials studied and the modifications that they can exercise on the magnetic field of a place. Then I study the environment of artificial electromagnetic radiation at low frequency (3 Hz to 3 kHz) and high frequency (800 MHz to 10 GHz) in housing and office, using some specific geometries: correcting radiation cards. These cards are placed in vertical and horizontal surfaces of an indoor space concerned by radiation. I conclude that an indoor space is affected by multiple simultaneous variables difficult to work separately and apparently it is not possible identify significant changes in measurements with and without correcting radiation cards. Then the artificial electromagnetic environment of low-frequency radiation associated with the electricity distribution network is studied. To see how the electromagnetic environment can be changed, correcting radiation cards are placed directly related to living organisms. On one hand, mung bean seeds subject to complex electromagnetic fields at low and high frequency, typical of an office; and on the other hand mung bean seeds, subjected to pure electromagnetic fields at 50 Hz, no influenced by high frequency radiation. It is observed that exist cause-effect relationship between the geometric design and their ability to reduce the impact of electromagnetic fields at high and low frequencies that arrives on on mung bean seeds. The correcting radiation cards were also used in a standard test in the bioelectromagnetics laboratory of Ramón y Cajal University Hospital, on human neuroblastoma cells. It is observed that exist cause-effect relationship between the geometric design and their ability to reduce the impact of electromagnetic fields at 50 Hz and 100 μT on human neuroblastoma cells and also decrease the rate of cell proliferation compared to the group of cells control. Finally the artificial electromagnetic radiation environment at high frequency associated with wireless communications was studied. Simulations with CST Study software were made to determine the behavior of correcting radiation cards in high-frequency. It is observed across the data information that exist causeeffect relationship between the geometric design and the ability to reduce the levels of high-frequency electromagnetic radiation. It also checks that radiation correcting cards decrease the intensity of radiation approaching exposure limits established by Institut für Baubiologie & Oekologie Neubeuern (IBN), which could be signaling biocompatibility standards.

RGS proteins reconstitute the rapid gating kinetics of Gβγ-activated inwardly rectifying K+ channels

G protein-gated inward rectifier K+ (GIRK) channels mediate hyperpolarizing postsynaptic potentials in the nervous system and in the heart during activation of Gα(i/o)-coupled receptors. In neurons and cardiac atrial cells the time course for receptor-mediated GIRK current deactivation is 20–40 times faster than that observed in heterologous systems expressing cloned receptors and GIRK channels, suggesting that an additional component(s) is required to confer the rapid kinetic properties of the native transduction pathway. We report here that heterologous expression of “regulators of G protein signaling” (RGS proteins), along with cloned G protein-coupled receptors and GIRK channels, reconstitutes the temporal properties of the native receptor → GIRK signal transduction pathway. GIRK current waveforms evoked by agonist activation of muscarinic m2 receptors or serotonin 1A receptors were dramatically accelerated by coexpression of either RGS1, RGS3, or RGS4, but not RGS2. For the brain-expressed RGS4 isoform, neither the current amplitude nor the steady-state agonist dose-response relationship was significantly affected by RGS expression, although the agonist-independent “basal” GIRK current was suppressed by ≈40%. Because GIRK activation and deactivation kinetics are the limiting rates for the onset and termination of “slow” postsynaptic inhibitory currents in neurons and atrial cells, RGS proteins may play crucial roles in the timing of information transfer within the brain and to peripheral tissues.

Relationships of dehydroepiandrosterone sulfate in the elderly with functional, psychological, and mental status, and short-term mortality: A French community-based study

In human beings of both sexes, dehydroepiandrosterone sulfate (DHEAS) circulating in blood is mostly an adrenally secreted steroid whose serum concentration (in the micromolar range and 30–50% higher in men than in women) decreases with age, toward ≈20–10% of its value in young adults during the 8th and 9th decades. The mechanism of action of DHEA and DHEAS is poorly known and may include partial transformation into sex steroids, increase of bioavailable insulin-like growth factor I, and effects on neurotransmitter receptors. Whether there is a cause-to-effect relationship between the decreasing levels of DHEAS with age and physiological and pathological manifestations of aging is still undecided, but this is of obvious theoretical and practical interest in view of the easy restoration by DHEA administration. Here we report on 622 subjects over 65 years of age, studied for the 4 years since DHEAS baseline values had been obtained, in the frame of the PAQUID program, analyzing the functional, psychological, and mental status of a community-based population in the south-west of France. We confirm the continuing decrease of DHEAS serum concentration with age, more in men than in women, even if men retain higher levels. Significantly lower values of baseline DHEAS were recorded in women in cases of functional limitation (Instrumental Activities of Daily Living), confinement, dyspnea, depressive symptomatology, poor subjective perception of health and life satisfaction, and usage of various medications. In men, there was a trend for the same correlations, even though not statistically significant in most categories. No differences in DHEAS levels were found in cases of incident dementia in the following 4 years. In men (but not in women), lower DHEAS was significantly associated with increased short-term mortality at 2 and 4 years after baseline measurement. These results, statistically established by taking into account corrections for age, sex, and health indicators, suggest the need for further careful trials of the administration of replacement doses of DHEA in aging humans. Indeed, the first noted results of such “treatment” are consistent with correlations observed here between functional and psychological status and endogenous steroid serum concentrations.

HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription

Increased histone acetylation has been correlated with increased transcription, and regions of heterochromatin are generally hypoacetylated. In investigating the cause-and-effect relationship between histone acetylation and gene activity, we have characterized two yeast histone deacetylase complexes. Histone deacetylase-A (HDA) is an ≈350-kDa complex that is highly sensitive to the deacetylase inhibitor trichostatin A. Histone deacetylase-B (HDB) is an ≈600-kDa complex that is much less sensitive to trichostatin A. The HDA1 protein (a subunit of the HDA activity) shares sequence similarity to RPD3, a factor required for optimal transcription of certain yeast genes. RPD3 is associated with the HDB activity. HDA1 also shares similarity to three new open reading frames in yeast, designated HOS1, HOS2, and HOS3. We find that both hda1 and rpd3 deletions increase acetylation levels in vivo at all sites examined in both core histones H3 and H4, with rpd3 deletions having a greater impact on histone H4 lysine positions 5 and 12. Surprisingly, both hda1 and rpd3 deletions increase repression at telomeric loci, which resemble heterochromatin with rpd3 having a greater effect. In addition, rpd3 deletions retard full induction of the PHO5 promoter fused to the reporter lacZ. These data demonstrate that histone acetylation state has a role in regulating both heterochromatic silencing and regulated gene expression.

Inhibiting transthyretin amyloid fibril formation via protein stabilization

Transthyretin (TTR) amyloid fibril formation is observed systemically in familial amyloid polyneuropathy and senile systemic amyloidosis and appears to be the causative agent in these diseases. Herein, we demonstrate conclusively that thyroxine (10.8 μM) inhibits TTR fibril formation efficiently in vitro and does so by stabilizing the tetramer against dissociation and the subsequent conformational changes required for amyloid fibril formation. In addition, the nonnative ligand 2,4,6-triiodophenol, which binds to TTR with slightly increased affinity also inhibits TTR fibril formation by this mechanism. Sedimentation velocity experiments were employed to show that TTR undergoes dissociation (linked to a conformational change) to form the monomeric amyloidogenic intermediate, which self-assembles into amyloid in the absence, but not in the presence of thyroxine. These results demonstrate the feasibility of using small molecules to stabilize the native fold of a potentially amyloidogenic human protein, thus preventing the conformational changes, which appear to be the common link in several human amyloid diseases. This strategy and the compounds resulting from further development should prove useful for critically evaluating the amyloid hypothesis—i.e., the putative cause-and-effect relationship between TTR amyloid deposition and the onset of familial amyloid polyneuropathy and senile systemic amyloidosis.

Long-term expression of erythropoietin in the systemic circulation of mice after intramuscular injection of a plasmid DNA vector.

Erythropoietin (Epo)-responsive anemia is a common and debilitating complication of chronic renal failure and human immunodeficiency virus infection. Current therapy for this condition involves repeated intravenous or subcutaneous injections of recombinant Epo. In this report, we describe the development of a novel muscle-based gene transfer approach that produces long-term expression of physiologically significant levels of Epo in the systemic circulation of mice. We have constructed a plasmid expression vector, pVRmEpo, that contains the murine Epo cDNA under the transcriptional control of the cytomegalovirus immediate early (CMV-IE) promoter, the CMV-IE 5' untranslated region, and intron A. A single intramuscular (i.m.) injection of as little as 10 micrograms of this plasmid into immunocompetent adult mice produced physiologically significant elevations in serum Epo levels and increased hematocrits from preinjection levels of 48 +/- 0.4% to levels of 64 +/- 3.3% 45 days after injection. Hematocrits in these animals remained elevated at greater than 60% for at least 90 days after a single i.m. injection of 10 micrograms of pVRmEpo. We observed a dose-response relationship between the amount of plasmid DNA injected and subsequent elevations in hematocrits. Mice injected once with 300 micrograms of pVRmEpo displayed 5-fold increased serum Epo levels and elevated hematocrits of 79 +/- 3.3% at 45 days after injection. The i.m. injected plasmid DNA remained localized to the site of injection as assayed by the PCR. We conclude that i.m. injection of plasmid DNA represents a viable nonviral gene transfer method for the treatment of acquired and inherited serum protein deficiencies.

On the etiology of Crohn disease.

