Although opioids have proven efficacy in the management of chronic moderate-to-severe pain, data on their long-term use is limited, as most research has used relatively short-term studies [37-39]. This issue has selleck products become progressively more important in recent years as the life expectancy of cancer patients increases owing to improved oncological therapies. As a result, long-term opioid use in cancer patients has become widespread, and therefore data on the safety and efficacy of long-term exposure is necessary [37-42]. This study was an extension study for patients successfully completing Inhibitors,research,lifescience,medical a previous equivalence study, which was a randomised,

double blind study to test the clinical equivalence of IR and CR formulations of hydromorphone and morphine in 200 adult patients with chronic moderate-to-severe cancer pain [34]. The primary objective of this extension Inhibitors,research,lifescience,medical study was to characterise the pain control achieved with long-term repeated dosing, for up to 1 year, of OROS® hydromorphone in patients with chronic cancer pain. Methods The study (DO-118X) was approved

by the independent ethics committee appropriate to each participating centre before any patients were enrolled at that centre, and was conducted in accordance with the recommendations of the Declaration of Helsinki and the European Community Inhibitors,research,lifescience,medical Commission Directive 91/507/EEC by adopting the Good Clinical Practice (GCP) principles

as defined in the International Conference on Harmonisation (ICH) guidelines for GCP (CPMP/ICH/135/95). All patients gave written informed consent before entering the study. Patients The study enrolled adult (≥ 18 years of age) patients Inhibitors,research,lifescience,medical with chronic cancer pain, who had completed the randomised, double blind equivalence study, and whose pain was controlled with a stable dose of study medication, Inhibitors,research,lifescience,medical ≥ 8 mg/day of either OROS® hydromorphone or an equivalent CR morphine sulphate dose, during the final 2 days of the CR phase of the equivalence study. The criteria used for patient selection are listed in Table ​Table1.1. It was planned to include Rutecarpine up to 140 patients. Table 1 Criteria for patient selection Study design This was a phase III, multicentre, open-label, single treatment arm, 1-year extension study. It was conducted at 17 centres in Europe and Canada. The screening process for patients entering the study was their participation in and completion of the previous equivalence study. Patients then completed a baseline visit (visit 1), which was also the final visit in the equivalence study, during which, the inclusion and exclusion criteria were reviewed, a physical examination was done, the BPI was administered, and the study drug was dispensed. All patients received the same treatment, OROS® hydromorphone.

After failure of first line therapy, however, the options continue to be even more limited. There are currently no widely accepted treatments beyond first line. The only regimen to show evidence of survival benefit in a context of a randomized trial in this setting is oxaliplatin/5-FU/leucovorin (OFF), which improved overall survival to

4.8 months from 2.3 months with best Selleck FK228 supportive care (4). Nab-paclitaxel (trade name, Abraxane), is paclitaxel bound to nano-particle albumin, a first drug of this type. Inhibitors,research,lifescience,medical Nab-paclitaxel was initially developed to avoid hypersensitivity reactions that resulted from solvents such as cremephor that are used to dissolve paclitaxel. Nab-paclitaxel has been approved by the Food and Drug Inhibitors,research,lifescience,medical Administration since 2004 for use in metastatic breast cancer as well as metastatic non-small cell lung cancer (5,6). In addition to eliminating hypersensitivity reaction, it has also been postulated that uptake of albumin by tumor cells may allow improved intra-tumoral delivery of nab-paclitaxel. This may be especially relevant in pancreatic cancer given the dense stromal component of this malignancy

that has been postulated as being central to its chemoresistance (7). In fact, a protein present in stroma of many pancreatic adenocarcinomas, secreted protein Inhibitors,research,lifescience,medical acidic and rich in cysteine (SPARC), may help serve as an albumin-binding Inhibitors,research,lifescience,medical protein that sequesters nab-paclitaxel to concentrate the drug intratumorally (8). Nab-paclitaxel was first used in pancreatic cancer two years ago in combination with gemcitabine in the setting of a phase I-II study, where it was found to be tolerable with substantial activity (9). The results of a phase III trial comparing gemcitabine to gemcitabine combined with nab-paclitaxel were recently presented in abstract form showing improved

survival of two months from 6.7 to 8.5 months with the combination Inhibitors,research,lifescience,medical therapy in previously untreated patients with advanced pancreatic cancer (10). In the second line setting, a small phase II study has also shown evidence of activity of nab-paclitaxel monotherapy in patients who have progressed through gemcitabine (11). This study involved 19 patients and showed an overall survival of 7.3 months. 36.8% of patients had stable or partial response on best imaging in this study. No other data is available, to the best of Adenylyl cyclase our knowledge, however, on the use of nab-paclitaxel monotherapy in refractory pancreatic cancer, which is an area of dire need. Here, we report the results of a retrospective and prospective registry study documenting our experience with nab-paclitaxel monotherapy in heavily pretreated pancreatic cancer patients. Materials and methods Patient population Patients with pancreatic adenocarcinoma at Washington University in St.

