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PubMed2006

Non contrast-enhanced four-detector multisection CT for the detection of ring lesions in seizures.

AIM: To evaluate the role of non contrast-enhanced multidetector computed tomography (MDCT) in the detection of ring lesions in the brain in patients from the Indian subcontinent, presenting with seizures. MATERIALS AND METHODS: Ninety-four patients presenting with seizures were examined using four-detector MDCT. Contiguous axial non contrast-enhanced CT of the brain was performed with a section width/section collimation of 5mm/5mm. A single axial non-contrast enhanced examinaton of section width 2.5mm was obtained through the region of interest, if necessary. This was followed by contrast-enhanced sequential imaging in all patients, using the same parameters as for unenhanced CT (i.e., 5mm/5mm). Non-contrast and contrast-enhanced CT images were recorded and reviewed separately. RESULTS: In 63 out of 94 cases non-enhanced MDCT (with section width 5mm) was able to identify the ring lesions. In 11 cases, which were doubtful on unenhanced CT (5mm), performing a single examination using a section width of 2.5mm through the area of interest, helped to detect the ring lesion. Hence in 74 out of 94 (79%) cases ring lesions could be detected using unenhanced MDCT. In the remaining 21% cases, the presence of ring lesions in the brain was confirmed only after the intravenous administration of contrast medium. CONCLUSION: Non contrast-enhanced MDCT is recommended for detecting ring lesions in the brain of patients on the Indian subcontinent, presenting with seizures. This can help to decrease the radiation dose to the patient and reduce the duration of examination. The risk of adverse reactions and patient discomfort associated with intravenous contrast medium injection are also reduced as are the costs incurred. Contrast-enhanced MDCT should be performed only in those cases in which the presence of ring lesions is doubtful on unenhanced CT.

Adolescent↗

PubMed2005

Enhanced efficacy of triprolidine by transdermal application of the EVA matrix system in rabbits and rats.

The bioavailability of triprolidine from the ethylene vinyl acetate (EVA) matrix system containing polyoxyethylene-2-oleyl ether was studied to determine the feasibility of enhanced transdermal delivery of triprolidine in rabbits. The antihistamine effects were also confirmed to determine the percutaneous absorption of triprolidine from the EVA matrix system containing a penetration enhancer and plasticizer in rats. The triprolidine-EVA matrix (50mg/kg) was applied to the abdominal skin of rabbits. Blood samples were collected via the femoral artery for 36 h and the plasma concentrations of triprolidine were determined by HPLC. The pharmacokinetic parameters were calculated using the LAGRAN computer program. The area under the curve(AUC) was significantly higher in the enhancer group (4582+/-1456 ng/mL h) than that (2958+/-997 ng/mL h) in the control group (P<0.05), showing an approximate 155% increased bioavailability. The average Cmax in the enhancer group (241+/-46.5 ng/mL) was significantly higher than that in the control group (198+/-28.9 ng/mL), (P<0.05). The mean Tmax in the enhancer group (8.0+/-2.57 h) was higher than that in the control group (6.0+/-2.24 h, but this was not statistically significantly. The relative bioavailability of triprolidine in the transdermal application was 35.9% in the control group and 55.6% in the enhancer group compared comparing with that after oral administration. As the triprolidine-EVA matrix, which contains polyoxyethylene-2-oleyl ether as an enhancer and triethyl citrate as a plasticizer was administered to the rabbits via the transdermal routes, the relative bioavailability increased approximately 1.55 fold compared with that in the control group, showing a relatively constant, sustained blood concentration with minimal fluctuation. The antihistamine effect was determined using the Evans blue dye procedure by comparing the changes in the vascular permeability increase following the transdermal application. The vascular permeability increase was reduced significantly by the transdermal application of the EVA-triprolidine system containing triethyl citrate and polyoxyethylene-2-oleyl ether. These results show that the plasticizer and penetration enhancer increase the skin permeation of triprolidine and the triprolidine-EVA matrix system could be developed as a transdermal delivery system providing the increased constant plasma concentration and antihistamine effects.

