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Background: Narcolepsy with cataplexy (NC) is caused by substantial loss of hypocretin neurons. NC patients carry the HLA-DQB1*0602 allele suggesting that hypocretin neuron loss is due to an autoimmune attack. We tested intravenous immunoglobulin (IVIG) treatment in early onset NC., Methods: 2 NC children received IVIG 1 g/kg/day in 2 days/month, 5 times, at 3 and 6 months disease duration, respectively. CSF and serum were analysed for hypocretin neuron autoantibodies. An association between disease duration and IVIG effect was calculated in all published NC cases., Results: Autoantibodies were not detectable. Cataplexy improved in both children but only temporarily in one patient. Subjective sleepiness temporarily improved, sleep paralysis emerged and hypnagogic hallucinations and REM sleep behaviour disorder worsened in one child. Sleep parameters and CSF hypocretin-1 remained abnormal. On a group level, IVIG treatment ≤ 9 months from disease duration predicted reduction of cataplexy (p=0.004) and sleepiness (p=0.066). Sleep parameters and CSF hypocretin-1 levels were unchanged except if treated extremely early., Conclusion: IVIG treatment initiated before 9 months disease duration has some clinical efficiency. The unaffected CSF hypocretin-1 levels and lack of autoantibodies suggest that any autoimmune process occurs very early in NC. The final IVIG effect needs to be investigated in a placebo-controlled study., (© Georg Thieme Verlag KG Stuttgart · New York.)

The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.

The in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT(6)R antagonist Lu AE58054 ([2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine) on impaired cognition were evaluated. Lu AE58054 displayed high affinity to the human 5-HT(6) receptor (5-HT(6)R) with a Ki of 0.83 nm. In a 5-HT(6) GTPgammaS efficacy assay Lu AE58054 showed no agonist activity, but demonstrated potent inhibition of 5-HT-mediated activation. Besides medium affinity to adrenergic alpha(1A)- and alpha(1B)-adrenoreceptors, Lu AE58054 demonstrated >50-fold selectivity for more than 70 targets examined. Orally administered Lu AE58054 potently inhibited striatal in-vivo binding of the 5-HT(6) antagonist radioligand [(3)H]Lu AE60157 ([(3)H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline), with an ED(50) of 2.7 mg/kg. Steady-state modelling of an acute pharmacokinetic/5-HT(6)R occupancy time-course experiment indicated a plasma EC(50) value of 20 ng/ml. Administration of Lu AE58054 in a dose range (5-20 mg/kg p.o.) leading to above 65% striatal 5-HT(6)R binding occupancy in vivo, reversed cognitive impairment in a rat novel object recognition task induced after subchronic treatment for 7 d with phencyclidine (PCP 2 mg/kg b.i.d., i.p. for 7 d, followed by 7 d drug free). The results indicate that Lu AE58054 is a selective antagonist of 5-HT(6)Rs with good oral bioavailability and robust efficacy in a rat model of cognitive impairment in schizophrenia. Lu AE58054 may be useful for the pharmacotherapy of cognitive dysfunction in disease states such as schizophrenia and Alzheimer's disease.

Herein we describe the discovery of a series of novel adenosine A(2A) receptor antagonists. A successful hit-to-lead optimization of an HTS hit led to replacement of a metabolically labile ester moiety with a heteroaromatic group. A compound from the series, (cyclopropanecarboxylic acid [5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-yl]-amide, compound 13), was shown to be effective in reversing haloperidol-induced hypolocomotion, a model of motor dysfunction in Parkinson's Disease., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The efficacy and safety of zanolimumab (HuMax-CD4) in patients with relapsed or refractory peripheral T Cell lymphoma (PTCL) was evaluated. Twenty-one adult patients with relapsed or refractory CD4(+) PTCL of non-cutaneous type (angioimmunoblastic T cell lymphoma (AITL) n = 9, PTCL-not otherwise specified (NOS) n = 7, anaplastic large cell lymphoma (ALCL) n = 4 and enteropathy type T cell lymphoma n = 1) were treated in a single-arm multi-centre study, with weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. Median age was 69 years (range 26-85). Seventeen of the patients had advanced stage disease (Ann Arbor stages III-IV). Objective tumour responses were obtained in 24% of the patients with two complete responses unconfirmed (CRu) and three partial responses (PR). One of the CRus lasted more than 252 d. Responses were obtained in different PTCL entities: AITL (n = 3), ALCL (n = 1) and PTCL-NOS (n = 1). In general, the trial drug was well tolerated with no major toxicity. Zanolimumab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor-prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be investigated.

The serotonin transporter (SERT) regulates extracellular levels of the neurotransmitter serotonin (5-hydroxytryptamine) in the brain by facilitating uptake of released 5-hydroxytryptamine into neuronal cells. SERT is the target for widely used antidepressant drugs, including imipramine, fluoxetine, and (S)-citalopram, which are competitive inhibitors of the transport function. Knowledge of the molecular details of the antidepressant binding sites in SERT has been limited due to lack of structural data on SERT. Here, we present a characterization of the (S)-citalopram binding pocket in human SERT (hSERT) using mutational and computational approaches. Comparative modeling and ligand docking reveal that (S)-citalopram fits into the hSERT substrate binding pocket, where (S)-citalopram can adopt a number of different binding orientations. We find, however, that only one of these binding modes is functionally relevant from studying the effects of 64 point mutations around the putative substrate binding site. The mutational mapping also identify novel hSERT residues that are crucial for (S)-citalopram binding. The model defines the molecular determinants for (S)-citalopram binding to hSERT and demonstrates that the antidepressant binding site overlaps with the substrate binding site.