7 The mechanism by which opioid and TRPV1 receptors induce reciprocal changes in expression has not yet been studied.

Two recent studies show that GABAA receptor associated protein (GABARAP) is involved in the expression of both TRPV1 receptors and opioid receptors.33,34 Thus, it may be suggested that this protein possibly mediates the interaction of opioid and TRPV1 ligands. The delayed effects of opioids on TRPV1 receptors may also be represented during opioid-induced hyperalgesia. Clinical studies have reported that opioids administered, particularly during rapid opioid dose escalation, can produce hyperalgesia and allodynia.8 Inhibitors,research,lifescience,medical Similarly, the study of Vardanyan et al.9 shows that unlike wild-type mice, TRPV1 knock-out mice do not develop thermal and tactile hypersensitivity induced by sustained morphine administration and morphine increases TRPV1 immunoreactivity in the Inhibitors,research,lifescience,medical DRG and induces functional changes in TRPV1 receptor at the periphery. Conclusion It may be concluded that TRPV1 receptors have a role in opioid dependence. More studies are Inhibitors,research,lifescience,medical required to evaluate the interaction of TRPV1 and opioid receptors in detail. Acknowledgment The authors of this article would like take this opportunity to thank Mr. Mohsen Shirazi for his assistance. This project was supported by a grant from the Rafsanjan University of Medical Sciences. Conflict of Interest: None declared.
Background: Severe

metabolic acidosis occurs during orthotopic liver Inhibitors,research,lifescience,medical transplantation (OLT) particularly during the anhepatic phase. Although NaHCO3 is considered as the current standard therapy, there are numerous adverse effects. The aim of this study was to determine whether the restricted use of normal saline during anesthesia could reduce the need for NaHCO3. Methods:

In this study we enrolled 75 patients with end-stage liver disease who underwent Inhibitors,research,lifescience,medical OLT from February 2010 until September 2010 at the Shiraz Organ Transplantation Center. Fluid management of two different transplant anesthetics were compared. The effect of restricted normal saline fluid was compared with non-restricted normal saline fluid on hemodynamic and acid-base parameters at three times during OLT: after the skin incision (T1), 15 min before reperfusion (T2), and 5 min after reperfusion (T3). Results: There were no buy Quisinostat significant differences in demographic characteristics of the donors and recipients (P>0.05). In the restricted normal saline group there was until significantly lower central venous pressure (CVP) than in the non-restricted normal saline group (P=0.002). No significant differences were noted in the other hemodynamic parameters between the two groups (P>0.05). In the non-restricted normal saline group arterial blood pH (P=0.01) and HCO3 (P=0.0001) were significantly less than the restricted normal saline group. The NaHCO3 requirement before reperfusion was significantly more than with the restricted normal saline group (P=0.001).

5µg/kg, 0.7–108.8µg/kg, and 0.4–490.7µg/kg respectively.21 In the present study aflatoxin levels in homemade weanimix ranged from 7.9 –500ppb (ug/kg). The data obtained showed that two out of the 36 samples (from different communities) have levels of 460 and 500ppb (ug/kg). Fumonisins have been found in maize samples worldwide, with levels of FB1 reaching > 10 ppm in the United States and > 100ppm in parts of Africa.22 Studies in Cote

d’Ivoire23 and Ghana24 have shown cooccurrence of aflatoxins and fumonisins in maize-based foodstuffs. The present study shows that, 83.3% of homemade weanimix contaminated with aflatoxin was above the action limit of 20ppb and 58.3% of the weanimix contaminated with fumonisin was above the action limit of 4ppm. This indicates that, the consumption of contaminated groundnuts and maize in I-BET151 datasheet these communities is likely to be very high. In a study involving anaemia among pregnant women in Ghana, strong association was shown between aflatoxin and women with malaria and even stronger when those with iron deficiency anaemia were excluded, there appeared to be a risk of low birth weights when high levels of blood aflatoxin biomarker (>11.34pg AFB1/mg albumin) were observed in pregnant women.25 In another study involving 507 Ghanaian participants, AFB1-lysine adduct levels were statistically