Administration, Cutaneous↗

PubMed2006

Contrast enhanced sonography of the gallbladder: a tool in the diagnosis of cholecystitis?

RATIONALE AND OBJECTIVES: To evaluate if contrast enhanced sonography (CES) can help to detect gallbladder inflammation and differentiate between acute and chronic cholecystitis. MATERIALS AND METHODS: Thirty-three patients with clinical suspicion of acute cholecystitis were examined with CES before cholecystectomy. Thirty patients with no history of gallbladder disease served as control. CES was performed using 2.5 mL SonoVue. A small mechanical index was chosen (0.1). The enhancement pattern of the gallbladder was ranked in a three-point scale: no enhancement, low enhancement and strong enhancement. 28/33 patients underwent surgery. Sonographic findings were compared to histological results. RESULTS: In 16/20 cases with histological proven acute cholecystitis, the gallbladder wall showed a strong enhancement. Low enhancement was found in four patients with acute and in six patients with chronic cholecystitis. The gallbladder wall of two patients with chronic inflammation and all patients (30/30) of the control group showed no enhancement. CONCLUSION: CES is a feasible tool for detecting gallbladder inflammation. Differentiating between acute and chronic cholecystitis seems to be possible.

Acute Disease↗

PubMed2004

Enhanced transdermal delivery of atenolol from the ethylene-vinyl acetate matrix.

To enhance transdermal delivery of atenolol, ethylene-vinyl acetate (EVA) matrix of drug containing penetration enhancer was fabricated. Effect of penetration enhancer on the permeation of atenolol through the excised rat skin was studied. Penetrating enhancers showed the increased flux probably due to the enhancing effect on the skin barrier, the stratum corneum. Among enhancers used such as glycols, fatty acids and non-ionic surfactants, polyoxyethylene 2-oleyl ether showed the best enhancement. For the controlling transdermal delivery of atenolol, the application of EVA matrix containing permeation enhancer could be useful in the development of transdermal drug delivery system.

Administration, Cutaneous↗

PubMed2004

Hydration status and cardiovascular function: effects of hydration enhancement on cardiovascular function at rest and during psychological stress.

This study examined the effects of a 3-day enhanced hydration regimen on resting cardiac function and reactivity to acute stress. Healthy volunteers (14 male, 14 female) were assigned to one of two groups: Enhanced Hydration and Normal Hydration Group. Participants in the Enhanced Group were given six 1-l bottles of water and instructed to drink two bottles a day in addition to normal fluid intake for 3 days preceding their laboratory session; no extra water was given to the Normal Group. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), cardiac output (CO), stroke volume (SV), and total peripheral resistance (TPR) were recorded during a 10-min baseline, 6-min Paced Auditory Serial Addition Test (PASAT), 5-min recovery, 5-min intermediate baseline, and 3-min Cold Pressor Test. Repeated-measures ANOVA revealed a significant Hydration GroupxTask interaction for DBP during the cold pressor (p<0.01) with the Enhanced Group exhibiting greater DBP reactivity to cold stress relative to the Normal Group. Analysis revealed significant Hydration GroupxGender interactions for SV and TPR (p<0.05) at rest and during both the PASAT and Cold Pressor Test. Females in the Enhanced Group displayed higher SV and lower TPR relative to Enhanced Group males, whereas females in the Normal Group displayed lower SV and greater TPR relative to Normal Group males. These results suggest that 3-day hydration enhancement influences blood pressure reactivity in both men and women, and that long-term hydration enhancement is related to resting gender differences in cardiac function.

Adolescent↗

PubMed2006

New insights into the passive force enhancement in skeletal muscles.

