Crohn's-like colitis, enterocolitis and perianal disease in Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessively inherited disorder consisting of the triad of oculocutaneous tyrosinase-positive albinism, prolonged bleeding time secondary to platelet storage pool defect and ceroid depositions within the reticuloendothelial system. Some patients also reportedly have gastrointestinal (GI) complications related to chronic granulomatous colitis, enterocolitis and extensive granulomatous perianal disease, the later previously unreported in the literature. These observations suggest that the GI complications of HPS are due to the development of classical Crohn's disease. The implications for disease pathogenesis and surgical management are discussed.

Non-steroidal steroid receptor modulators.

The last ten years much attention has been focused on the finding of non-steroidal ligands for steroidal nuclear receptors for reasons such as diminishing cross-reactivity to eliminate side effect profiles, changing physicochemical properties which might cause different tissue distribution profiles and altering binding modes which influence the binding of cofactors. Compounds with a selective functionality profile are referred to as selective nuclear receptor modulators (e.g., SARMs or SPRMs). In the following paragraphs non-steroidal ligands which have full or partial agonistic activity will be described for the following receptors: PR, GR, AR, LXR and FXR.

Chronic physical exercise reduces anxiety-like behavior in rats.

While many individuals with anxiety disorders receive drug therapy, many do not respond or adversely respond to drugs. An alternative treatment, exercise, has been shown to relieve negative feelings and induce positive shifts in mood. The purpose of this study was to establish an animal model to specifically test the effects of chronic physical exercise on anxiety-related behaviors. Thirty-two male Sprague Dawley rats were divided into two groups: runners (R) and nonrunners (NR). Runners ran on a treadmill for 45 minutes a day, five days a week, for ten weeks at a moderate intensity. Nonrunners remained in their cages in the treadmill room during the running period and were handled for an equal amount of time. After ten weeks of training, two behavioral tests were administered including the elevated plus maze and open field tests. Results comparing R and NR showed higher responses by R in percent open arm time and center square time during the elevated plus maze test, as well as in number of entries into the center, number of rears, and lower fecal boli count during the open field test, p < 0.05. In addition, there were no differences in total activity levels between groups as indicated by similar closed arm entries in the elevated plus maze test and total lines crossed in the open field test. These results indicate that treadmill training reduces anxiety-like behaviors in two animal tests of anxiety, without a significant change in total activity levels. These data are in support of treadmill training as a model to test the anxiolytic effects of exercise.

Modification of diamond single crystals by chromium ion implantation with sacrificial layers.

Single-crystal diamond surfaces were implanted with chromium ions. Ion energies chosen were 120 and 180 keV. Ion doses of 1x10(17) cm(-2) were applied at a substrate temperature of 750 degrees C. Reduced lattice damage could be obtained by deposition of a titanium sacrificial layer with a thickness of 10 and 50 nm before implantation. Depth profiles of the elemental binding states were taken by photoelectron spectroscopy. The effect of the sacrificial layer thickness on diamond lattice damage was investigated by infrared spectroscopy.

Changes in defensive behaviors following olfactory bulbectomy in male and female rats.

The present study examined if olfactory bulbectomy (OBX) altered defensive behaviors on the elevated plus-maze and the open-field differently in male and female rats. Similar increases in defensive behaviors in male and female rats were observed in both tests following OBX. No significant correlations were detected between defensive behaviors and activity, supporting the hypothesis that some behavioral changes following OBX may be due to decreased defensive behaviors and not increased activity.

Sex differences in relation to conditioned fear-induced enhancement of morphine analgesia.

A number of studies have reported that both the immediate and proactive effects of exposure to a shock stressor are less pronounced in female than in male rats. A separate area of research has demonstrated that female rats are less sensitive to the analgesic effects of morphine than males. Experiments from our laboratory, as well as others, have found that exposure to a context associated with shock (i.e., conditioned fear context) at the time of morphine administration, enhances the analgesic effects of morphine. Since previous studies have exclusively employed male rats, the purpose of Experiment 1 was to determine if a sex difference exists to this context conditioned fear-induced enhancement of morphine-induced analgesia. The findings of Experiment 1 showed that females do not appear to exhibit conditioned fear-induced enhancement of morphine analgesia as compared to males. Experiment 2 demonstrated that females exhibited higher levels of conditioned fear-induced enhancement of morphine analgesia during diestrus I than estrous. Experiment 3 demonstrated that females exhibited lower levels of conditioned analgesia compared to males, while both groups exhibited similar freezing levels. The findings of the present experiments suggest that the sex difference observed in Experiment 1 may be due to differences in conditioned analgesia.