higher in subjects who had low levels of both vitamins

A and E compared to subjects who had high vitamins A and E.26 A cohort study involving 472 Gambian children of ages 6–9 years were recruited for analysis of see more possible correlation of aflatoxin exposure and immune status. Immune parameters included secretory IgA (sIgA) in saliva and cell-mediated immunity (CMI). secondly It was found out that, saliva IgA (sIgA) was markedly lower in children with detectable aflatoxin-lysine compared with those with non-detectable levels of 50.4µg/mg protein.7 The co-occurance of (70.8%) of aflatoxins and fumonisins contaminations seen in this study with the 53% as reported by27 indicates about 0.74-fold increase which may be due to poor storage conditions of the maize, groundnuts and beans used to prepare weanimix. The toxicosis that AFB1 and FB1 cause in humans and animals as well as the possible carryover of aflatoxins into consumable animal products, such as milk and infant feed is of widespread concern for child health in Sub-Saharan African countries.28 The results of the present study suggest that very young children from the Ejura-Sekyedumase district of the Ashanti Region of Ghana are likely to be exposed to high levels of aflatoxin from consumption of Aflatoxin contaminated homemade weanimix. The possible consequences on child immunity and growth in the district warrant further studies.

51-53 Table 2. The number of people screening positive for subclinical psychotic experiences

who needed to be treated to prevent one case of full-blown psychotic disorder, as a function of the predictive value of the test and the success rate of the MI-773 in vivo prodromal treatment … For screening and prevention of schizophrenia, not much can be done with predictive and diagnostic values of 4 of 8 %. Cans these values be improved? The conclusion so far has been very simple: it is very difficult to predict or diagnose a rare disease in the general population on the basis of a test Inhibitors,research,lifescience,medical resembling some precursor phenomenon. Is it possible to improve on this state of affairs? The answer to this question

is yes, and the strategy to follow is to change schizophrenia from a rare disease to a common disease: if instead of 1%, the prevalence of schizophrenia were 50%, the predictive Inhibitors,research,lifescience,medical value of any test, even pointing at random to a person with one’s eyes closed, would be at least 50%, clearly Inhibitors,research,lifescience,medical a much more attractive situation epidemiological than the 8% probability reported above. As of course the incidence and prevalence of schizophrenia cannot be changed, some indirect manipulation must be employed in order to make the disease more “predictable.” Below, three possible strategies will be described. Raising the rate of schizophrenia by changing the context of risk In the previous sections, the predictive and diagnostic values of a single predictor, subclinical psychotic experiences, were examined. However, if there are other predictors, and their Inhibitors,research,lifescience,medical effects are additive, the predictive value will increase accordingly,

as illustrated in Figure 4. The problem with this strategy, however, is that Inhibitors,research,lifescience,medical although the combination of predictors into a single criterion will make schizophrenia more predictable, it will also apply to fewer patients (Figure 4). For example, if a family history of schizophrenia is used as an additional criterion for prediction, not the maximum proportion of all future schizophrenia patients that can be predicted is 20%, as only 20% of all patients with schizophrenia have a positive family history. Therefore, the more predictors one combines, the greater the probability that a transition to psychotic disorder is going to take place in the near future, but also the greater the probability that this is not relevant for the bulk of schizophrenia cases that one is trying to prevent from occurring. In the case of a deadly disease for which a curative treatment existed in the prodromal phase, the strategy of combining predictors to enhance specificity at the expense of sensitivity would be disastrous, as one would need to reduce the number of false-negatives to an absolute minimum.