The steady-state isometric force following active stretching of a muscle is always greater than the steady-state isometric force obtained in a purely isometric contraction at the same length. This phenomenon has been termed "residual force enhancement" and it is associated with an active and a passive component. The origin of these components remains a matter of scientific debate. The purpose of this work was to test the hypothesis that the passive component of the residual force enhancement is caused by a passive structural element. In order to achieve this purpose, single fibers (n=6) from the lumbrical muscles of frog (Rana pipiens) were isolated and attached to a force transducer and a motor that could produce computer-controlled length changes. The passive force enhancement was assessed for three experimental conditions: in a normal Ringer's solution, and after the addition of 5 and 15mM 2,3-butanedione monoxime (BDM) which inhibits force production in a dose-dependent manner. If our hypothesis was correct, one would expect the passive force enhancement to be unaffected following BDM application. However, we found that increasing concentrations of BDM decreased the isometric forces, increased the normalized residual force enhancement, and most importantly for this study, increased the passive force enhancement. Furthermore, BDM decreased the rate of force relaxation after deactivation following active stretching of fibers, passive stretching in the Ringer's and BDM conditions produced the same passive force-sarcomere length relationship, and passive force enhancement required activation and force production. These results led to the conclusion that the passive force enhancement cannot be caused by a structural component exclusively as had been assumed up to date, but must be associated, directly or indirectly, with cross-bridge attachments upon activation and the associated active force.

Animals↗

PubMed2005

Buccal penetration enhancers--how do they really work?

Certain agents that increase drug delivery through the skin, including surfactants, bile salts, and fatty acids, have been shown to exert a similar effect on the buccal mucosa. These agents enhance skin permeability by interacting with and disrupting the ordered intercellular lipid lamellae within the keratinized stratum corneum, and it has been assumed that a similar mechanism of action occurs in the nonkeratinized buccal mucosa. However, the chemical and structural nature of the lipids present within the intercellular regions of the buccal mucosa is quite different to that found within the stratum corneum, and so extrapolation of results between these two tissues may be misleading. To assume that the mechanism of action of buccal penetration enhancers is based on the disruption of intercellular lipids may be erroneous, and may result in the inappropriate prediction that certain skin penetration enhancers will similarly enhance drug delivery through the buccal mucosa. The data available in the literature suggest that agents that enhance buccal penetration exert their effect by a mechanism other than by disruption of intercellular lipids. Rather, buccal penetration enhancement appears to result from agents being able to (a) increase the partitioning of drugs into the buccal epithelium, (b) extract (and not disrupt) intercellular lipids, (c) interact with epithelial protein domains, and/or (d) increase the retention of drugs at the buccal mucosal surface. The purpose of this review is to identify the major differences in the structural and chemical nature of the permeability barriers between the buccal mucosa and skin, to clarify the mechanisms of action of buccal penetration enhancers, and to identify the limitations of certain models that are used to assess the effect of buccal penetration enhancers.

Absorption↗

PubMed2005

Nitric oxide donors can enhance the intestinal transport and absorption of insulin and [Asu(1,7)]-eel calcitonin in rats.

The characteristics of three NO donors, 3-(2-hydroxy-1-(1-methylethyl)-2-nitrosohydrazino)-1-propanamine (NOC5), N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC12) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) as absorption enhancers for peptide drugs were examined in rats using a modified Ussing chamber method and an in situ closed loop method. Insulin and [Asu(1,7)]-eel calcitonin (ECT) were used as a model drug to investigate the effectiveness of the tested enhancers. The NO donors significantly increased the in vitro permeability of insulin across all intestinal membranes. In general, the absorption enhancement effects of these NO donors were greater in the colon than those in the jejunum and ileum. Of these NO donors, SNAP was the most effective enhancer. Their effects were concentration-dependent over the range of 0.01 to 0.1 mM. However, 0.1 mM NO donors had almost the same effects as those at 1 mM concentration. The absorption-enhancing effects of the three NO donors were inhibited by the co-administration of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide, sodium salt (carboxy-PTIO), an NO scavenger, suggesting that NO might be responsible for the efficacy of NO donors. In the in situ closed loop experiments, the three enhancers significantly improved the pharmacological availability % (PA%) of insulin in the small and large intestine. Similar results were also obtained when NO donors were added to ECT solution by an in situ closed loop method. These results suggest that NO donors possess excellent effectiveness for the use as absorption enhancers of peptide drugs and they are very effective at lower concentrations compared to the conventional enhancers.