Dopamine (DA) is known to play an important role in numerous brain functions and has been suggested to be involved in several neuropsychiatric and neurological disorders. From early on, positron emission tomography (PET) studies of the DA system have yielded high interest. Currently, several aspects of the functionality of DA neurons can be imaged, including the DA synthesis rate and the expression of DA-related proteins (receptors and transporters). A more recent application of radioligands targeting DA receptors is to study the endogenous neurotransmitter levels in vivo in brain. In vitro binding studies have suggested that in general DA receptors, as many other G-protein coupled receptors, exist in two affinity states for agonist binding. The high affinity state is thought to represent the functional state of the receptor, and the proportion between high and low affinity states may change with the development of disease. PET imaging with agonist radioligands may provide information on the existence of the high affinity state in vivo. In addition, DA receptor agonist radioligands may be superior tools for measuring changes in endogenous DA levels as antagonist radioligands inherently bind to both the low and the high affinity state. This review primarily summarizes the present status of the D(2)/D(3) receptor agonist PET radioligands. In addition several PET studies evaluating the utility of the agonist concept are discussed.

Aim: This study examined the efficacy of sertindole in comparison with a selective 5-HT(6) and a 5-HT(2A) receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats., Methods: In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT(2A) receptor antagonist M100.907 or the selective 5-HT(6) receptor antagonist SB-742457., Results: The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose-response relationship for sertindole in this study most closely correlates with affinity for 5-HT(6) receptor in vivo binding in striatum, although contribution from binding to 5-HT(2A) receptors in vivo in cortex may also provide an important mechanism., Conclusion: The efficacies of selective 5-HT(2A) and 5-HT(6) receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.

A challenge model for comparison of the virulence of epizootic haematopoietic necrosis virus (EHNV) to European stocks of redfin perch, Perca fluviatilis L., and rainbow trout, Oncorhynchus mykiss (Walbaum), was tested. The model investigated intraperitoneal (IP), bath and cohabitation routes at 10, 15 and 20 degrees C for 5-6 g fish and 15 degrees C for 20 g perch. In the IP challenges of perch, significant mortality occurred at 15 degrees C and 20 degrees C. In challenge trials for rainbow trout, significant mortalities were observed in IP and bath challenges at 20 degrees C. The mortality observed in IP challenged 20 g perch was not significantly different from that recorded for 6 g fish challenged IP. No significant mortality was observed in any other treatment groups. Re-isolation of ranavirus was confirmed by IFAT and was consistently associated with dead or moribund fish in the trial groups challenged with EHNV. The findings indicate that EHNV does not pose a high risk for wild perch and trout populations in Europe by natural exposure. Mortality appears to be primarily a function of environmental factors, with temperature playing an important role, and not just the presence of the virus in the fish.

The biogenic monoamine transporters are integral membrane proteins that perform active transport of extracellular dopamine, serotonin and norepinephrine into cells. These transporters are targets for therapeutic agents such as antidepressants, as well as addictive substances such as cocaine and amphetamine. Seminal advances in the understanding of the structure and function of this transporter family have recently been accomplished by structural studies of a bacterial transporter, as well as medicinal chemistry and pharmacological studies of mammalian transporters. This feature article focuses on antidepressant drugs that act on the serotonin and/or the norepinephrine transporters. Specifically, we focus on structure-activity relationships of these drugs with emphasis on relationships between their molecular properties and the current knowledge of transporter structure.

Binding studies in vitro have demonstrated that the dopamine D2 receptor may exist in two affinity states for agonists. The high affinity state is thought to represent the functional state of the receptor and proportions might alter during disease. In vitro studies further indicate that agonists induce measurable D(2) receptor occupancy at clinically relevant concentrations but only when measured at the high affinity state. Recently developed PET-radioligands, such as [11C]MNPA, have now made it possible to directly study agonist binding in vivo. The aim of this study was to compare the inhibition by apomorphine of agonist and antagonist radioligand binding to D(2/3) receptors in vivo. A total of 36 PET measurements were performed with the D(2/3) antagonist [11C]raclopride or the D(2/3) agonist [11C]MNPA in two cynomolgus monkeys. On each study day, a baseline measurement was followed by two consecutive pretreatment studies with rising doses of apomorphine (0.01, 0.05, 0.15, 0.5, 1.0, and 3.0 mg/kg). Binding potential (BP(ND)) values were calculated for the striatum with cerebellum as reference region. Apomorphine inhibited [11C]raclopride and [11C]MNPA binding in a dose-dependent manner and to a similar extent. ID(50) and K(i) values were 0.26 mg/kg and 29 ng/ml for [11C]raclopride and 0.50 mg/kg and 31 ng/ml for [11C]MNPA. The present observations do not support the existence of two affinity states in vivo. It might thus be speculated that all D(2/3) receptors are in the high affinity state at in vivo conditions.

Arrays of microcantilevers are increasingly being used as physical, biological, and chemical sensors in various applications. To improve the sensitivity of microcantilever sensors, this study analyses and compares the deflection and vibration characteristics of rectangular and trapezoidal profile microcantilevers. Three models of each profile are investigated. The cantilevers are analyzed for maximum deflection, fundamental resonant frequency and maximum stress. The surface stress is modelled as in-plane tensile force applied on the top edge of the microcantilevers. A commercial finite element analysis software ANSYS is used to analyze the designs. Results show paddled trapezoidal profile microcantilevers have better sensitivity.

In this study the ability of salmon tissue extracts to stimulate interleukin 8 (IL-8) production in airway epithelial cells (A549) was investigated; in particular, the role of serine protease enzymes and endotoxin was examined with respect to IL-8-stimulating ability. A549 cells were stimulated by various concentrations of fish tissue extracts for 6 h. Parallel samples were incubated with a protease inhibitor cocktail, a serine protease inhibitor, or an endotoxin inhibitor. The amount of secreted IL-8 in the supernatant was determined by an enzyme-linked immunosorbent assay. A549 cells showed a concentration-dependent increase in IL-8 secretion after stimulation with extracts of salmon tissues. The IL-8-stimulating effect was inhibited by serine protease inhibitors but not by endotoxin inhibitors.

