Self-assembly of Janus disks confined in a slit.

Using Monte Carlo simulations, we investigate the self-organization of Janus disks confined in two-dimensional slits. Janus particles are modeled as circles composed of attractive and repulsive parts. We consider the slits with identical walls and slits with competing walls (the so-called Janus-like pores). We investigate how the system morphology depends on the slit width, density, and temperature. Different unique orientationally ordered structures are found. The mechanism of formation of these structures is discussed in detail. We show that the anisotropic interactions between the confined molecules, the nature of the "walls," and the slit size strongly affect the self-organization.

Non-melanoma Hutchinson's sign: a reappraisal of this important, remarkable melanoma simulant.

BACKGROUND: More than 20 years ago, our reappraisal of the Hutchinson's sign (HS) gave birth to the concept of the pseudo-Hutchinson's sign. OBJECTIVES: We have found it interesting to emphasize some important histologic points and to expand the list of the numerous HS simulants. METHODS: We have examined the cutaneous samples taken from the pigmented skin of patients in association with nail matrix biopsy. We have also extended the long list of non-melanoma HS based on comprehensive literature review. RESULTS: Histologically, HS may present only as an epidermal pigmentation, depending on the area sampled. Occasionally, there may be a sparse junctional melanocytic proliferation which does not demonstrate cytologic atypia due to an underlying melanocytic naevus of the nail matrix. However, early HS often shows a melanoma in situ, with a HS at the proximal nail fold (PNF) and confluent "atypical" melanocytes in the nail matrix. Finally, involvement of the PNF, nail matrix and nail bed containing atypical melanocytes in irregular array may be seen in more advanced lesions. The recent literature on non-melanoma HS simulants is summarized and clinical examples are provided. CONCLUSION: The mere presence of periungual pigmentation is neither clinically nor histologically pathognomonic of subungual melanoma and justifies the usefulness of this work stressing the non-melanoma HS.

Effective interactions between a pair of particles modified with tethered chains.

Using molecular dynamics, we evaluate the potential of mean force for two models of hybrid nanoparticles, namely, for the models with fixed and movable chain ligands. We also investigate the structure of segments of chains around nanoparticles and its change when one nanoparticle approaches the other. In the case of an isolated particle, we also employ a density functional theory to compute the segment density profiles. Moreover, to determine the structure of segments around a core, we have employed the concept of the so-called mass dipoles.

Serotonin1B receptor ligands in the nucleus accumbens shell do not affect the discriminative stimulus effects of amphetamine in rats.

Enhanced dopamine neurotransmission particularly, in the target area of the mesolimbic system, i.e. the nucleus accumbens (NAc), seems to be critical for the behavioral effects of amphetamine in rodents. Nonetheless, recent findings have also demonstrated a modulatory role of 5-hydroxytryptamine (5-HT; serotonin) in these effects. In the present study, we examined whether 5-HT1B receptors in the NAc shell are engaged in the discriminative stimulus of amphetamine. To this end male Wistar rats were trained to discriminate amphetamine (1 mg/kg, ip) from saline (ip) in a two-lever, water reinforced fixed ratio (FR) 20 task. After acquiring the amphetamine-saline discrimination, rats were stereotaxically implanted with bilateral cannulae aimed at the NAc shell and then infused with selective 5-HT1B receptor ligands. The ability of these drugs to substitute for or to alter (enhance or antagonize) the discriminative stimulus effects of amphetamine was examined. When given systemically, amphetamine (0.125-1 mg/kg) produced a dose-dependent increase in drug-lever responding. In substitution studies, microinjection of the 5-HT1B receptor agonist CP 93129 (1-10 microg/side) or the 5-HTIB receptor antagonist GR 55562 (1-10 microg/side) into the NAc shell did not evoke amphetamine-lever responding. Combination tests of 5-HT1B receptor ligands demonstrated that local injection with fixed doses of CP 93129 (1 or 10 microg/side) or GR 55562 (1 or 10 microg/side) with the submaximal doses of amphetamine (0.125-0.5 mg/kg) did not modify dose-response curves of the psychostimulant, nor did it affect its ED50 value. Our results seem to exclude a role for the NAc shell 5-HT1B receptors in the control of the discriminative stimulus effects of amphetamine. These findings also show that pharmacological stimulation of those receptors does not affect the amphetamine discrimination in rats.

Activation of serotonin (5-HT)1A receptors inhibits amphetamine sensitization in mice.