Animals↗

PubMed2006

Clinical feasibility of free-breathing, gadolinium-enhanced magnetic resonance angiography for assessing extracardiac thoracic vascular abnormalities in young children with congenital heart diseases.

OBJECTIVE: Congenital heart diseases in pediatric patients are associated with a wide variety of extracardiac thoracic vascular abnormalities. This study analyzed the value of gadolinium-enhanced magnetic resonance angiography during quiet free breathing for assessing extracardiac thoracic vascular abnormalities in young children with congenital heart diseases. METHODS: Fifty-three children with congenital heart diseases (age range, 1 day-40 months; mean, 10.9 months) associated with extracardiac thoracic vascular abnormalities who had undergone both free-breathing, gadolinium-enhanced magnetic resonance angiography and cardiac catheterization, surgical intervention, or both within 2 weeks were reviewed. Diagnostic findings on gadolinium-enhanced magnetic resonance angiography among patients grouped according to 3 major conditions of conotruncal abnormalities (n = 33), aortic or venous abnormalities (n = 11), and pulmonary vascular abnormalities (n = 9), as well as associated extracardiac thoracic vascular abnormality findings, were compared with findings made by using cardiac catheterization, surgical intervention, or both. RESULTS: Extracardiac thoracic vascular abnormality findings on gadolinium-enhanced magnetic resonance angiography were similar to those on catheterization, surgical intervention, or both in patients with conotruncal abnormalities (124 vs 127, P = .083), aortic or venous abnormalities (36 vs 33, P = .083), and pulmonary vascular abnormalities (24 vs 25, P = .317). The overall sensitivity of gadolinium-enhanced magnetic resonance angiography for detection of these lesions identified by means of catheterization, surgical intervention, or both was 97.9%. However, gadolinium-enhanced magnetic resonance angiography revealed 11 additional extracardiac thoracic vascular abnormalities that were not found on cardiac catheterization. The kappa coefficient for the correlation of image quality and diagnostic value of gadolinium-enhanced magnetic resonance angiography by using a 4-point-scale (1 = nondiagnostic to 4 = excellent) assessed by 2 independent reviewers was excellent (mean score = 3.66), with superb interobserver agreement (kappa = 0.727-0.874). CONCLUSIONS: Free-breathing, gadolinium-enhanced magnetic resonance angiography is clinically feasible for detailed anatomic delineation and treatment planning of various extracardiac thoracic vascular abnormalities in young children with congenital heart diseases.

Cardiovascular Abnormalities↗

PubMed2005

Human stem cell factor-antibody [anti-SCF] enhances chemotherapy cytotoxicity in human CD34+ resistant myeloid leukaemia cells.