In this study, we focus on salmon trypsin as an activator of inflammatory responses in airway cells in vitro. The rationale behind the investigation is that salmon industry workers are exposed to aerosols containing enzymes, which are generated during industrial processing of the fish. Knowing that serine proteases such as trypsin are highly active mediators with diverse biological activities, the stimulation of nuclear factor-kappa B (NF-kappaB) and interleukin (IL)-8 and the role of protease-activated receptors (PAR) in inflammatory signal mediation were investigated. Protease-activated receptors are considered important under pathological situations in the human airways, and a thorough understanding of PAR-induced cellular events and their consequences in airway inflammation is necessary. Human airway epithelial cells (A549) were exposed to trypsin isolated from fish (Salmo salar), and we observed that purified salmon trypsin could generate secretion of IL-8 in a concentration-dependent manner. Furthermore, we demonstrate that PAR-2 activation by salmon trypsin is coupled to an induction of NF-kappaB-mediated transcription using a PAR-2 transfected HeLa cell model. Finally, we show that the release of IL-8 from A549 following stimulation with purified salmon trypsin is mediated through activation of PAR-2 using specific small interfering RNAs (siRNAs). The results presented suggest that salmon trypsin, via activation of PAR-2, might influence inflammation processes in the airways if inhaled in sufficient amounts.

Citalopram and talopram are structurally closely related, but they have very distinct pharmacological profiles as selective inhibitors of the serotonin and norepinephrine transporters, respectively. A systematic structure-activity relationship study was performed, in which each of the four positions distinguishing the two compounds were varied. The inhibitory potencies of the resulting 16 compounds were tested at both serotonin and norepinephrine transporters. This showed that particularly two of the four positions are determinants for the biological activity.

Aims: To investigate the prevalence of musculoskeletal complaints among male and female production workers in different types of seafood industries in North Norway and to analyse associations between musculoskeletal symptoms and some possible risk factors in the seafood industry., Methods: A self-administered anonymous questionnaire, covering several aspects concerning occupational environment and health issues, was mailed to employees in seafood-processing plants in North Norway., Results: A total of 1767 employees in 118 seafood-processing plants participated giving a 50% response rate. This included 744 production workers in whitefish, shrimp and salmon industries, and 129 administrative workers in all types of seafood industries. The prevalence of musculoskeletal symptoms was high among seafood production workers. The odds ratio for symptoms from upper limbs was significantly higher for females compared to men. Production workers had the highest relative risk for symptoms from wrist/hands (OR = 4.1-9.4) and elbows (OR = 3.5-5.2) when compared to administrative workers. The main difference between types of seafood industries was the high prevalence of symptoms from wrist/hands among female (82%) and male (64%) production workers in the salmon industry compared to whitefish (62 and 47%, respectively) and shrimp industry (66 and 37%, respectively)., Conclusions: Musculoskeletal symptoms were found among the majority of production workers in the whitefish, shrimp and salmon industry, the highest prevalence being among female workers. The main difference between types of seafood industries was the high prevalence of symptoms from wrist/hands among workers in the salmon industry. Cold work was an important risk factor for musculoskeletal symptoms.

The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K(i)=5 nM) and competitive antagonism (K(b)=8 nM) at dopamine D(4) receptors combined with potent 5-HT uptake inhibition (IC(50)=3.2 nM) and moderate alpha(1)-adrenoceptor affinity (K(i)=45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by d-amphetamine (0.5 mg/kg; ED(50)=4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED(50)=13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of d-amphetamine (2.0 mg/kg), which indicates a preferential action on limbic versus striatal structures. A similar limbic selectivity of Lu 35-138 was indicated in voltammetric measure of dopamine output in the core and shell subdivisions of the nucleus accumbens in rats. Furthermore, a relatively large dose of Lu 35-138 (18 mg/kg, s.c.) counteracted d-amphetamine-induced disruption of pre-pulse inhibition in rats and repeated administration of Lu 35-138 (0.31 or 1.25 mg/kg, p.o. once daily for 3 weeks) reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, underlining its antipsychotic-like profile. Lu 35-138 failed to induce catalepsy in rats or dystonia in Cebus apella monkeys and did not deteriorate spatial memory in rats as assessed by water maze performance. Collectively, these results suggest that Lu 35-138 possesses antipsychotic activity combined with a low extrapyramidal and cognitive side effect liability.

Background: Although respiratory viral infections in early childhood can enhance the development of airway allergen sensitization, the exact mechanisms of the effects of viral infections on the adaptive immune response to inhaled allergens are controversial., Objective: We sought to evaluate the effects of double-stranded RNA (dsRNA) on airway sensitization to inhaled allergens., Methods: Novel mouse models were created through simultaneous airway sensitization to an allergen and low or high doses of dsRNA. The mouse models were applied to Toll-like receptor 3-, IL-13-, IL-4-, signal transducer and activator of transcription (STAT) 6-, IFN-gamma-, and T-box expressed in T cells (T-bet)-deficient mice to evaluate underlying pathophysiologic mechanisms in the development of allergic lung inflammation., Results: We found that airway allergen sensitization with dsRNA induced lung inflammation that was not present in Toll-like receptor 3-deficient mice. Moreover, lung inflammation enhanced by low-dose dsRNA was impaired in IL-13-deficient mice, whereas lung inflammation by high-dose dsRNA was impaired in IFN-gamma-deficient mice. The models also demonstrated that low-dose dsRNA enhanced IL-4 expression during allergen sensitization and that inflammation enhanced by low-dose dsRNA was not present in IL-4- or STAT6-deficient mice. In contrast, the present study showed that high-dose dsRNA enhanced IFN-gamma expression during allergen sensitization and that the development of lung inflammation enhanced by high-dose dsRNA was impaired in T-bet-deficient mice., Conclusion: These findings suggest that airway allergen exposure during respiratory viral infections might induce asthma induced by both T(H)1 and T(H)2 immune responses to inhaled allergens., Clinical Implications: Targeting both T(H)1 and T(H)2 lung inflammation might be important in the treatment of virus-associated asthma.

