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Physiologic Levels (physiologic + level)
Selected AbstractsCentral nervous system effects of natural and synthetic glucocorticoidsPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 5 2009Pierluigi Fietta MD Natural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress, involving almost all organs and tissues, including brain. Since their therapeutic availability, synthetic GC (SGC) have been successfully prescribed for a variety of diseases. Mounting evidence, however, demonstrated pleiotropic adverse effects (AE), including central nervous system (CNS) disturbances, which are often misdiagnosed or underestimated. The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC. A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database. Cortisolemia plays a crucial role in control of behavior, cognition, mood, and early life programming of stress reactivity. Hypercortisolemia or SGC treatments may induce behavioral, psychic and cognitive disturbances, due to functional and, over time, structural alterations in specific brain target areas. These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses <20 mg/day) and usually reversible. Pediatric patients are particularly susceptible. Behavioral changes, including feeding and sleeping modifications, are common. Psychic AE are unpredictable and heterogeneous, usually mild/moderate, severe in 5,10% of cases. Manic symptoms have been mostly associated with short SGC courses, and depressive disorder with long-term treatments. Suicidality has been reported. Cognitive AE peculiarly affect declarative memory performance. Physiologic levels of NGC are essential for efficient brain functions. Otherwise, hypercortisolemia and SGC treatments may cause dose-/time-dependent neuropsychic AE and, over time, structural alterations in brain target areas. Clinicians should carefully monitor patients, especially children and/or when administering high doses SGC. [source] The relative kinetics of clotting and lysis provide a biochemical rationale for the correlation between elevated fibrinogen and cardiovascular diseaseJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2007P. Y. KIM Summary.,Background:,Elevated plasma fibrinogen is a well known risk factor for cardiovascular disease. The mechanistic rationale for this is not known.Objectives:,These studies were carried out to determine the fibrinogen concentration dependencies of clotting and lysis times and thereby determine whether these times rationalize the correlation between an increased risk of cardiovascular disease and elevated plasma fibrinogen.Methods:,The time courses of clot formation and lysis were measured by turbidity in systems comprising a) fibrinogen, thrombin and plasmin, or b) fibrinogen, thrombin, plasminogen and t-PA, or c) plasma, thrombin and t-PA. From the lysis times, kcat and Km values for plasmin action on fibrin were determined.Results:,The time to clot increased linearly from 2.9 to 5.6 minutes as the fibrinogen concentration increased from 1 to 9 ,M and did not increase further as the fibrinogen concentration was raised to 20 ,M. In contrast, the clot lysis time increased linearly over the input fibrinogen concentration range of 2 to 20 ,M. A similar linear trend was found in the two systems with t-PA and plasminogen. Apparent Km and kcat values for plasmin were 1.1 ± 0.6 ,M and 28 ± 2 min,1, respectively. Km values for plasmin in experiments initiated with t-PA and plasminogen were 1.6 ± 0.2 ,M in the purified system and 2.1 ± 0.9 ,M in plasma.Conclusion:,As the concentration of fibrinogen increases, especially above physiologic level, the balance between fibrinolysis and clotting shifts toward the latter, providing a rationale for the increased risk of cardiovascular disease associated with elevated fibrinogen. [source] The melanoma-associated 24 base pair duplication in p16INK4a is functionally impairedINTERNATIONAL JOURNAL OF CANCER, Issue 4 2005Therese M. Becker Abstract Melanoma-associated germline mutations affecting the tumor suppressor and cyclin-dependent kinase (CDK) inhibitor, CDKN2A/p16INK4a, have been identified in over 100 melanoma-prone families worldwide. To predict the melanoma risk for carriers of specific mutations, mutant p16INK4a can be tested in biochemical and cellular assays. In most cases, p16INK4a mutations with predicted disease relation, due to segregation with melanoma, are functionally impaired in such assays. The N-terminal 