Acute myeloid leukaemia (AML) is a heterogenous malignant disease with diverse biological features in which disease progression at the level of CD34+ cells has a major impact on the resistance to chemotherapy and relapse. The AML blast cells in these elderly patients are often characterised by several unfavourable covariates that predict the poor treatment outcome, including high stem cell marker CD34 expression, minimally or undifferentiated features, high P-glycoprotein expression, high bcl-2/bax ratio, unfavourable karyotype and more frequent internal tandem duplications (ITDs) and mutations of class III receptor-type tyrosine kinase for key haematopoietic cytokines: Flt-3 (receptor for Flt-ligand), c-kit (receptor for stem cell factor) and fms (receptor for M-CSF). Testing the new and more specific molecular-targeted therapeutic approaches in CD34+ AML cells can provide the basis for a more effective combined molecular/chemotherapy regimen and may consequently improve the treatment outcome in elderly AML patients. Therefore, the present study was performed to evaluate whether stem cell factor-antibody (anti-SCF) can enhance the efficacy of the two main chemotherapeutic drugs used in AML therapy: cytarabine and daunorubicin at low doses in human-resistant CD34+ AML cells, in an attempt to identify a novel effective regimen with tolerable side-effects for elderly AML patients. The effect of anti-SCF on each of the two chemotherapeutic drugs-induced apoptosis and necrosis was investigated in KG1a human-resistant CD34+ AML cells expressing P-glycoprotein to determine its enhancing activity. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells from 12.0+/-1.7 to 40.9+/-5.9% and from 16.3+/-0.9 to 48.9+/-1.0%, respectively, p<0.01. It has also exerted its significant enhancement activity on the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells in the presence of SCF, p<0.05. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells from 26.7+/-0.6 to 64.6+/-1.0% and from 59.8+/-3.1 to 80.1+/-7.9%, respectively, p<0.01. The addition of SCF has not altered the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells (Table 4). Anti-SCF has also significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells in the presence of SCF, p<0.05. The unique potent enhancing activity of anti-SCF on low dose chemotherapy-induced apoptosis and necrosis in extremely resistant AML cells suggest a novel promising role for the treatment of elderly AML patients. Further studies are warranted to evaluate a similar enhancing effect for anti-SCF in blast cells from elderly AML patients in primary cultures before its introduction in a pilot clinical study. In conclusion, the combination of anti-SCF and the low dose cytarabine provides a promising solution for the dilemma of therapy in elderly AML patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Atomoxetine and nicotine enhance prepulse inhibition of acoustic startle in C57BL/6 mice.

Deficits in sensory-gating, often measured as deficits in prepulse inhibition of acoustic startle (PPI), are associated multiple with disorders including schizophrenia, attention deficit and hyperactivity disorder (ADHD), and withdrawal from nicotine. Drugs that can reverse deficits in PPI may serve as therapeutic agents for nicotine withdrawal, ADHD, and/or schizophrenia. The present study investigated the effects of acute atomoxetine, a norepinephrine reuptake inhibitor, nicotine, and mecamylamine, a nicotinic acetylcholinergic antagonist, on PPI and acoustic startle in C57BL/6 mice. Three doses of atomoxetine (0.2, 2.0, and 20 mg/kg) were administered prior to testing PPI and startle. The 0.2 and 2.0 mg/kg doses enhanced PPI and the 20 mg/kg dose enhanced startle. A second experiment investigated the effects of 2.0 mg/kg atomoxetine and 1.0mg/kg mecamylamine administered alone or together on PPI and startle. As before, atomoxetine enhanced PPI. Mecamylamine did not alter PPI and did not block the enhancement of PPI by atomoxetine. Neither drug altered startle. A third experiment investigated the effects of 2.0 mg/kg atomoxetine and 0.125 mg/kg nicotine administered alone or together on PPI and startle. Both drugs enhanced PPI when administered alone. However, when co-administered, no enhancement of PPI was seen. Neither nicotine nor atomoxetine altered startle. The present results demonstrate that acute doses of nicotine and atomoxetine enhance PPI independent of effects on startle and that the enhancement of PPI by atomoxetine occurs independent of the nicotinic acetylcholinergic system. Thus, the newly available medication for ADHD, atomoxetine, could be a potential therapeutic agent for disorders associated with disrupted PPI such as withdrawal from nicotine.

Acoustic Stimulation↗

PubMed2005

Activities of hypothalamic angiotensin II-sensitive neurons are greately enhanced even in prehypertensive spontaneously hypertensive rats.