A series of ring-substituted analogues of imidazole-4-acetic acid (IAA, 4), a partial agonist at both GABAA and GABAC receptors (GABA = gamma-aminobutyric acid), have been synthesized. The synthesized compounds 8a-l have been evaluated as ligands for the alpha1beta2gamma2S GABAA receptors and the rho1 GABAC receptors using the FLIPR membrane potential (FMP) assay and by electrophysiology techniques. None of the tested compounds displayed activity at the GABAA receptors at concentrations up to 1000 microM. However, the 5-Me, 5-Ph, 5-p-Me-Ph, and 5-p-F-Ph IAA analogues, 8a,c,f,g, displayed full agonist activities at the rho1 receptors in the FMP assay (EC50 in the range 22-420 microM). Ligand-protein docking identified the Thr129 in the alpha1 subunit and the corresponding Ser168 residue in rho1 as determinants of the selectivity displayed by the 5-substituted IAA analogues. The fact that GABA, 4, and 8a displayed decreased agonist potencies at a rho1Ser168Thr mutant compared to the WT rho1 receptor strongly supported this hypothesis. However, in contrast to GABA and 4, which exhibited increased agonist potencies at a alpha1(Thr129Ser)beta2gamma2 mutant compared to WT GABAA receptor, the data obtained for 8a at the WT and mutant receptors were nonconclusive.

Allergic asthma is characterized by airway inflammation initiated by adaptive immune responses to aeroallergens. Recent data suggest that severe asthma may be a different form of asthma rather than an increase in asthma symptoms and that innate immune responses to LPS can modulate adaptive immune responses to allergens. In this study, we evaluated the hypothesis that airway exposure to different doses of LPS induces different form of asthma. Our study showed that neutrophilic inflammation and IFN-gamma expression were higher in induced sputum from severe asthma patients than from mild to moderate asthmatics. Animal experiments indicated that allergen sensitization with low-dose LPS (0.1 microg) induced type 2 asthma phenotypes, i.e., airway hyperresponsiveness, eosinophilic inflammation, and allergen-specific IgE up-regulation. In contrast, allergen sensitization with high-dose LPS (10 microg) induced asthma phenotypes, i.e., airway hyperresponsiveness and noneosinophilic inflammation that were not developed in IFN-gamma-deficient mice, but unaffected in the absence of IL-4. During the allergen sensitization period, TNF-alpha expression was found to be enhanced by both low- and high-dose LPS, whereas IL-12 expression was only enhanced by high-dose LPS. Interestingly, the asthma phenotypes induced by low-dose LPS, but not by high-dose LPS, were completely inhibited in TNF-alpha receptor-deficient mice, whereas the asthma phenotypes induced by high-dose LPS were abolished in the homozygous null mutation of the STAT4 gene. These findings suggest that airway exposure levels of LPS induces different forms of asthma that are type 1 and type 2 asthma phenotypes by high and low LPS levels, respectively.

Inhibition of serotonin (5-HT) reuptake has been a central theme in the therapy of depression for half a century. Through the years these therapies have improved, particularly with regard to side effects, and today's selective serotonin reuptake inhibitors (SSRIs) constitute a reasonably effective offer for the patients. However, there is still room for major improvement and considering that almost 20% of the population in the western world will experience a depressive period in their lifetime, there is a large need for improved therapies. A large spectrum of targets and strategies are currently being pursued, but so far none of these new approaches have been successful, mainly due to lack of a deeper understanding of the disease biology. Since inhibition of 5-HT reuptake ensures a certain degree of antidepressant efficacy, there has been a large interest in various combinations with serotonin reuptake inhibitors (SRIs) in order to improve on the shortcomings of treatment with SSRIs. Some of these approaches have resulted in marketed antidepressants, eg combinations of SRI with norepinephrine (NE) reuptake inhibition, whereas other approaches are still at an experimental stage. This review attempts to present the current status of these add-on/combination approaches with particular focus on the medicinal chemistry aspects.

Alternative treatments such as spiritual healing and prayer are increasingly popular, especially among patients with life-threatening diseases such as cancer. According to theories of spiritual healing, this intervention is thought to influence living cells and organisms independently of the recipient's conscious awareness of the healer's intention. The aim of this study was to test the hypothesis that spiritual healing will reduce proliferation and viability of two cancer cell lines in vitro. Three controlled experiments were conducted with three different healers and randomised allocation of cells to five different doses of healing or control. Researchers conducting the assays and statistical analyses were blinded to the experimental conditions. Main outcome measures were MTT viability, 3H-thymidine incorporation and counts of an adherent human breast cancer cell line (MCF-7), and a nonadherent mouse B-lymphoid cell line (HB-94). Analyses of variance (ANOVAs) revealed no significant main or dose-related effects of spiritual healing compared to controls for either of the two cell lines or any of the assays (P-values between 0.09 and 0.96). When comparing healing and control across all three experimental days, doses, assays, and cells, 34 (51.6%) of 66 independent comparisons showed differences in the hypothesised direction (P = 0.90). The average effect size across cell lines, days, assays, and doses approached zero (Cohen's d = -0.01). The results do not support previous reports of beneficial effects of spiritual healing on malignant cell growth in vitro. Reported beneficial effects of spiritual healing on the well-being of cancer patients seem more likely to be mediated by psychosocial and psychophysiological effects of the healer-patient relationship.

Objective: In this study, we explored airway symptoms and exposure to bioaerosols and exhaust gases in seafood industry plants., Methods: The study details the results from personal and environmental exposure measurements (17 plants), a questionnaire (n = 984), and clinical examinations (n = 225)., Results: The workers were exposed to allergens, endotoxins, molds, and exhaust. The 1-year prevalence of work-related airway symptoms was 42.8% for production workers and 25.9% for administrative workers. Mean levels of forced expiratory volume in 1 second and forced vital capacity were less than the predicted values in all exposed nonsmoker groups. A total of 20.5% had increased levels of total IgE (>/=100 kU/L). Specific IgE-mediated reactions seemed to be relevant only in the shrimp industry., Conclusions: Seafood industry workers showed a high prevalence of work-related airway symptoms. Further research on the relationship between exposure and effects is necessary.

Lipid rafts are cholesterol-enriched microdomains in plasma membranes. The functional activity of many membrane proteins, including death and growth factor receptors, depends on their insertion in lipid rafts. We have previously demonstrated the presence of lipid rafts in keratinocytes and shown that lipid rafts are involved in the control of keratinocyte proliferation and metabolic activity. In this work, we investigated the effect of lipid-raft disruption on HaCaT keratinocyte survival. Lipid rafts could be disrupted or rearranged with cholesterol-targeting detergents: methyl-beta-cyclodextrin and filipin III. Moreover, cholesterol oxidation by a specific oxidase or blocking of cholesterol synthesis by mevastatin had a similar effect on lipid rafts. All cholesterol-modifying substances caused cell death in a concentration-dependent manner. More detailed studies on the effects of cyclodextrin revealed apoptotic cell death at concentrations >or=0.5% (w/v). The molecular mechanism of apoptosis precipitated by raft disruption remains unknown but does not seem to be dependent of either membrane permeabilization or cell-cycle arrest imposed by cholesterol-modifying compounds.