7, 9–11 Studies from sub-Saharan Africa suggested that asymptomatic parasitaemia in children in high-transmission settings could be as high Z-VAD-FMK order as 71% in under-five children12, and between 37% and 68% in children aged up to ten years of age.13, 14 A hospital-based study in Kenya in 1996 found that up to 45% of children admitted with respiratory signs (indicative of severe ARI) had malaria as the primary diagnosis.15 In Ghana and Kenya, the probability of fever that could be attributed to malaria was found to be as

high as 61% and 67% respectively.16, 17 Up to half of all mortality among African children aged 6 months to 5 years was considered to be due to malaria 18 and nearly 3% of disability adjusted life years was attributed to malaria mortality globally.19 With such high levels of malaria-related morbidity and mortality, it was considered neither cost-effective nor safe to routinely distinguish malaria from non-malaria cases, and restrict antimalarial drugs to only confirmed cases, particularly where the selleck compound attempt to do so could lead to rapid clinical deterioration and possibly death. The evidence supported the use of fever as a proxy indicator of malaria in both clinical care and epidemiological surveys. 7, 20, 21 Availability of affordable, yet effective antimalarials

The availability of affordable, yet effective antimalarials such as chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) was another important justification for the presumptive approach. Both Oxymatrine were effective first-line antimalarial drugs in endemic countries in sub-Saharan Africa for many years. Being synthetic products, CQ and SP were cheap to produce and were affordable. They were also safe to use, including as chemoprophylaxis in pregnant women. Drug pressure exerted through their use in the presumptive treatment of uncomplicated malaria22 contributed to development of resistance. In 2004, Ghana joined many countries across sub-Saharan Africa in changing its

first-line drug for the treatment of uncomplicated malaria from chloroquine to artemisinin-based combination treatments. Reports of resistance and or prolonged parasite clearance associated with use of the artemisinins in Western Cambodia, and along the Thailand-Myanmar (Burma) border raise concern about the need to protect the ACTs from unwarranted use. 23–25 Lack of appropriate diagnostic tools The lack of easy-to-use, accurate and reliable malaria diagnostic tools was another important justification for adoption of the presumptive approach. 7, 26, 27 Blood smear microscopy using Giemsa stain techniques which had been the mainstay of parasitological confirmation of malaria for many years, was too elaborate, technical, and expensive to set-up and maintain in all primary care facilities and was time-consuming.

The results showed that M-CTX-Fc had a higher affinity than D-CTX-Fc and that 100nM of M-CTX-Fc saturated the binding (GPCR Compound Library Figure 2(b)). Figure 2 Immunofluorescence image and binding assay for M/D-CTX-Fcs using A172 cells. (a) The M/D-CTX-Fcs attached to cell surfaces

at 4°C (upper). Fifteen minutes incubation at 37°C promoted the internalization of M/D-CTX-Fcs into cells (lower). … 3.3. Effect of M/D-CTX-Fcs on the Migration of A172 Cells The effect of M/D-CTX-Fcs on the migration of A172 Inhibitors,research,lifescience,medical cells was assessed (Figure 3(a)). Although M-, D-CTX-Fcs, and CTX at a concentration of 300nM significantly inhibited the migration of the cells, M-CTX-Fc exhibited the inhibition clearly depending on the concentration. In the wound healing assay, the effect of inhibition by both M- and D-CTX-Fcs appeared to be dose dependent in the range of 3–300nM (Figure 3(b)). The results showed that M-CTX-Fc had a more efficient inhibitory effect Inhibitors,research,lifescience,medical than D-CTX-Fc. Figure 3 Cell migration and wound healing assays. (a) The effect of M/D-CTX-Fcs on the migration of A172 cells was assessed using a PET track-etched membrane culture insert (pore Inhibitors,research,lifescience,medical size, 8.0μm). The cells were incubated with M/D-CTX-Fcs in the range … We then evaluated the effects of M/D-CTX-Fcs on the proliferation and viability of A172 cells. M-CTX-Fc strongly suppressed the cell

viability Inhibitors,research,lifescience,medical compared with D-CTX-Fc and CTX (Figure 4(a)). IC50 was estimated at around 100nM. After treatment with 300nM M/D-CTX-Fcs for 48h, the growth of cells resumed in the next 24h when the medium was replaced with a medium without M/D-CTX-Fcs or CTX (Figure 4(b)). Figure 4 Proliferation inhibition activity. (a)