The effects of serotonin (5-HT)1A drugs on the development and expression of sensitization to the locomotor effect of amphetamine (AMPH) were studied in mice. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A agonist, dose-dependently reduced the expression of AMPH (2.5 mg/kg)-induced sensitization. The latter inhibitory effect of 8-OH-DPAT was reversed by (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenyl propamine (WAY 100135), a 5-HT1A antagonist. WAY 100135 given alone did not affect expression of AMPH sensitization. Combined injections of 8-OH-DPAT, but not WAY 100135, with AMPH (2.5 mg/kg) during the development of sensitization, protected against the expression of sensitization to a challenge dose of AMPH (2.5 mg/kg) 3 days after withdrawal. The above inhibitory effect of 8-OH-DPAT on the development of AMPH sensitization was blocked by pretreatment with WAY 100135. The AMPH-induced conditioned locomotion was unaffected by pretreatment with 8-OH-DPAT. These results indicate that 5-HT1A receptors are not involved in AMPH-induced sensitization per-se, whereas their pharmacological activation leads to the inhibition of both the development and the expression of AMPH-induced sensitization.

Effect of kainic acid and pentetrazole administration on the activity of nitric oxide synthase in the mouse brain.

The present study examined ex vivo effect of kainic acid and pentetrazole administration on the activity of nitric oxide synthase (NOS) in the mouse brain. NOS activity was assayed by measuring the formation of [3H] citrulline from [3H]arginine in the homogenates of mouse hippocampus, neocortex and cerebellum. The highest basal activity of the enzyme was found in this latter brain region. Administration of kainic acid (30 mg/kg) increased the NOS activity in all brain regions examined. On the other hand, pentetrazole (60 mg/kg) did not evoke any significant changes in the NOS activity at 5 min after the administration. Only in cerebellum, at 10 min after administration of pentetrazole, the increase in the activity of the enzyme was observed. The obtained results indicate that the two particular convulsants used in this study differ not only in respect of behavioral signs of seizures which they evoke, but also in respect of the effect on mouse brain NOS activity.

[Evaluation of bacteriological research data and laboratory symptoms of infection in the diagnosis of congenital and acquired infections]. / Ocena wyników badán bakteriologicznych oraz laboratoryjnych wykladników infekcji w rozpoznawaniu zakazen wrodzonych oraz nabytych.

The predisposition of the newborns to contract infections diseases is dependent upon the limited efficiency of their immune mechanisms. Congenital infections amount to 5.7% in the research material, and the acquired infections 1.15%. The isolation of the microorganism is the basis for treating infections-the profiles of the pathogenic bacterial in flora were subjected to analysis. Im generalised infections Stafphylococcus epidermidis makes 56.6% and E. Coli accounts for 87.5 of the infections of the urinary system. In our research the late sepsis and pneumonia are more frequently the result of the hospital infection (14.2%) in the cases of congenital infections-pneumonia and the infection of the urinary system (72%). Hematologic indicators such as: leucopenia, thormbocytopenia, I/T are distinct infection markers (those were found in 31% of the cases). The CRP protein shows the lowest values in congenital infections, still monitoring its level is useful for assessing the effectiveness of the undertaken antybacterial treatment. The newborns of male sex (58%) more often prone to infection. Pneumonia is the manifestation pertaining to an organ in 70% of congenital infections, the infection of urinary system amounts to 17.1%.

Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization.

A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for antagonistic effects at the strychnine-insensitive modulatory site of the N-methyl-D-aspartate (NMDA) receptor (glycineB). All compounds displaced [3H]MDL-105,519 binding to rat cortical membranes with IC50 values of between 90 nM and 3.6 microM. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 microM, glycine 1 microM) were antagonized by these same compounds with IC50 values of 0.14 to 13.8 microM. The antagonism observed was typical for glycineB antagonists, i.e., they induced desensitization and their effects were not use or voltage dependent. Moreover, increasing concentrations of glycine were able to decrease their apparent potency. Much higher concentrations (>100 microM) were required to antagonize alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced currents. They were potent, systemically active NMDA receptor antagonists in vivo against responses of single neurons in the rat spinal cord to microelectrophoretic application of NMDA with ID50 values in the low milligram per kilogram i.v. range. They also inhibited pentylenetetrazol-, NMDA- and maximal electroshock-induced convulsions in mice with ED50 values ranging from 8 to 100 mg/kg i.p. The duration of anticonvulsive action was rather short but was prolonged by the organic acid transport inhibitor probenecid (200 mg/kg). The agents tested represent a novel class of systemically active glycineB antagonists with greatly improved bioavailability.