A survey of occupational skin problems, based on a questionnaire, was carried out among 883 workers in different types of seafood-processing industries in northern Norway. The prevalence of dry skin, itching, rash/eczema, chapped skin and chronic sores was significantly higher among production workers (55.6%) in the white fish-, shrimp- and salmon-processing industries, compared to administrative workers in the same industries (27.5%). Among production workers, there was a significantly higher prevalence of skin symptoms among females (60.2%) compared to males (50.1%). A strong sex division of work tasks rather than sex itself may explain this. There was no sex difference among administrative workers. Several risk factors for skin symptoms to occur are indicated. The workers are exposed to raw materials and a mixture of water and juice from the fish or shrimp, salt, detergents and disinfectants. Gloves may also cause skin problems. Major risk factors believed to cause skin symptoms were contact with raw materials, fish juice, water and gloves. The results also indicate that skin symptoms are of moderate severity and seldom interfere with working capacity.

Caspases, members of the cysteine protease family, execute UVB-induced apoptosis in several cell lines and keratinocytes. Several researchers investigating UVB-induced apoptosis have demonstrated a dose-dependent protective effect of the synthetic peptide caspase inhibitor zVAD-fmk. However, zVAD-fmk displays a dose-dependent protective effect against UVB-induced apoptosis, even at doses higher than those required to block all known proapoptotic caspases. In addition, it is known that zVAD-fmk also inhibits other cysteine proteases including cathepsins and calpains, and these proteases have recently been demonstrated to play a role in the execution of programmed cell death induced by other stimuli, e.g. TNF-alpha. The purpose of the present study was therefore to investigate whether inhibitors of cysteine cathepsins and calpains could prevent UVB-induced apoptosis in HeLa cells and keratinocytes. This was done by investigating the effect of the irreversible cysteine protease inhibitor zFA-fmk, the cathepsin B inhibitor CA-074-Me and the calpain inhibitor ALLN on the viability of UVB-irradiated human keratinocytes and HeLa cells. At concentrations of 10 microM and above zVAD-fmk conferred partial dose-dependent protection against UVB-induced apoptosis in HeLa cells and keratinocytes. Moreover, caspase-3 activity was completely blocked at zVAD-fmk concentrations of 1 microM in HeLa cells. This indicates that caspase-independent mechanisms could be involved in UVB-induced apoptosis. However, the protease inhibitors zFA-fmk, CA-074-Me and ALLN all failed to prevent UVB-induced apoptosis in HeLa cells and keratinocytes. In conclusion, the protective effect of zVAD-fmk at high concentrations indicates that other proteases than caspases are active in the execution of UVB-induced apoptosis but further studies are needed to identify these proteases., (Copyright 2004 Springer-Verlag)

The first direct resolution of racemic 2-(2,3-dihydro-lH-indol-3-yl)ethanol-prepared by catalytic hydrogenation of 2-(lH-indol-3-yl)ethanol-has been accomplished by chiral simulated moving bed (SMB) chromatography. The single enantiomers were isolated as their dihydrogen phosphate salts. Single-crystal X-ray analyses were successful, revealing that the (+)-enantiomer of 2-(2,3-dihydro-lH-indol-3-yl)ethanol has the (S) configuration. Chirality 16:126-130, 2004., (Copyright 2004 Wiley-Liss, Inc.)

In vitro studies with human cell lines have demonstrated that the death receptor Fas plays a role in ultraviolet (UV)-induced apoptosis. The purpose of the present study was to investigate the relation between Fas expression and apoptosis as well as clustering of Fas in human epidermis after a single dose of UVB irradiation. Normal healthy individuals were irradiated with three minimal erythema doses (MED) of UVB on forearm or buttock skin. Suction blisters from unirradiated and irradiated skin were raised, and Fas, FasL, and apoptosis of epidermal cells quantified by flow cytometry. Clustering of Fas was from skin biopsied. Soluble FasL in suction blister fluid was quantified by ELISA. Flow cytometric analysis demonstrated increased expression intensity of Fas after irradiation, with 1.6-,2.2- and 2.7-fold increased median expression at 24, 48 and 72 h after irradiation, respectively (n=4). Apoptosis was demonstrated by the TUNEL reaction, and the maximum of apoptotic cells was detected at 48 h after irradiation. Double-staining of Fas and TUNEL showed that apoptosis was restricted to the Fas-positive epidermal subpopulation, but there was no correlation between the intensities of Fas expression and TUNEL reaction. Median expression intensity of FasL-positive cells transiently decreased to 0.9- and 0.8-fold of the preirradiation respective level after 24 h and 48 h, respectively, and returned to the respective preirradiation level at 72 h after irradiation (n=4). Concentrations of soluble FasL in suction blister fluid from UVB-irradiated skin did not differ from those in unirradiated skin (n=5). Confocal laser scanning microscopy showed a rapid clustering of Fas within 30 min after irradiation. A simultaneous clustering of the adapter signalling protein FADD suggested that Fas clustering has a functional significance. Our results ar in accordance with previous findings from in vitro studies, and suggest that Fas is activated in vivo in human epidermis after UVB exposure.

The mechanisms underlying induction of UVB-induced immunosuppression are not fully understood, but tumor necrosis factor alpha (TNF-alpha) is suggested to play a central role. A single base pair polymorphism at position --308 in the promoter region of the TNF-alpha gene associated with an enhanced secretion of TNF-alpha has been identified in humans. We have therefore investigated the association of the --308 polymorphism with the risk of basal cell carcinoma (BCC) in humans. The frequency of TNF G and TNF A alleles among Caucasian patients with a previous BCC (n=191) and health adults (n-107) were compared. For the TNF--308 polymorphism there was significant association between the genotype or allele frequencies and having BCC. To determine whether patients with a previous BCC had an increased capacity to secrete TNF-alpha, mononuclear cells were stimulated with lipopolysaccharide. Mononuclear cells from patients with a previous BCC (n=15) demonstrated a significantly increased release of TNF-alpha upon stimulation with lipopolysaccharide (P<0.03) compared with mononuclear cells age-matched control subjects (n=16). Further studies of other polymorphisms of the TNF-alpha gene associated with increased TNF-alpha production and BCC and necessary.