Gender and gonadal hormone effects in the olfactory bulbectomy animal model of depression.

Major depressive disorder (MDD) affects women to a greater extent then men; however, the few studies that have examined the role of gender in an animal model of depression have shown inconsistent results. The purpose of the present study was to determine if the gonadal hormone milieu of the animal modulated behavioral changes following olfactory bulbectomy (OBX), a well-documented animal model of depression. Body weight, sucrose preference levels and open-field activity levels were measured once a week for a period of 2 weeks in gonadally intact and gonadectomized male and female rats. Following these baseline measurements, animals underwent either OBX or sham surgery. Body weight, sucrose preference and activity levels were assessed for 4 weeks post-OBX surgery. OBX-gonadectomized animals exhibited higher activity levels than OBX gonadally intact and control animals. This effect of gonadectomy was more robust in males. OBX-females (both intact and gonadectomized) exhibited significantly lower sucrose preference levels than OBX-males (both intact and gonadectomized) and control animals. These results suggest that the gonadal hormone milieu of the animal plays a role in modulating sucrose preference and activity levels following OBX.

Outline of a diabetes disease management model: principles and applications.

A complex interactive computer model was developed to determine the health outcomes and economic consequences of different diabetes interventions for user-defined observation periods. The interventions include intensive or conventional insulin therapy, different oral hypoglycaemic medications, different screening and treatment strategies for micro-vascular complications, different treatment strategies for end-stage complications, or multi-factorial interventions. The analyses can be performed on different sub-groups of type 1 and 2 diabetic patients, defined in terms of age, gender, baseline risk factors and pre-existing complications. The model performs real-time simulations. Full on-screen documentation of the model structure, logic, calculations and data sources is available to maximize the model's transparency. Economic and clinical data used in the disease management model are editable by the user, allowing the input of new data as they become available, the creation of country-specific, HMO-specific, or provider-specific versions of the model, and the exploration of new hypotheses ('what-if' analyses). The approach used allows maximum flexibility, adaptability, and transparency within the model structure. For the user-defined patient cohorts and intervention strategies the diabetes disease management model compares life expectancy, expected incidence and prevalence of complications as well as expected life-time (or shorter) treatment cost. Diabetes and complication management strategies can be compared in different patient populations in a variety of realistic clinical settings. The model allows extrapolation of results obtained from relatively short-term clinical trials to longer-term medical outcomes, and from trial populations to real-life populations providing a tangible yardstick to judge the quality of diabetes care. The model was used to evaluate diabetes care options in Germany, France, Switzerland, UK and US.

A lack of tolerance to the anxiolytic effects of diazepam on the plus-maze: comparison of male and female rats.

RATIONALE: The demonstration of tolerance to the anxiolytic effects of benzodiazepines remains inconsistent. OBJECTIVES: The present study tested the hypothesis that intact and gonadectomized male and female rats might exhibit differential tolerance to the anxiolytic effects of diazepam (DZ). METHODS: Following acute (3 days) or chronic (3 weeks) DZ exposure, all animals were tested on the elevated plus-maze and immediately sacrificed for analysis of corticosterone, adrenocorticotropin hormone, estrogen and progesterone levels in serum. In experiment 2, following acute or chronic DZ exposure, animals were treated with a DZ challenge dose on the test day. RESULTS: In experiment 1, both acute and chronic DZ treatment similarly enhanced percentage open arm time and entries, regardless of the hormonal status of the animal. The results of experiment 2 showed that both acute and chronic DZ-treated animals exhibited a significantly higher percentage open arm time than control animals after the DZ challenge dose, and males and females did not differ in their responses to DZ exposure. CONCLUSIONS: The findings from these experiments suggest that tolerance to the anxiolytic effects of DZ did not develop in males or females, and that the hormonal status of the animal does not significantly alter the anxiolytic effects of DZ following either acute or chronic exposure. Following plus-maze exposure, females had significantly higher corticosterone levels than males and acute DZ treatment diminished this stress response.