24 base pair duplication of CDKN2A, however, encodes a p16INK4a variant previously shown to have wild-type function, despite segregating with melanoma in at least 5 melanoma families. To clarify whether the duplication mutation has a cell cycle regulatory defect or behaves like wild-type p16INK4a, we reanalyzed the cell cycle-inhibitory activity of this mutation. Stable cell clones of the p16-null WMM1175 melanoma cell line inducible for ectopic p16INK4a were used in this study. In these cells, p16INK4a expression can be controlled at physiologic levels. Our results show that in comparison to wild-type p16INK4a, the duplication mutant induced weaker S-phase inhibition and cells expressing this mutant form of p16INK4a retained colony formation ability. We also show that the cell cycle-regulatory defect of the p16INK4a duplication mutant was associated with decreased inhibition of pRb phosphorylation even though it retained significant binding to CDK4. © 2005 Wiley-Liss, Inc. [source] Ras signaling in prostate cancer progressionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Michael J. Weber Abstract When prostate cancer is first detected it generally is dependent on the presence of androgens for growth, and responds to androgen ablation therapies. However, the disease often recurs in a disseminated and apparently androgen independent (AI) form, and in this state is almost invariably fatal. Considerable evidence indicates that the Androgen receptor (AR) continues to be required even in androgen independent (AI) disease. Thus, a key to understanding hormone independent prostate cancer is to determine the mechanism(s) by which the AR can function even in the absence of physiologic levels of androgen. In this article, we argue that growth factors and receptors that utilize Ras family members drive prostate cancer progression to a state of androgen hypersensitivity; and that post-translational modifications (e.g., phosphorylations) of transcriptional cofactors might be responsible for modulating the function of the AR so that it is active even at low concentrations of androgen. © 2003 Wiley-Liss, Inc. [source] Carrier proteins determine local pharmacokinetics and arterial distribution of paclitaxelJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2001Mark A. Lovich Abstract The growing use of local drug delivery to vascular tissues has increased interest in hydrophobic compounds. The binding of these drugs to serum proteins raises their levels in solution, but hinders their distribution through tissues. Inside the arterial interstitium, viscous and steric forces and binding interactions impede drug motion. As such, this might be the ideal scenario for increasing the amount of drug delivered to, and residence time within, arterial tissues. We quantified carrier-mediated transport for paclitaxel, a model hydrophobic agent with potential use in proliferative vascular diseases, by determining, in the presence or absence of carrier proteins, the maximum concentration of drug in aqueous solution, the diffusivity in free solution, and the diffusivity in arterial tissues. Whereas solubility of paclitaxel was raised 8.1-, 21-, and 57-fold by physiologic levels of ,1 -acid glycoproteins, bovine serum albumin, and calf serum over that in protein-free solution, diffusivity of paclitaxel in free solution was reduced by 41, 49, and 74%, respectively. When paclitaxel mixed in these solutions was applied to arteries both in vitro and in vivo, drug was more abundant at the tissue interface, but protein carriers tended to retain drug in the lumen. Once within the tissue, these proteins did not affect the rate at which drug traverses the tissue because this hydrophobic drug interacted with the abundant fixed proteins and binding sites. The protein binding properties of hydrophobic compounds allow for beneficial effects on transvascular transport, deposition, and distribution, and may enable prolonged effect and rationally guide local and systemic strategies for their administration. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1324,1335, 2001 [source] Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2007E. A. SILVA Summary. Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) delivery may provide a new approach for the treatment of ischemic diseases, but current strategies to deliver VEGF rely on either bolus delivery or systemic administration, resulting in limited clinical utility, because of the short half-life of VEGF in vivo and its resultant low and transient levels at sites of ischemia. We hypothesize that an injectable hydrogel system can be utilized to provide temporal control and appropriate spatial biodistribution of VEGF in ischemic hindlimbs. A sustained local delivery of relatively low amounts of bioactive VEGF (3 ,g) with this system led to physiologic levels of bioactive VEGF in ischemic murine (ApoE,/,) hindlimbs for 15 days after injection of the gel, as contrasted with complete VEGF deprivation after 72 h with bolus injection. The gel delivery system resulted in significantly greater angiogenesis in these limbs as compared to bolus (266 vs. 161 blood vessels mm,2). Laser Doppler perfusion imaging showed return of tissue perfusion to normal levels by day 28 with the gel system, whereas normal levels of perfusion were never achieved with saline delivery of VEGF or in control mice. The system described in this article could represent an attractive new generation of therapeutic delivery vehicle for treatment of cardiovascular diseases, as it combines long-term in vivo therapeutic benefit (localized bioactive VEGF for 1,2 weeks) with minimally invasive delivery. [source] Conditional expression of PTEN alters the androgen responsiveness of prostate cancer cells,THE PROSTATE, Issue 10 2006Z. Wu Abstract BACKGROUND Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is lost as a function of prostate tumor androgen dependence. While the transcriptional activity of the androgen receptor (AR) is inhibited by PTEN in androgen sensitive prostate cancer (CaP), the role of PTEN in androgen disease is unclear. METHODS We developed a system where PTEN can be conditionally re-expressed at physiologic levels into a PTEN null metastatic human CaP cell line, C4-2, and androgen responsiveness examined. RESULTS PTEN induction reduces cell growth and blocks the growth effect of synthetic androgen R1881. The anti-androgen Casodex enhances the growth-inhibitory action of PTEN and this effect is independent of Akt phosphorylation. Combined PTEN induction and Casodex, result in a further decrease in prostate specific antigen promoter activity compared to PTEN but not Casodex alone. CONCLUSIONS PTEN induction confers androgen independent CaP cells enhanced responsiveness to the anti-proliferative effects of anti-androgens and this action may involve non-AR mediated effects. Prostate 66: 1114-1123, 2006. © 2006 Wiley-Liss, Inc. [source] Human ex vivo bone tissue strains around immediately loaded implants supporting maxillary overdenturesCLINICAL ORAL IMPLANTS RESEARCH, Issue 6 2005vanç Akça Abstract Purpose: To evaluate ex vivo bone tissue strains around maxillary implants supporting immediately loaded bar-retained overdentures. Material and methods: Ninety degree two-element rosette strain gauges were bonded on the labial bone of four ITI® dental implants placed in the maxillary anterior region of four completely edentulous maxilla of fresh human cadavers. The installation torque value (ITV) of each implant was measured by a custom-made torque wrench and resonance frequency analyses (RFAs) were undertaken. A bar-retained overdenture was fabricated for each cadaver, and two miniature load cells were integrated in the first molar region of the overdentures for controlled loading experiments. Strain measurements were performed at a sample rate of 10 kHz and under a maximum load of 100 N, simultaneously monitored from a computer connected to a data acquisition system. Finally, removal torque values (RTVs) of the implants were measured. Results: RFA values did not mirror ITVs, while RTVs of implants were slightly lower than the ITVs. Any correlation could not be obtained between RFA values and ITVs or RTVs. Maximum strains around loaded implants ranged between ,100 and ,550 ,, under 25,100 N. The axial and lateral strain values of posterior implants of both sides were higher than those of anterior implants under all loads (P<0.05). Conclusion: Because occlusal forces in humans tend to decrease because of age-related factors, maximum strains around immediately loaded implants supporting maxillary overdentures fall within physiologic levels. Résumé Le but de cette étude a été d'évaluer les tensions du tissu osseux ex vivo autour d'implants maxillaires portant des prothèses amovibles retenues sur une barre placée immédiatement après l'insertion des implants. Deux jauges de force en rosette à 90° ont été attachées au côté lingual de l'os de quatre implants