Background: Quartz and dust are known to cause respiratory problems. Slate workers in Alta, Norway are exposed to these compounds even today, and the need for improvement of their work environment was evaluated., Methods: Respiratory health was examined using chest X-ray, lung function tests and a self-administered questionnaire in a cross-sectional study., Results: The prevalence of silicosis among the slate workers varied between 1.9 and 6.5%. The slate workers had significantly more respiratory symptoms than the controls when adjusted for smoking. Peak expiratory flow was significantly lower among slate workers than among controls., Conclusion: The work environment of the slate workers may cause adverse effects in their airways. Improvements to their work environment are indicated.

Lipid rafts are dynamic membrane microdomains enriched in cholesterol and sphingolipids and are involved in the regulation of a variety of cellular processes, such as proliferation, apoptosis and cell motility. We have previously described that large lipid raft aggregates are readily detectable on cultured keratinocyte cell line HaCaT by staining with the fluorescein-tagged cholera toxin (CTx-FITC). In this paper we adopted this method for the detection of lipid rafts in human epidermis and keratinocytes in culture. Double labelling of showed the non-overlapping clusters of basal cells in human epidermis: CD29dimCTx-FITCbright cells in the deep rate ridges and CD29brightCTx-FITCdim cells at the tips of dermal papillae. A similar patchy, non-overlapping staining pattern was observed in cultured keratinocytes in vitro. CTx-FITCbright cells are mitotically active whereas a large proportion of CTx-FITCdim cells are quiescent. We conclude that the epidermal stem-like cells, previously shown to occupy the tips of dermal papillae and to exhibit high density of membrane beta1 integrin have a low content of lipid rafts. In contrast, the putative transit amplifying cells in deep rate ridges show enrichment in lipid rafts. Thus, lipid rafts may be a factor controlling the mitotic activity of epidermal keratinocytes and possibly the differentiation of stem cells into the transit amplifying cells.

Background: Apoptosis has been proposed to act as an important mechanism for eliminating keratinocytes that have been irreversibly damaged by ultraviolet (UV) irradiation. One way to induce apoptosis in keratinocytes is through activation of the cell surface receptor Fas (CD95), either with the ligand (FasL) or directly with UV radiation., Objectives: To investigate the regulation of Fas and FasL expression in human skin and the formation of apoptotic cells after in vivo exposure to UVB or long-wave UVA radiation., Methods: Volunteers were irradiated with either 3 minimal erythema doses (MED) of UVB (n = 6) or 3 MED of long-wave UVA (n = 6) on buttock skin 12, 24 and 72 h before skin punch biopsies were taken. Expression of Fas and FasL was demonstrated by immunohistochemistry on cryostat sections. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated fluorescein-deoxyuridine triphosphate nick-end labelling reaction., Results: In five of six subjects, exposure to UVB radiation resulted in increased homogeneous expression of Fas on epidermal cells, with greatest expression at 24 and 72 h after irradiation. In all subjects, exposure to long-wave UVA resulted in increased homogeneous expression of Fas on epidermal cells, with greatest expression at 12 h after irradiation. In five of six subjects, exposure to UVB radiation resulted in temporarily decreased expression of FasL, but after 72 h the expression of FasL had returned to the preirradiation level. The expression of FasL on epidermal cells after exposure to long-wave UVA showed considerable variation. UVB irradiation was a stronger inducer of epidermal apoptosis than was UVA irradiation. The number of apoptotic epidermal cells did not correlate with expression of Fas or FasL., Conclusions: In human skin the expression of Fas on epidermal cells increases after in vivo exposure to UVB or long-wave UVA. Exposure to UVB causes a temporary decrease in the expression of FasL on epidermal cells.

This is a case report of transient neurologic symptoms (TNS) after spinal anesthesia with 4% hyperbaric mepivacaine,which have not been reported before. The patient was a 44-year-old man with a meniscus lesion who received spinal anesthesia with 80 mg 4% mepivacaine while undergoing knee arthroscopy. A L3-L4 mid-line approach was used with a 26-gauge Quincke needle and a 21-gauge introducer. The local anaesthetic was injected over approximately 30 s with the aperture of the Quincke needle in a cephalad direction. A transient pain syndrome was observed 4 h after spinal anesthesia, which included symmetric pain and/or dysesthesia in the buttocks and posterior thighs appearing 4 h after recovery from the spinal anesthesia and had a duration of 2 days. The patient stated that the pain radiated through the hips, buttocks, and posterior thighs and extended past the buttocks and lower legs. The pain was described as strong and aching,occasionally decreasing when walking around. It responded well to NSAID and resolved spontaneously within 3 days. No other neurologic symptoms or signs were noted.

Nuclear factor-kappaB (NF-kappaB) activity affects cell survival in ROS 17/2.8 osteoblasts. Preventing NF-kappaB transcription activity with a potent NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), results in apoptosis. Thus, we explored the effect of pyrrolidine dithiocarbamate (PDTC), which potently blocks the activation of nuclear factor-kappaB (NF-kappaB) in serum-exposed condition, on the activation of mitogen activated protein kinase (MAPK), especially, JNK/SAPK and p38 MAPK induction. PDTC transiently increased the phosphotransferase activity of c-Jun N-terminal Kinase1 (JNK1), which might in turn activates transcriptional activity of activating protein-1 (AP-1). The activation of JNK was completely decreased in dominant negative JNK1 transfected cells and the PDTC-induced cell death was attenuated in these cells. In addition, AP-1 activation was decreased in the JNK1 transfected cells, compared with vector-transfected cells. The NF-kappaB inhibitor also transiently activates p38 MAPK but SB203580, a specific p38 MAPK inhibitor, does not have any regulatory effect on PDTC-induced cell death, suggesting that the cell death is mediated by JNK not by p38 MAPK. Thus, overall, these results show that PDTC induces apoptosis and suggest that JNK/SAPK and subsequent AP-1 activation may be involved in the apoptotic pathway in ROS 17/2.8 osteoblasts.