Lack of sex differences in anxiety behaviors during precipitated benzodiazepine withdrawal in rats.

Nonprecipitated benzodiazepine (BZ) withdrawal has been reported to increase anxiety levels in rats. The present experiment determined if gender or hormonal status would modulate putative changes in anxiety-related behaviors during precipitated BZ withdrawal in rats. Intact and gonadectomized male and female rats were treated for 4 weeks with empty or diazepam (DZ)-filled silastic capsules. Animals were injected with the BZ antagonist flumazenil (RO15-1788; 5 mg/kg, i.p.) or vehicle, and immediately placed on the elevated plus-maze. Following the 10-min behavioral test, rats were decapitated and trunk blood was collected to measure corticosterone and gonadal hormone levels. During precipitated BZ withdrawal rats showed significantly decreased percent open-arm time; however, this finding was confounded by a significant decrease in activity levels (e.g., closed-arm entries and total-arm entries). Precipitated BZ withdrawal did not significantly attenuate percent open-arm entries, which factors out drug-induced changes in activity levels, compared to vehicle control animals. Overall, the results of this experiment suggest that precipitated BZ withdrawal does not significantly increase anxiety levels when compared to control animals.

Carbon/Titanium multilayers as soft-x-ray mirrors for the water window.

C/Ti multilayers with a period thickness of 2.1-2.7 nm were produced by electron-beam evaporation in ultrahigh vacuum as soft-x-ray mirrors in the water window (lambda = 2.3-4.4 nm). For smoothing the individual interfaces and thus enhancing the total reflectance, each layer was ion polished with an Ar(+) ion beam after deposition. For a multilayer of 85 bilayers, a reflectance of approximately 11% at an angle of incidence of 59 degrees (with respect to the surface normal) by use of s-polarized radiation at a wavelength of 2.77 nm was achieved.

Enhancement of morphine analgesia in rats following removal from contextual conditioned fear cues.

1. Previous studies have shown that morphine analgesia is enhanced when analgesia testing is conducted in an environment that has been previously paired with shock, but not in a novel or neutral environment. 2. Two experiments were conducted to assess if enhanced morphine analgesia could be demonstrated in a neutral context if rats were first exposed to conditioned fear cues. This was done by pre-exposing rats to a context previously paired with shock and testing for enhanced morphine analgesia in a neutral context immediately following removal from the conditioned fear context. To determine if conditioned analgesia contributed to the enhanced morphine analgesia, rats were tested for analgesic responsiveness immediately following removal from conditioned fear cues, prior to morphine administration. 3. In Experiment 1, although conditioned analgesia was not observed, a small enhancement of morphine analgesia was demonstrated in an neutral context in rats pre-exposed to conditioned fear cues, compared to non-conditioned controls. 4. In Experiment 2, which employed more sensitive test procedures, a strong enhancement of morphine analgesia was observed in a neutral context only in those rats that demonstrated conditioned analgesia.

Carbon buffer layers for smoothing superpolished glass surfaces as substrates for molybdenum /silicon multilayer soft-x-ray mirrors.

Zerodur and BK7 glass substrates (developed by Fa. Glaswerke Schott, D-55014 Mainz, Germany) from Carl Zeiss Oberkochen polished to a standard surface roughness of varsigma = 0.8 nm rms were coated with a C layer by electron-beam evaporation in the UHV. The roughness of the C-layer surfaces is reduced to 0.6 nm rms. A normal-incidence reflectance of 50% at a wavelength of 13 nm was measured for a Mo/Si multilayer soft-x-ray mirror with 30 double layers (N = 30) deposited onto the BK7/C substrate, whereas a similar Mo/Si multilayer (N = 30) evaporated directly onto the bare BK7 surface turned out to show a reflectance of only 42%.