Effect of nitric oxide synthase inhibitors and molsidomine on the anticonvulsant activity of some antiepileptic drugs.

The present study examined effects of the two nitric oxide synthase (NOS) inhibitors, N-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), as well as of the NO donor molsidomine on the anticonvulsant activity of conventional antiepileptic drugs (diphenylhydantoin and carbamazepine) and competitive (CGP 37,849) and non-competitive (dizocilpine) NMDA receptor antagonists against the maximal electroshock in mice. It was found that L-NAME (25 and 50 mg/kg) did not affect the anticonvulsant activity of either drug, having had no influence on their anticonvulsive ED50 values. 7-NI (50 and 100 mg/kg) reduced the anticonvulsive ED50 (augmentation of the anticonvulsant activity) of CGP 37,849 and dizocilpine, raised the anticonvulsive ED50 (attenuation of the anticonvulsant activity) of diphenylhydantoin and had no influence on the anticonvulsant effect of carbamazepine. At the same time, augmentation of the anticonvulsant activity (reduction of the ED50 values) of diphenylhydantoin, carbamazepine and CGP 37,849, but not of dizocilpine, was observed after molsidomine (100-150 mg/kg). Moreover, 7-NI (100 mg/kg) and molsidomine (100 and 150 mg/kg), but not L-NAME (25 and 50 mg/kg), raised the threshold for electroconvulsions. The obtained results indicate that alterations in the anticonvulsant activity of the investigated drugs evoked by 7-NI and mosidomine, may result from non-specific effects of the NOS inhibitor and the NO donor, having no connection with the brain NO pathway.

Prediction of bone marrow involvement in patients with malignant lymphoma by GM-CSF stimulation test.

Recently, a stimulation test with colony stimulation factors was found useful to predict bone marrow cellularity. We examined the usefulness of this test to predict the bone marrow involvement in patients with malignant lymphoma. A single dose of GM-CSF (5 micrograms/kg) was given subcutaneously to 12 patients with malignant lymphoma. Six patients had normocellular bone marrow. Five of these 6 patients showed an increase in neutrophils of more than 5 x 10(9)/l after GM-CSF administration. The remaining 6 patients who had bone marrow lymphoma involvement had a neutrophil count of less than 5 x 10(9)/l. Therefore, the change in neutrophil count with a cut-off value of 5 x 10(9)/l distinguished the marrow lymphoma involvement with a sensitivity and specificity of 83% and 100%, respectively. The nadir neutrophil count was significantly higher in patients with normal marrow than in patients with marrow involvement after chemotherapy (P < 0.02). In conclusion, the GM-CSF stimulation test is useful to predict the marrow involvement in patients with malignant lymphoma.

The role of nitric oxide in chemically- and electrically-induced seizures in mice.

The effect of the nitric oxide synthase (NOS) inhibitors N-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) on seizures induced by N-methyl-D-aspartate (NMDA), pilocarpine (PIL) and pentylenetetrazol (PTZ), as well as on the electroconvulsive threshold was studied in mice. It was found that L-NAME and 7-NI decreased the dose of NMDA necessary to produce clonic convulsions in 50% of animals (CD50). Such a proconvulsant effect was not observed in mice pretreated with N-nitro-D-arginine methyl ester (D-NAME), an inactive isomer of L-NAME. Neither L-NAME nor 7-NI affected the convulsions induced by PIL (clonic seizures) or PTZ (clonic and tonic seizures), having no effect on their CD50 values. Similarly, neither NOS inhibitor affected the electroshock threshold. These results, together with some literature data, indicate that nitric oxide (NO) may be regarded as an anticonvulsant substance in relation to seizures induced by NMDA and other excitatory amino acids, but not by other agents, in mice.

Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo.