We have previously shown that the 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA, 2), binds to AMPA receptors in a manner different from that of AMPA (1) itself and that 2, in contrast to 1, also binds to kainic acid receptor sites. To elucidate the structural requirements for selective activation of the site/conformation of AMPA receptors recognized by 2, a number of isosteric analogues of 2 have now been synthesized and pharmacologically characterized. The compound 2-amino-3-(5-carboxy-3-methoxy-4-isoxazolyl)propionic acid (3a) (IC(50) = 0.11 microM; EC(50) = 1.2 microM), which is a regioisostere of 2 with a methoxy group substituted for the methyl group, was approximately equipotent with 2 (IC(50) = 0.020 microM; EC(50) = 1.0 microM) as an inhibitor of [(3)H]AMPA binding and as an AMPA agonist, respectively, whereas the corresponding 3-ethoxy analogue 3b (IC(50) = 1.0 microM; EC(50) = 4.8 microM) was slightly weaker. The analogues 3c-e, containing C3 alkoxy groups, were an order of magnitude weaker than 3b, whereas the additional steric bulk of the alkoxy groups of 3f-i or the presence of an acidic hydroxyl group at the 3-position of the isoxazole ring of 3j prevented interaction with AMPA receptor sites. The 2-amino-3-(2-alkyl-5-carboxy-3-oxo-4-isoxazolyl)propionic acids 4a,b, i, which are regioisosteric analogues of 3a,b,i, showed negligible interaction with AMPA recognition sites. Similarly, replacement of the carboxyl group of 3b by isosteric tetrazolyl or 1,2,4-triazolyl groups to give 5 and 6, respectively, or conversion of 3b into analogue 7, in which the diaminosquaric acid group has been bioisosterically substituted for the alpha-aminocarboxylic acid unit, provided compounds completely devoid of effect at AMPA receptors. In contrast to the parent compound ACPA (2) (IC(50) = 6.3 microM), none of the analogues described showed detectable inhibitory effect on [(3)H]kainic acid receptor binding.

Non-melanoma skin cancer is the most common type of cancer in Denmark and it is mainly caused by ultraviolet radiation from sunlight. Ultraviolet radiation of the skin not only causes DNA damage in skin cells, but it is also able to activate T cells that suppress the function of the immune system. The exact phenotype of these T cells is not known, but the mechanisms by which they are activated include: 1) Suppressed function of the Langerhans' cells, probably because of altered expression of co-stimulatory molecules; 2) induction of epidermal macrophages; and 3) an altered balance in epidermal cytokines, with increased levels of TNF-alpha and IL-10 and suppressed release of IL-12. The importance of a suppressed function of the immune system is stressed by the fact that patients with transplanted organs who receive immunosuppressive therapy have a markedly increased risk of developing non-melanoma skin cancer.

We have previously shown that (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (2-Me-Tet-AMPA) is a selective agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, markedly more potent than AMPA itself, whereas the isomeric compound 1-Me-Tet-AMPA is essentially inactive. We here report the enantiopharmacology of 2-Me-Tet-AMPA in radioligand binding and cortical wedge electrophysiological assay systems, and using cloned AMPA (GluR1-4) and kainic acid (KA) (GluR5, 6, and KA2) receptor subtypes expressed in Xenopus oocytes. 2-Me-Tet-AMPA was resolved using preparative chiral HPLC. Zwitterion (-)-2-Me-Tet-AMPA was assigned the (R)-configuration based on an X-ray crystallographic analysis supported by the elution order of (-)- and (+)-2-Me-Tet-AMPA using four different chiral HPLC columns and by circular dichroism spectra. None of the compounds tested showed detectable affinity for N-methyl-D-aspartic acid (NMDA) receptor sites, and (R)-2-Me-Tet-AMPA was essentially inactive in all of the test systems used. Whereas (S)-2-Me-Tet-AMPA showed low affinity (IC(50) = 11 microM) in the [(3)H]KA binding assay, it was significantly more potent (IC(50) = 0.009 microM) than AMPA (IC(50) = 0.039 microM) in the [(3)H]AMPA binding assay, and in agreement with these findings, (S)-2-Me-Tet-AMPA (EC(50) = 0.11 microM) was markedly more potent than AMPA (EC(50) = 3.5 microM) in the electrophysiological cortical wedge model. In contrast to AMPA, which showed comparable potencies (EC(50) = 1.3-3.5 microM) at receptors formed by the AMPA receptor subunits (GluR1-4) in Xenopus oocytes, more potent effects and a substantially higher degree of subunit selectivity were observed for (S)-2-Me-Tet-AMPA: GluR1o (EC(50) = 0.16 microM), GluR1o/GluR2i (EC(50) = 0.12 microM), GluR3o (EC(50) = 0.014 microM) and GluR4o (EC(50) = 0.009 microM). At the KA-preferring receptors GluR5 and GluR6/KA2, (S)-2-Me-Tet-AMPA showed much weaker agonist effects (EC(50) = 8.7 and 15.3 microM, respectively). It is concluded that (S)-2-Me-Tet-AMPA is a subunit-selective and highly potent AMPA receptor agonist and a potentially useful tool for studies of physiological AMPA receptor subtypes., (Copyright 2000 Wiley-Liss Inc.)

The purpose of this study was to explore the clinical and pathogenic significance of vitamin D metabolites in primary Sjögren's syndrome (primary SS). We measured blood concentrations of 25-hydroxyvitamin D (25 OH D) and calcitriol (1,25(OH)2D)vc in 41 patients and correlated the results with blood levels of various immune activation products, as well as with patients' clinical status. Levels of 25 OH D were slightly decreased as compared to normal controls and the reduced levels of 25 OH D were stable over the observed period of 2 years. Levels of 25 OH D correlated inversely with levels of soluble interleukin-2 receptor, status indices for global disease, total exocrine disease, surface exocrine disease, internal organ exocrine disease, and mediator-induced disease. Levels of 1,25(OH)2D varied considerably and compared to normal control values. Levels of 1,25(OH)2D did not correlate with clinical/immunopathological status. In conclusion the inverse correlations found between levels of 25 OH D and measures of clinical and immunoinflammatory status support the notion that vitamin D metabolism may be involved in the pathogenesis of primary SS.