The inhibition of cell growth in the presence of M/D-CTX-Fcs for 48h. (b) The viable cells at 48h were kept cultured without M/D-CTX-Fcs up to 72h. Cell numbers in each well Inhibitors,research,lifescience,medical were assessed … 3.4. Internalization of CTX-Fc-BNCs The M-CTX-Fc was multivalently displayed on the surface of ZZ-BNCs, thereby exploiting the affinity of the ZZ peptide for the IgG-Fc region [20]. CTX-Fc-BNCs (2nM, 10μg/mL) were incubated with A172 cells at 37°C for 1h, and the specific binding of CTX-Fc-BNCs was observed competing with free CTX (Figure 5(a)). Adenosine To evaluate the internalization of CTX-Fc-BNCs, the cells were incubated with M-CTX-Fc, human IgG-BNCs, or CTX-Fc-BNCs at 37°C or 4°C. The incubation of cells at 37°C facilitated the intracellular localization of BNCs, indicating that the temperature-dependent internalization was attributable to a membrane-dependent mechanism (Figures 5(b) and 5(c)). Figure 5 Evaluation of CTX-Fc-BNCs internalized by A172 cells. (a) A172 cells were incubated with CTX-Fc-BNCs at 37°C. In “CTX competition”, the cells were treated primarily with CTX at 4°C for 20min before incubating with …

This held for all three outcomes examined: CPR skill retention, confidence for CPR, or intent to help in a cardiac emergency. However, interpreting this “intent to treat” result is difficult because many

subjects did not actually review the electronic refreshers that were sent. Comparing outcomes for those exposed to the electronic refreshers vs. those not exposed indicated a significant effect for one of the three outcomes, confidence in performing CPR. According to social-cognitive theory, because increased confidence in being able to perform a behavior should increase the likelihood of performing Inhibitors,research,lifescience,medical that behavior, there is at least a potential that the novel refreshers can influence whether the subjects would conduct CPR in an emergency. The study identified a significant effect of refresher website exposure specifically on increased behavioral

Inhibitors,research,lifescience,medical intent. The website refresher can be considered more interactive than the other novel refreshers. The algorithm-based web program engaged the subject in critical thinking, leading them to appropriate Nutlin-3a in vitro responses in contrast to the other refreshers Inhibitors,research,lifescience,medical which were more didactic in their approach to reviewing CPR technique. The greater degree of active engagement in reviewing the principal CPR skills made possible by the website format may be responsible for the more positive outcome Inhibitors,research,lifescience,medical of this refresher compared with the others. This result bears more investigation, although of course it may be a chance finding, given the multiple comparisons made in the exploratory analyses. The number of refresher episodes (one vs. two) did not show a significant effect on any outcomes. This indicates that repeating the refreshers during a one year post-training period is not an effective strategy for retaining CPR capability. Examining the pattern of the satisfaction data, highest satisfaction occurred for the e-mails, Inhibitors,research,lifescience,medical second highest for the brochure, third highest for the website, and lowest for the text messaging. Those who received

e-mails also had the highest rate of exposure to any of the novel refreshers, measured by whether they opened any refresher e-mails. From these data, we might conclude that e-mail was the most successful of the novel CPR refreshers, Parvulin at least in terms of subject acceptance of and reactions to the refresher. It is possible, however, that a higher proportion looked at the mailed brochure than viewed any of the novel refreshers, although the data are ambiguous on this point, because of possible confusion with the CPR reminder “card” received at the initial training. One predictor model determined that age (younger), education (higher) and race (White) were significant predictors of skill retention, although these variables only accounted for 19% of the variation in skill.

The ultradian rhythm of LH was clear, with 1 to 6 nocturnal peaks by visual Inspection, depending on the subjects. The amplitude of the secretory peaks varied, but the mean nocturnal value of LH concentration did not depend on the number of peaks. The nocturnal Increase In Temsirolimus Cortisol was absent In one subject (No 3)

and the expected nocturnal peak concentrations were only slightly higher than the early evening values in subject No 6. There was quite a lot of variability In the timing of the Cortisol surge. It started between 24:00 and 02:00 In two subjects (Nos 1 and 6), and between 02:00 and 04:30 in the other subjects, except for subject No 3 (no Increase). Inhibitors,research,lifescience,medical Figure 1. Nocturnal secretion patterns of luteinizing hormone in six subjects over 2 nights. Closed circles, first night (N1); Inhibitors,research,lifescience,medical open circles, second night (N2). Lights on/off indicated by dashed lines. Figure 2 Nocturnal secretion patterns of Cortisol in six subjects over 2 nights. Closed circles, first night (N1); open circles, second night (N2). Lights on/off indicated by dashed lines. Figure 3 shows the nocturnal plasma concentration of six other hormones In 1 subject (No 5) over 2 nights. The stability of the patterns Is apparent, mostly with Inhibitors,research,lifescience,medical testosterone and melatonin, while the GH patterns differ. Figure 3. Nocturnal secretion