We have previously demonstrated that some neurons in the anterior hypothalamic area (AHA) of rats are tonically activated by endogenous angiotensins and that reactivities of these neurons to angiotensin II are enhanced in 15- to 16-week-old spontaneously hypertensive rats (SHR). To investigate whether the enhanced reactivity of SHR AHA neurons to angiotensin II is secondary to raised blood pressure, we examined whether the enhanced reactivity to angiotensin II also occurs in prehypertensive SHR. We also examined whether reactivities of AHA angiotensin II-sensitive neurons to intracerebroventricular hypertonic saline are enhanced in prehypertensive SHR, since intracerebroventricular injection of hypertonic saline increases the firing rate of AHA neurons via release of angiotensins at AHA neuron levels. Male 4-week-old SHR and age-matched Wistar Kyoto rats (WKY) were used in this study. There was no difference in systolic blood pressure between both rats. They were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Pressure application of angiotensin II onto some AHA neurons increased their firing rate. The basal firing rate of angiotensin II-sensitive neurons was increased in SHR as compared with WKY. The increase of unit firing by angiotenisn II was enhanced in SHR as compared with WKY. Intracerebroventricular injection of hypertonic saline increased the firing rate of AHA angiotensin II-sensitive neurons. The average threshold sodium concentration for the saline-induced increase of neural firing was lower in SHR than in WKY. These findings demonstrate that basal activities and responsiveness to angiotensin II in AHA angiotensin II-sensitive neurons are enhanced in prehypertensive SHR as compared with age-matched WKY. In addition, these findings indicate that central saline-induced activation of AHA angiotensin II-sensitive neurons is also enhanced in SHR. It appears that the enhanced reactivity of SHR AHA neurons to angiotensin II occurs primarily in nature but not secondarily to raised blood pressure in SHR.

Action Potentials↗

PubMed2004

Haemodynamic responses to sensory stimulation are enhanced following acute cocaine administration.

Cocaine enhances neural activity in response to sensory stimulation, an effect that may play a role in the development of drug craving. However, cocaine-induced sensory enhancement may be difficult to study in humans using neuroimaging if the global increases in baseline haemodynamic parameters, which cocaine produces, interfere with the ability of enhanced sensory-related neural activity to lead to enhanced haemodynamic responses. To investigate the effect of cocaine-induced baseline haemodynamic changes on sensory-related haemodynamic (and electrophysiological) responses, field potential (FP) and haemodynamic responses (obtained using optical imaging spectroscopy and laser-Doppler flowmetry) in the barrel cortex of the anaesthetised rat were measured during mechanical whisker stimulation following cocaine (0.5 mg/kg) or saline administration. During cocaine infusion, the relationship between blood flow and volume transiently decoupled. Following this, cocaine caused large baseline increases in blood flow (133%) and volume (33%), which peaked after approximately 6 min and approached normal levels again after 25 min. During the peak baseline increases, FP responses to whisker stimulation were similar to saline whereas several haemodynamic response parameters were slightly reduced. After the peak, significant increases in FP responses were observed, accompanied by significantly enhanced haemodynamic responses, even though the haemodynamic baselines remained elevated. Hence, the haemodynamic response to sensory stimulation is transiently reduced in the presence of large increases in baseline but, after the baseline peak, enhanced neural responses are faithfully accompanied by enhanced haemodynamic responses. The findings suggest that any cocaine-induced enhancement of sensory-related neural activity in humans is likely to be detectable by neuroimaging.

Animals↗

PubMed2005

ERbeta-selective SERMs produce mnemonic-enhancing effects in the inhibitory avoidance and water maze tasks.

Estradiol (17beta-E2) can have mnemonic-enhancing effects; however, its mechanisms for these effects are not well-understood. The present studies examined effects of 17beta-E2 and selective estrogen receptor modulators (SERMs) on emotional and spatial memory of female, Long-Evans rats. First, whether or not 17beta-E2 has dose-dependent effects on inhibitory avoidance memory was investigated. Only the highest concentration of 17beta-E2 examined (10 microg), which produces physiological concentrations of E2, was effective at enhancing inhibitory avoidance memory (Experiment 1). Further studies were designed to elucidate whether SERMs may produce mnemonic effects similar to those of 17beta-E2. Compounds utilized were, the ERalpha-selective SERMs, propyl pyrazole triol (PPT) or 17alpha-E2, the ERbeta-specific SERMs, diarylpropionitrile (DPN) or 7,12-dihydrocoumestan (coumestrol), or vehicle (oil). Post-training administration of 10 microg 17beta-E2 or coumestrol enhanced memory in the inhibitory avoidance task compared to vehicle (Experiment 2). Memory in the water maze was enhanced by post-training administration of 17beta-E2, coumestrol, or DPN, compared to vehicle (Experiment 3). Co-administration of 17alpha-E2&DPN enhanced inhibitory avoidance memory similar to that seen following 17beta-E2 or coumestrol (Experiment 4). Administration of E2 2 h post-training was not effective at enhancing memory in the inhibitory avoidance or water maze tasks (Experiment 5). Lordosis of rats was enhanced by 17beta-E2, 17alpha-E2, or PPT, compared to vehicle (Experiment 6). These data suggest that: E2's actions at ERbeta, rather than ERalpha, may enhance spatial memory, E2's actions at ERalpha can facilitate sexual behavior, and that E2's actions involving both ERalpha and ERbeta may be important for emotional memory.