A number of 3-isoxazolol bioisosteres, 7a-i, of (S)-glutamic acid (Glu), in which the methyl group of (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 1) was replaced by different 5-membered heterocyclic rings, were synthesized. Comparative in vitro pharmacological studies on this series of AMPA analogues were performed using receptor binding assays (IC50 values) and the electrophysiological rat cortical slice model (EC50 values). None of these compounds showed detectable affinity for the N-methyl-D-aspartic acid subtype of Glu receptors. Some of the compounds were weak inhibitors of [3H]kainic acid binding. The inhibitory effects on [3H]AMPA binding and agonist potencies at AMPA receptors of 7a-i were strictly dependent on the structure, electrostatic potential, and methyl substitution of the heterocyclic 5-substituent. Thus, while 7a (IC50 = 0.094 microM; EC50 = 2.3 microM) was approximately equipotent with AMPA (IC50 = 0.023 microM; EC50 = 5.4 microM), (RS)-2-amino-3-[3-hydroxy-5-(1H-imidazol-2-yl)isoxazol-4-yl]propio nic acid (7b) (IC50 = 48 microM; EC50 = 550 microM) was some 2 orders of magnitude weaker than AMPA, and (RS)-2-amino-3-[3-hydroxy-5-(1-methyl-1H-imidazol-2-yl)-isoxazol-4 -yl] propionic acid (7c) (IC50 > 100 microM; EC50 > 1000 microM) was inactive. Furthermore, (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (7i) (IC50 = 0.030 microM; EC50 = 0.92 microM) was more potent than AMPA, whereas its N-1 methyl isomer, (RS)-2-amino-3-[3-hydroxy-5-(1-methyl-1H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (7h) (IC50 = 54 microM; EC50 > 1000 microM) was inactive as an AMPA agonist. A quantitative structure-activity relationship (QSAR) analysis revealed a positive correlation between receptor affinity, electrostatic potential near the nitrogen atom at the "ortho" position of the heterocyclic 5-substituent, and the rotational energy barrier around the bond connecting the two rings. We envisage that a hydrogen bond between the protonated amino group and an ortho-positioned heteroatom of the ring substituent at the 5-position stabilize receptor-active conformations of these AMPA analogues.

Conclusions: Pseudocyst contents are not indicative of pancreatic function. We presume that the nonresolving pseudocysts did not resolve because they were noncommunicating. The question of the kinetics of secretion into pancreatic pseudocysts is still unresolved., Background: Pseudocysts are one of the complications of chronic pancreatitis. We wanted to investigate whether it is of any value to measure enzyme activities (amylase and lipase) in pseudocyst contents, in order to answer the following questions: Is the enzymatic activity: 1. Reproducible in consecutive punctures of the same cyst; 2. Related to cyst age; 3. Indicative for the risk of relapse; and 4. Representative of exocrine pancreatic function., Methods: In a retrospective study we examined 28 patients with chronic pancreatitis complicated with pancreatic pseudocysts., Results: Reproducibility of enzyme activity in cyst juice in consecutive punctures of the same cyst was poor. We did not observe any correlation between enzyme activity and cyst age defined as the time between two cyst punctures. Enzyme activity in cyst juice was without indication for the risk of relapse. No correlation between enzyme activity and exocrine pancreatic function was found. The pseudocyst contents are not pancreatic juice in the common sense of the word

The risks associated with blood transfusion can be minimized using autologous blood. The efficiency of preoperative blood deposit, preoperative acute-hemodilution spinal anesthesia, controlled hypotension and intra and postoperative autotransfusion in reducing homologous transfusion has been demonstrated. In a prospective study the effectivity of this concept is demonstrated. 141 patients scheduled for total hip arthroplasty were divided in three groups: group I--total hip arthroplasty without cement (n = 55); group II--total hip arthroplasty with cement (n = 52); and group III total hip revision arthroplasty (n = 34). The mean quantity of the donated blood was 900 mL. The donation was not associated with serious complications. In group I 52 patients (94.5%), in group II 40 patients (77%) and in group III 14 patients (41.2%) did not require homologous transfusion. The difference between group I and II was significant (p < 0.05). Under the conditions studied, preoperative autologous blood deposit, acute hemodilution, spinal anesthesia and controlled hypotension are effective for decreasing the application of homologous transfusions in hip arthroplasty. The efficiency of preoperative hemodilution alone is limited. Preoperative deposit of autologous blood is a simple, effective, economical, and low-risk method of reducing homologous transfusion. Autotransfusion with a cell separator can save approximately 50% of the erythrocytes lost during revision total hip arthroplasty.

[[(4-Nitrophenyl)X]alkyl]imidazole isosteres (where X = NH, S, CH2S, O) of previously described [[(5-nitropyrid-2-yl)X]ethyl]imidazoles (where X = NH, S) have been synthesized and evaluated for H3-receptor histamine antagonism in vitro (Ki for [3H]histamine release from rat cerebral cortex synaptosomes) and in vivo (ED50 per os in mice on brain tele-methylhistamine levels). Encouraging results led to the synthesis and testing of a novel series of substituted (phenoxyethyl)- and (phenoxypropyl)imidazoles. From the latter, 4-[3-(4-cyanophenoxy)propyl]-1H-imidazole (10a, UCL 1390; Ki = 12 nM, ED50 = 0.54 mg/kg) and 4-[3-[4-(trifluoromethyl)-phenoxy]propyl]-1H-imidazole (10c, UCL 1409; Ki = 14 nM, ED50 = 0.60 mg/kg) have been selected as potential candidates for drug development. For 16 [(aryloxy)ethyl]imidazoles the relationship between in vitro and in vivo potency is described by the equation log ED50 = 0.47 log Ki + 0.20 (r = 0.78).