The amino-adamantane derivatives memantine (1-amino-3,5-dimethyladamantane) and amantadine (1-amino-adamantane) are relatively low affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists which have been used clinically in the treatment of dementia and Parkinson's disease respectively for several years without serious side effects. The aim of this study was to test whether memantine, amantadine and other low affinity uncompetitive NMDA receptor antagonists also have better therapeutic indices than high affinity antagonists in preclinical models of epilepsy by assessing the potency, kinetics and voltage-dependency of open channel blockade for a series antagonists in vitro and comparing these effects to anticonvulsive and motor impairment activity in vivo. The compounds tested were memantine, amantadine, 14 other amino-adamantanes, (+)-MK-801, ketamine, dextrorphan, dextromethorphan and phencyclidine. The offset kinetics of open-channel blockade assessed with whole cell patch clamp recordings from cultured superior colliculus neurones were highly correlated to potency i.e. the less potent antagonists showed faster unblocking kinetics (Koff, r = 0.904). Although, onset kinetics as assessed by Kon were not correlated to potency (r = 0.023), tau on estimated at IC50 is perhaps a more meaningful measure of onset kinetics at equieffective concentrations and was also well correlated to potency (r = -0.863). All amino-adamantanes tested were strongly voltage-dependent. There was also a good correlation between the in vitro potencies of uncompetitive NMDA receptor antagonists assessed with patch clamp recordings and displacement of equilibrium [3H](+)-MK-801 binding and their in vivo activity against maximal electroshock (MES) and pentylenetetrazol (PTZ) induced tonic convulsions and NMDA-induced lethality in mice. Memantine and four other amino-adamantanes with somewhat lower potency and faster blocking kinetics had better therapeutic indices (ED50 rotarod and traction reflex over ED50 in MES-induced convulsions; TI = 2-4) than substances with higher affinity such as ketamine, dextrorphan and (+)-MK-801 (TI < 2). However, amantadine and several other amino-adamantanes with lower potency than memantine actually had poorer therapeutic indices (TI < or = 0.5) which may have been due to additional actions at other ion channels or receptors at the doses necessary to protect against seizures. In fact, ED50 in the MES test was negatively-correlated to therapeutic indices (traction r = -0.790, rotarod r = -0.797) i.e. the less potent uncompetitive antagonists had worse therapeutic indices. The data from the present study do not lend support to the idea that low affinity, open channel NMDA receptor blockers are also effective in models of epilepsy at doses having little effect on physiological processes. It should be stressed that these data do not contradict the known therapeutic safety of memantine and amantadine in dementia and Parkinson's disease respectively. Thus the good clinical profile of memantine in dementia has been attributed not only to its fast blocking/unblocking kinetics but also to its strong voltage-dependency. These biophysical properties may allow therapeutically-relevant concentrations to block chronic, low level pathological activation of NMDA receptors whilst leaving their synaptic activation intact. Precisely these properties may also underlie the poor therapeutic indices seen in the present study on antiepileptic activity due to the synaptic nature of both seizures and normal glutamatergic transmission.

Role of 5-hydroxytryptamine receptor subtypes in the 1-[3-(trifluoromethyl)phenyl] piperazine-induced increase in threshold for maximal electroconvulsions in mice.

The effect of 1-[3-(trifluoromethyl)phenyl] piperazine (TFMPP), a 5-hydroxytryptamine (5-HT) receptor agonist, on the threshold for maximal electroconvulsions was studied in mice. TFMPP in intraperitoneal (i.p.) doses of 10, 20 and 40 mg/kg increased the convulsive threshold (the amperage necessary to produce the hindleg tonic extensor component of seizures in 50% of animals) by 28, 60, and 85%, respectively. The effect of TFMPP (20 mg/kg) was dose-dependently blocked by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine (NAN-190), prazosin, spiperone, mesulergine, ketanserin, and ritanserin. On the other hand, pindolol and cyanopindolol had no effect on the convulsive threshold increased by TFMPP. The results indicate that the TFMPP-induced decrease in the susceptibility to seizures is connected to stimulation of 5-HT2 or of both 5-HT1C and 5-HT2 receptors. Moreover, alpha 1-adrenoceptors also appear to be engaged in this effect.

The role of nitric oxide in the kainate-induced seizures in mice.

The effect of L-arginine (L-Arg), D-arginine (D-Arg), N-nitro-L-arginine methyl ester (L-NAME) and N-monomethyl-L-arginine (L-NMMA) on the kainate-induced seizures was studied in mice. It was found that the precursor of nitric oxide (NO) L-Arg (150-600 mg/kg i.p.) increased dose-dependently the dose of kinate necessary to produce clonic convulsions in 50% of the animals (CD50). Such an anticonvulsant effect was not observed in mice pretreated with D-Arg (150-600 mg/kg i.p.), the latter drug not being a substrate for NO formation. The inhibitors of NO synthase L-NAME and L-NMMA, both administered in doses of 30-30 mg/kg i.p., reduced the convulsive threshold by decreasing the CD50 of kainate. Moreover, L-NAME (3 mg/kg) antagonized the anticonvulsant effect of L-Arg (300 mg/kg). These results indicate that NO may play a role of an endogenous anticonvulsant substance in mice.