Pavlovian aversive context conditioning using carbon dioxide as the unconditional stimulus.

Four experiments were conducted to examine the utility of carbon dioxide (CO2) as an aversive unconditioned stimulus (US) in a Pavlovian context conditioning paradigm. Experiment 1 demonstrated that rats exposed to CO2 in a distinctive context showed elevated levels of freezing relative to controls. Experiment 2 replicated this basic effect with a modified conditioning procedure and additionally demonstrated conditioned analgesia. Experiment 3 demonstrated a positive monotonic relationship between US duration and resistance to extinction of freezing behavior as well as conditioned analgesia. Experiment 4 demonstrated extinction and an extinction-related phenomenon, renewal. These studies clearly demonstrate the utility of CO2 as a Pavlovian US.

Synthesis of Enantiomerically Pure Thiocrown Ethers Derived from 1,1'-Binaphthalene-2,2'-diol.

Synthetic methodology is given for the preparation of two different types of thiocrown ethers from optically pure 1,1'-binaphthalene-2,2'-diol (10). The conceptually simplest approach starts from optically pure 10 itself, which is alkylated (4 equiv of K(2)CO(3) in DMF at 110 degrees C) with 2-chloroethanol followed by mesylation to provide 2,2'-bis(2-(mesyloxy)ethoxy)-1,1'-binaphthyl (14). When allowed to react with ethane-1,2-dithiol, propane-1,3-dithiol, 1,4,7-trithiaheptane, 1,4,8,11-tetrathiaundecane, 2,2-dimethylpropane-1,3-dithiol, 2-(mercaptomethyl)-1-propene-3-thiol, and 1,2-benzenedithiol in the presence of Cs(2)CO(3) in DMF at 60 degrees C the corresponding thiocrown ethers 22-25, 28, 30, and 32 are formed in 30-54% yields. Test reactions were carried out to establish that no racemization occurs during alkylation under these conditions. Reaction of optically pure 10 with tetrahydropyranyl (THP)-protected 3-chloropropanol under similar conditions for the preparation of 14 proceeded more sluggishly but cleanly. Removal of the THP protecting groups afforded 2,2'-bis(3-bromopropoxy)-1,1'-binaphthyl (20), which on reaction with propane-1,3-dithiol, 1,5,9-trithianonane, 2,2-dimethylpropane-1,3-dithiol, 2-(mercaptomethyl)-1-propene-3-thiol, and 1,2-bis(mercaptomethyl)benzene provided the respective thiocrown ethers 26, 27, 29, 31, and 33 in 24-68% yields. Another class of thiocrown ethers was prepared from optically active 10, which was converted via ortho-lithiation to 3,3'-bis(bromomethyl)-2,2'-dimethoxy-1,1'-binaphthyl (39) by means of methylation (K(2)CO(3)/CH(3)I), ortho-lithiation followed by formylation (n-C(4)H(9)Li/N,N,N',N'-tetramethylethylenediamine (TMEDA)/ether followed by DMF and H(2)O workup) followed by reduction (NaBH(4)) followed by bromination (PBr(3) in C(5)H(5)N). Reaction (Cs(2)CO(3) in DMF at 60 degrees C) with 1,4,7-trithiaheptane, 1,4,8-trithiaoctane, 1,4,7,10-tetrathiadecane, 1,4,8,11-tetrathiaundecane, and 1,5,10,14-tetrathiatetradecane afforded the corresponding thiocrown ethers 40-44 in 40-75% yields. Despite repeated attempts using a wide range of reagents, demethylation of the methoxy ether functionalities failed. Attempts to prepare the free phenol derivatives of the latter type of crown ethers by oxidative coupling of two naphthol units failed.

Methotrexate does not interfere with an appetitive Pavlovian conditioning task in Sprague-Dawley rats.