Crohn disease (CD) is a chronic, panenteric intestinal inflammatory disease. Its etiology is unknown. Analogous to the tuberculoid and lepromatous forms of leprosy, CD may have two clinical manifestations. One is aggressive and fistulizing (perforating), and the other is contained, indolent, and obstructive (nonperforating) [Gi]-berts, E. C. A. M., Greenstein, A. J., Katsel, P., Harpaz, N. & Greenstein, R. J. (1994) Proc. Natl. Acad. Sci. USA 91, 12721-127241. The etiology, if infections, may be due to Mycobacterium paratuberculosis. We employed reverse transcription PCR using M. paratuberculosis subspecies-specific primers (IS 900) on total RNA from 12 ileal mucosal specimens (CD, n = 8; controls, n = 4, 2 with ulcerative colitis and 2 with colonic cancer). As a negative control, we used Myobacterium avium DNA, originally cultured from the drinking water of a major city in the United States. cDNA sequence analysis shows that all eight cases of Crohn's disease and both samples from the patients with ulcerative colitis contained M. paratuberculosis RNA. Additionally, the M. avium control has the DNA sequence of M. paratuberculosis. We demonstrate the DNA sequence of M. paratuberculosis from mucosal specimens from humans with CD. The potable water supply may be a reservoir of infection. Although M. paratuberculosis signal in CD has been previously reported, a cause and effect relationship has not been established. In part, this is due to conflicting data from studies with empirical antimycobacterial therapy. We conclude that clinical trials with anti-M. paratuberculosis therapy are indicated in patients with CD who have been stratified into the aggressive (perforating) and contained (nonperforating) forms.

Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2.

Injection of mineral oils such as pristane into the peritoneal cavities of BALB/c mice results in a chronic peritonitis associated with high tissue levels of interleukin 6 (IL-6). Here we show that increased prostaglandin E2 (PGE2) synthesis causes induction of IL-6 and that expression of an inducible cyclooxygenase, Cox-2, may mediate this process. Levels of both PGE2 and IL-6 are elevated in inflammatory exudates from pristane-treated mice compared with lavage samples from untreated mice. The Cox-2 gene is induced in the peritoneal macrophage fraction isolated from the mice. A cause and effect relationship between increased macrophage PGE2 and IL-6 production is shown in vitro. When peritoneal macrophages are activated with an inflammatory stimulus (polymerized albumin), the Cox-2 gene is induced and secretion of PGE2 and IL-6 increases, with elevated PGE2 appearing before IL-6. Cotreatment with 1 microM indomethacin inhibits PGE2 production by the cells and reduces the induction of IL-6 mRNA but has no effect on Cox-2 mRNA, consistent with the fact that the drug inhibits catalytic activity of the cyclooxygenase but does not affect expression of the gene. Addition of exogenous PGE2 to macrophages induces IL-6 protein and mRNA synthesis, indicating that the eicosanoid stimulates IL-6 production at the level of gene expression. PGE2-stimulated IL-6 production is unaffected by addition of indomethacin. Taken together with the earlier finding that indomethacin diminishes the elevation of IL-6 in pristane-treated mice, the results show that PGE2 can induce IL-6 production in vivo and implicate expression of the Cox-2 gene in the regulation of this cytokine.

Potentiation of the bioavailability of daidzin by an extract of Radix puerariae.

The dose effect of pure daidzin on the suppression of ethanol intake in Syrian golden hamsters was compared with that of crude daidzin contained in a methanol extract of Radix puerariae (RP). EC50 values estimated from the graded dose-response curves for pure daidzin and RP extract daidzin are 23 and 2.3 mg per hamster per day, respectively. Apparently the antidipsotropic activity of the RP extract cannot be accounted for solely by its daidzin content (22 mg/g). In addition to daidzin, six other isoflavones were identified in the RP extract and quantified--namely, puerarin (160 mg per g of extract), genistin (3.7 mg/g), daidzein (2.6 mg/g), daidzein-4',7-diglucoside (1.2 mg/g), genistein (0.2 mg/g), and formononetin (0.16 mg/g). None of these, administered either alone or combined, contributes in any significant way to the antidipsotropic activity of the extract. Plasma daidzin concentration-time curves determined in hamsters administered various doses of pure daidzin or RP extract by i.p.injection indicate that the crude extract daidzin has approximately 10 times greater bioavailability than the pure compound. Reconstruction of the dose-response effects for pure and crude daidzin using bioavailable daidzin rather than administered dose gives a single curve. Synthetic daidzin added to the RP extract acquires the bioavailability of the endogenous daidzin that exists naturally in the extract. These results show that (i) daidzin is the major active principle in methanol extracts of RP, and (ii) additional constituents in the methanol extract of RP assist uptake of daidzin in golden hamsters.