The anxiolytic-like effects of 5-hydroxytryptamine3 (5-HT3) receptor antagonists.

The effect of six 5-HT3 receptor antagonists: ondansetron (0.01-3 mg/kg ip), granisetron (0.01-1 mg/kg ip), zacopride (0.01-3 mg/kg ip), tropisetron (0.001-0.1 mg/kg ip), MDL 72222 (0.01-3 mg/kg ip) and DAU 6215 (0.01-3 mg/kg sc) were examined in the conflict drinking test (Vogel test) and in the elevated plus-maze test in rats. Ondansetron (0.1-0.3 or 1 mg/kg), zacopride (0.1-1 mg/kg) and tropisetron (0.01 mg/kg) increased the punished responding in the Vogel test and showed anxiolytic effects in the elevated plus-maze test. Their effects were limited to a narrow dose range and were not dose-dependent. Granisetron (0.1 mg/kg) exhibited an anti-conflict activity, but was ineffective in the elevated plus-maze test. MDL 72222 and DAU 6215 were ineffective in both those tests. On the other hand, diazepam (2.5-10 mg/kg), used as a reference drug, was active in either procedure and its effects were dose-dependent. These results indicate that an anxiolytic-like activity is not a common characteristic of 5-HT3 receptor antagonists. Moreover, even the anxiolytic action of drugs which were active in the experimental models used should be accepted with caution.

Captopril lacks the antidepressant-like activity in animal models.

Captopril, an angiotensin converting enzyme inhibitor, was evaluated for a potential antidepressive activity in several animal models. The drug administered in doses of 3-30 mg/kg ip neither affected the reserpine- or apomorphine-induced hypothermia in mice nor reduced the immobility time in the forces swimming test in mice and rats. Moreover, captopril administered repeatedly (10 mg/kg ip, twice daily for 14 days) neither changed the density or affinity of cortical beta-adrenoceptors nor modified the nomifensine-induced locomotor hyperactivity in rats. These results suggest that captopril has no antidepressant-like activity in animal models.

[The agonists of I-A serotoninergic receptors restore in rats behavior impaired by L-dihydroxyphenylalanine]. / Agonisty I-A-serotoninovykh retseptorov vosstanavlivaiut povedenie krys, narushennoe L-dioksifenilalaninom.

The ability of selective and nonselective 5-HT1A agonists, nondirect 5-HT agonists and 5-HT2 antagonists influence on the L-DOPA-disturbed rats behaviour were studied. The results indicate that agonists 5-HT1A like receptors largely than 5-HT2,3 agonists, 5-HT2 antagonists and nondirect 5-HT agonists promote restoration of the L-DOPA disturbed escape behaviour in acute stress situation.

Repeated treatment with imipramine, amitriptyline or electroconvulsive shock does not affect the 8-OH-DPAT-induced increase in food intake in free feeding rats.

We studied the effect of repeated treatment with imipramine, amitriptyline (10 mg/kg po, twice daily for 14 days) or electroconvulsive shock (ECS, once daily for 10 days) on the 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced increase in food intake in free feeding rats. The response to 8-OH-DPAT, measured 24 h after the last administration of the antidepressant drugs or ECS, was not modified. These results, together with literature data, indicate that the presynaptic 5-HT1A receptors involved in the 8-OH-DPAT-induced feeding are not affected by long-term antidepressant administration.

The effect of repeated treatment with antidepressant drugs on the thyrotropin-releasing hormone (TRH)-induced hyperthermia in mice.

The effect of acute (single dose) or repeated (twice daily, for 14 days) administration of 10 mg kg-1 p.o. of imipramine, amitriptyline, citalopram or mianserin has been examined on the hyperthermia induced by thyrotropin-releasing hormone (TRH) (40 mg kg-1 i.p., 2, or 2 and 72 h after single or last dose of antidepressants, respectively) in mice. Both imipramine and amitriptyline, given repeatedly, potentiated the TRH response, though the effect was observed 2 but not 72 h after the last dose of those drugs. Potentiation was also found after the single dose of imipramine or amitriptyline. On the other hand, citalopram and mianserin, administered either acutely or repeatedly, did not affect the TRH-induced hyperthermia.