Animals↗

PubMed2004

Enhancement revisited: the effects of multiple depletions on sodium intake in rats vary with strain, substrain, and gender.

Repeated sodium depletion enhances spontaneous sodium intake in animals and humans, and may be a significant determinant of lifelong sodium intake. In rats, even a single sodium depletion is reported to enhance both need-induced and spontaneous sodium intakes enduringly. Both types of increases are reported to plateau after two to three depletions, and to be greater in females. Here, in two strains of rats, Wistar (W) and Sprague-Dawley (SD), and in two laboratories using different W substrains, in Israel and France, we studied the influence of repeated sodium depletions on need-induced and spontaneous sodium intake. Need-induced intake in W increased incrementally, but in SD, need-induced intake occurred fully at the first depletion. In both cases, the response was not related to changes in the diuretic efficacy of furosemide. In all strains, depletions enhanced spontaneous sodium intake, but the enhancement dissipated within days following each depletion, and only attained significance over the whole 7-week experiment in male SD. Enhancement was not greater in females, despite their greater spontaneous sodium intakes. Finally, in rats given a choice of NaCl and CaCl2, depletions enhanced only NaCl intake, both need-induced and spontaneous, attesting to the specificity of the appetite in both its forms. Our findings show that enhancement of need-induced and spontaneous sodium intake resulting from repeated sodium depletions depends upon the gender and strain of rats, and it does not result from an altered diuretic response. Persistent enhancement of spontaneous sodium intake is not a ubiquitous phenomenon.

Analysis of Variance↗

PubMed2004

Exposure to 4-tert-octylphenol, an environmentally persistent alkylphenol, enhances interleukin-4 production in T cells via NF-AT activation.

4-tert-Octylphenol (OP) is a representative endocrine disruptor that may have adverse effects on human health. The influence of this compound on allergic immune responses remains unclear. In this study, we have examined the effects of OP on production of interleukin-4 (IL-4), a pro-inflammatory cytokine closely associated with allergic immune responses. OP significantly enhanced IL-4 production in antigen-primed T cells in a dose-dependent manner. Treatment with OP in vivo resulted in significant increase of IL-4 production in T cells and of IgE levels in sera of antigen-primed mice. Furthermore, OP enhanced the activation of IL-4 gene promoter in EL4 T cells transiently transfected with IL-4 promoter/reporter constructs, and the enhancing effect mapped to a region in the IL-4 promoter containing binding sites for nuclear factor of activated T cell (NF-AT). Activation of T cells by phorbol-12-myristate-13-acetate (PMA) resulted in markedly enhanced binding activities to the NF-AT site, which significantly increased upon addition of OP, indicating that the transcription factor NF-AT was involved in the enhancing effect of OP on IL-4 production. The enhancement of IL-4 production by OP was blocked by FK506, a calcineurin inhibitor, but not by the estrogen receptor (ER) antagonist ICI 182780. FK506 inhibited the NF-AT-DNA binding activity and IL-4 gene promoter activity enhanced by OP in a dose-dependent manner. These findings demonstrate that OP enhances IL-4 production in T cells via the stimulation of calcineurin-dependent NF-AT activation.

Animals↗

PubMed2001

Adenosine-enhanced ischemic preconditioning modulates necrosis and apoptosis: effects of stunning and ischemia-reperfusion.