dentaires ITI® placés dans la région antérieure du maxillaire de quatre cadavres humains frais aux maxillaires édentées. La valeur du couple de torsion lors de l'installation (ITV) de chaque implant a été mesurée par un couple fabriqué et des analyses de fréquence de résonnance (RFA) ont été faites. Une prothèse retenue par une barre a été fabriquée pour chaque cadavre et deux cellules de charge miniatures ont été intégrées dans la région de la première molaire de ces prothèses pour les expériences de charge contrôlées. Les mesures de force ont été effectuées à un taux d'échantillonnage de 10 kHz et sous une charge maximale de 100 N, suivies simultanément par un ordinateur connectéà un système d'acquisition de données. Finalement les valeurs des couples de torsion à l'enlèvement (RTV) des implants ont été mesurées. Les valeurs RFA n'étaient pas en ligne avec les ITV tandis que les RTV des implants étaient légèrement inférieurs aux ITV. Aucune corrélation n'a pûêtre établie entre les valeurs RFA et ITV ou RTV. Les forces maximales autour des implants chargés s'étalaient de ,100 ,e à,550 ,e sous 25 N à 100 N. Les valeurs des forces axiales et latérales des implants postérieurs des deux côtés étaient supérieures à celles des implants antérieurs sous toutes les charges (P<0.05). Zusammenfassung Ziel: Es war das Ziel dieser Arbeit, an bis vor kurzem vitalen Knochengewebe Spannungen um Oberkieferimplantate zu untersuchen, welche sofortbelastete und stegverankerte Hybridprothesen tragen. Material und Methoden: Auf den labialen Knochen von vier ITI-Implantaten in der vorderen Region des zahnlosen Oberkiefers von vier frisch verstorbenen Menschen klebte man Dehnmessinstrumente an. Man mass den Wert der Eindrehkraft (ITV) jedes einzelnen Implantates mit einem handelsblichen Drehmomentschlssel und fhrte eine Resonanzfrequenzanalyse (RFA) durch. Man stellte fr jede Leiche eine stegverankerte Hybridprothese her und man baute in der Region der ersten Molaren zwei kleine Messgerte ein, die kontrollierte Belastungsexperimente erlaubten. Dehnmessungen fhrte man mit einer Frequenz von 10 kHz und einer maximalen Belastung von 100 N durch, simultan aufgezeichnet von einem mit dem Messsystem verbundenen Komputer. Schliesslich mass man auch die Krfte, die es brauchte um die Implantate wieder auszudrehen (RTV). Resultate: Die RFA wiederspiegelte die ITV-Werte nicht, whrenddem die RTV-Werte der Implantate geringfgig tiefer waren als die ITV-Werte. Man konnte weder zwischen der RFA, den ITV-Werten oder den RTV-Werten eine Korrelation herstellen. Die maximalen Dehnungen um die Implantate erreichte Werte zwischen ,100 E und ,550 E bei einer Belastung zwischen 25 N und 100 N. Die axialen und lateralen Dehnkrfte bei posterioren Implantaten waren unter smtlichen getesteten Belastungen beidseits grsser als diejenigen der anterioren Implantate (P<0.05). Resumen Propósito: Evaluar las tensiones del tejido óseo ex vivo alrededor de implantes maxilares soportando sobredentaduras retenidas por barras con carga inmediata. Material y Métodos: Se pegaron dos indicadores de tensión de roseta de dos elementos de 90° en el hueso labial de cuatro implantes dentales ITI® colocados en la región maxilar anterior de cuatro maxilares completamente edéntulos de cadáveres humanos frescos. Se midió el valor del torque de instalación (ITV) de cada implante por medio de una chicharra de torque hecha a medida y se llevó a cabo análisis de frecuencia de resonancia (RFA). Se fabricó una sobredentadura retenida por barras para cada cadáver y se integraron dos células miniatura de carga en la región del primer molar de las sobredentaduras para los experimentos de carga controlada. Se llevaron a cabo mediciones de la tensión a un índice de muestra de 10 kHz y bajo una carga máxima de 100 N, simultáneamente monitorizada desde un ordenador conectado a sistema de adquisición de datos. Finalmente, se midieron los valores del torque de remoción (RTV) de los implantes. Resultados: Los valores de RFA no se reflejaron en los ITVs, mientras que los RTVs de los implantes fueron ligeramente más bajos que los ITVs. No se pudieron obtener correlaciones entre los valores de RFA y los ITVs o RTVE. Las tensiones máximas alrededor de los implantes cargados variaron entre ,100 ,, y ,550 ,, bajo 25 N a 100 N. Los valores de las tensiones axiales y laterales de los implantes posteriores de ambos lados fueron mayores que aquellos implantes anteriores bajo todas las cargas (P<0.05). [source] | ||||||||||