patterns of six hormones in one subject over 2 nights. Closed circles, first night (N1); open circles, second night (N2). Lights on/off indicated by dashed lines. Calculation of intraindividual stability based on area under the concentration Inhibitors,research,lifescience,medical versus time curve (AUG) between Individual AUCs from the first and second night (n=6 subjects) showed highest values for LH (Pearson r=0.98), and lowest values for Cortisol (Pearson r=0.25). This correlation on AUC concerns the amount of hormone secreted (assuming a constant hormone clearance). Pearson’s correlations coefficients calculated on hormone concentrations over the 2 nights, within each subjects,

gives an evaluation of both the amount of hormone and the temporal organization Inhibitors,research,lifescience,medical of secretion. Indeed, in this case, the coefficient will be high only if the temporal patterns are similar and occur with no phase shift between the two successive nights of measurement in the same subject. The mean values (n=6 subjects) were lowest for LH (mean Pearson’s r=0.41) and SB-3CT highest with melatonin (mean Pearson r=0.89), These data suggest that there can be marked changes in temporal patterns with little changes in the amount of hormone produced during the night (eg, subjects No 1 and 4 for LH, Figure 1) and, conversely, no changes in temporal patterns, but marked changes in nocturnal hormone production (eg, subject No 6 for Cortisol, Figure 2). This study of the nocturnal concentration of several hormones in the plasma showed that the temporal pattern of secretion varied interindividually, and that it was relatively stable over time.

It is under tight feedback control and is modulated by afferent connection from multiple brain areas,

including the amygdala and hippocampus. In the hypothalamus, arginine vasopressin and corticotrophin-releasing hormone (CRH) are synthesized by parvocellular neurones of the paraventricular nuclei which project widely to the limbic system, brain stem and spinal cord and to the median eminence. Secretion into the hypothalamo-pituitary portal system of these two peptides regulates the secretion from the #selleck products keyword# anterior lobe of the pituitary gland into the systemic circulation of adrenocorticotropic hormone (ACTH). ACTH, a polypeptide derived from the pro-opiomelanocortin precursor molecule, acts at the adrenal cortex to rapidly stimulate the biosynthesis of corticosteroid hormones such as cortisol from cholesterol. Circulating cortisol acts at two types of receptor – type

1 mineralocorticoid receptors (MRs) and type 2 glucocorticoid Inhibitors,research,lifescience,medical receptors (GRs) [Herman et al. 1989a]. GRs have high affinity for dexamethasone. Regions of high GR mRNA levels include CA1, CA2 and dentate subregions of the hippocampus, paraventricular Inhibitors,research,lifescience,medical hypothalamus, lateral geniculate, lateral and medial amygdala, and cerebellum. Regions of high MR mRNA levels include all hippocampal pyramidal cell fields, dentate gyrus granule cell layer, lateral septum, medial and lateral amygdala, and to a lesser extent, cerebellum [Patel et al. 2000]. Cortisol diffuses through the cell membrane, binds to intracellular Inhibitors,research,lifescience,medical GRs and MRs and promotes their translocation to the nucleus. In response to stress, glucocorticoid levels rise, MR saturate and GR becomes the primary mediator of feedback inhibition of CRH (and the HPA

axis) (Pariante and Miller, 2001, De Kloet et al., 1998). GR acts as a transcription factor to both positively and negatively regulate target genes. A decrease in glucocorticoid bioavailability might stem from decreased production of upstream glucocorticoid click here secretagogues including CRH and Inhibitors,research,lifescience,medical ACTH, this mechanism has been implicated in the pathogenesis of a range of neuropsychiatric diseases including atypical depression (Geracioti et al., 1997). Reduced glucocorticoid bioavailability may also be caused by a primary deficit in adrenal hormone production and/or release. Decreased glucocorticoid bioavailability might also result from alterations in 1) binding proteins, which have been identified for both cortisol and CRH (Rosner, 1991), 2) enzymes such as 11-β-hydroxysteroid dehydrogenase, which metabolize endogenous glucocorticoid hormones upon entry into the cell (Seckl and Walker, 2001), and 3) the multidrug resistance pump, which extrudes cortisol but not corticosterone from the cell (Karssen et al., 2001).