There has been considerable interest in developing an animal model of the neuropsychological toxicity of chemotherapeutic agents used in the treatment of patients with cancer, especially children, since these agents often cause significant, long-term neuropsychological deficits. Yanovski, Packer, Levine, Davidson, Micalizzi, D'Angio (13) recently proposed such a model based on their finding that methotrexate retarded the formation of aversive Pavlovian excitatory associations. The present experiment examined the generality of methotrexate induced cognitive impairments by testing rats in Appetitive Pavlovian Conditioning tasks and a Conditioned Taste Aversion paradigm. The results of our study revealed no impairment following methotrexate exposure on the Appetitive Pavlovian tasks or on the Taste Aversion task, relative to two control conditions. While there were a number of methodological differences between the present experiment and those conducted by Yanovski et al. (13), the present results question the robustness and generality of Yanovski's et al. (13) animal model.

Conditioned fear exacerbates acute morphine dependence.

A variety of physical stressors have been shown to enhance reactivity to opioid drugs. Few studies have examined the effects of nonphysical stressors on opioid drug reactivity. In this regard, it has previously been shown that animals administered morphine in the presence of shock-associated cues demonstrate increases in hypoalgesia relative to nonshock control animals. These findings have typically been viewed as being mediated by the activation of endogenous pain inhibition systems via conditioned fear. In this series, we further examined the nature of these effects by assessing the effects of conditioned fear on acute morphine dependence. Experiment 1 revealed that animals administered 3 mg/kg morphine in the presence of context fear cues demonstrated an enhanced withdrawal response when removed and administered 3 mg/kg naloxone. Because it is known that conditioning effects do not diminish over time, a second experiment examined whether the enhancement of acute dependence by context fear would still be evident 72 h postconditioning. As in Experiment 1, animals administered morphine in a context associated with shock demonstrated an enhancement of acute dependence. Experiment 2b revealed that the shock parameters used in these studies can induce a hypoalgesic response on the test that is opioid mediated. These findings are discussed with regard to the neuroanatomy of fear systems as they relate to the neuropharmacological study of opioid withdrawal.

Mo/Si multilayer-coated ruled blazed gratings for the soft-x-ray region.

Two Mo/Si multilayer-coated blazed gratings have been fabricated for operation at soft-x-ray wavelengths above the Si L edge, λ ≥ 12.4 nm, at (near) normal incidence. The sawtooth profile of the grating structure was mechanically ruled into a 200-nm Au film that was deposited onto a plane glass substrate. To smooth the rough Au surface and to prevent interdiffusion of the Au film with the upper Mo/Si multilayer, a carbon film was evaporated onto the Au grating surface of one of the gratings before the deposition of the multilayer coating. We matched the multilayer grating, working on blaze in the third diffraction order, in which an absolute diffraction efficiency of 3.4% at a wavelength of 14 nm was measured, whereas only 1.1% was achieved for a similar grating (without a carbon interlayer). These efficiencies are higher than those obtained for other ruled blazed gratings reported in the literature. As a result of the multilayer and grating periodicity, the wavelength of diffraction can be tuned bya rotation of the grating, which is important for application in a soft-x-ray monochromator.

Modulation of hypoalgesia by morphine and number of shock trials: covariation of a measure of context fear and hypoalgesia.

In a recent series of studies, we observed that exposure to prolonged foot shock increased hypoalgesia induced by morphine. This increase was observed only when testing was conducted in the presence of shock-associated cues, suggesting that it resulted from context-conditioned fear. However, we do not know whether the extended stressor parameters employed in that study are necessary for an observance of the effect. Therefore, in the present study, we assessed the effect of the number of shock trials (either 0, 20, 100, or 200) on the hypoalgesia observed following morphine administration. In addition, we measured activity as an independent index of context-conditioned fear, because in prior studies there had been no independent behavioral assessment of the conditioning of fear to the context. Although others have shown a covariation of conditioned fear and context-induced hypoalgesia using shock parameters and test paradigms different from our own, we sought to assess whether the same covariation would hold for conditioned fear and the hypoalgesia observed following the administration of morphine. The results showed increased hypoalgesia in all groups exposed to foot shock, demonstrating that prolonged exposure to foot shock is not necessary for an observance of this effect. In addition, the results revealed a linear relationship between number of trials of shock and hypoalgesia, but a U-shaped relationship between trials and activity. The pattern of results is considered in light of Fanselow's Perceptual-Defensive-Recuperative model.