BACKGROUND: Adenosine-enhanced ischemic preconditioning extends the protection of ischemic preconditioning by both significantly decreasing infarct size and significantly enhancing postischemic functional recovery. METHODS: The effects of adenosine-enhanced ischemic preconditioning on necrosis and apoptosis were investigated in the sheep heart using models of stunning (15 minutes regional ischemia, 120 minutes reperfusion) and ischemia-reperfusion (30 and 60 minutes regional ischemia, 120 minutes reperfusion). Ischemic preconditioned hearts received 5 minutes regional ischemia, 5 minutes reperfusion before ischemia. Adenosine-enhanced ischemic preconditioned hearts received a 10 mmol/L adenosine bolus (10 mL) through the left atrium coincident with ischemic preconditioning. Adenosine hearts received a 10 mmol/L bolus (10 mL) of adenosine. Regional ischemic hearts received no pretreatment. RESULTS: Minimal apoptosis (< 45 per 3,000 myocytes) was observed in the stunning models but was significantly increased with ischemia-reperfusion in regional ischemic hearts after 30 minutes (p < 0.05 versus ischemic preconditioning, adenosine, or adenosine-enhanced ischemic preconditioning) and in adenosine and ischemic preconditioned hearts after 60 minutes ischemia (p < 0.05 versus adenosine-enhanced ischemic preconditioning). DNA laddering was apparent after 60 minutes ischemia in regional ischemia, adenosine, and ischemic preconditioning but not in adenosine-enhanced ischemic preconditioned hearts. CONCLUSIONS: Adenosine-enhanced ischemic preconditioning significantly ameliorates necrosis and apoptosis in the regional ischemic blood-perfused heart.

Adenosine↗

PubMed2002

Saturated anionic phospholipids enhance transdermal transport by electroporation.

Anionic phospholipids, but not cationic or neutral phospholipids, were found to enhance the transdermal transport of molecules by electroporation. When added as liposomes to the milieus of water-soluble molecules to be delivered through the epidermis of porcine skin by electroporation, these phospholipids enhance, by one to two orders of magnitude, the transdermal flux. Encapsulation of molecules in liposomes is not necessary. Dimyristoylphosphatidylserine (DMPS), phosphatidylserine from bovine brain (brain-PS), dioleoylphosphatidylserine (DOPS), and dioleoylphosphatidylglycerol (DOPG) were used to test factors affecting the potency of anionic lipid transport enhancers. DMPS with saturated acyl chains was found to be a much more potent transport enhancer than those with unsaturated acyl chains (DOPS and DOPG). There was no headgroup preference. Saturated DMPS was also more effective in delaying resistance recovery after pulsing, and with a greater affinity in the epidermis after pulsing. Using fluorescent carboxyl fluorescein and fluorescein isothiocyanate (FITC)-labeled Dextrans as test water-soluble molecules for transport, and rhodamine-labeled phospholipids to track anionic phospholipids, we found, by conventional and confocal fluorescence microscopy, that transport of water-soluble molecules was localized in local transport spots or regions (LTRs) created by the electroporation pulses. Anionic phospholipids, especially DMPS, were located at the center of the LTRs and spanned the entire thickness of the stratum corneum (SC). The degree of saturation of anionic phospholipids made no difference in the densities of LTRs created. We deduce that, after being driven into the epidermis by negative electric pulses, saturated anionic phospholipids mix and are retained better by the SC lipids. Anionic lipids prefer loose layers or vesicular rather than multilamellar forms, thereby prolonging the structural recovery of SC lipids to the native multilamellar form. In the presence of 1 mg/ml DMPS in the transport milieu, the flux of FITC-Dextran-4k was enhanced by 80-fold and reached 175 microg/cm(2)/min. Thus, the use of proper lipid enhancers greatly extends the upper size limit of transportable chemicals. Understanding the mechanism of lipid enhancers enables one to rationally design better enhancers for transdermal drug and vaccine delivery by electroporation.

Animals↗