The impact of Sambucus nigra L. extract on inflammation, oxidative stress and tissue remodeling in a rat model of lipopolysaccharide-induced subacute rhinosinusitis.

Rhinosinusitis is a common disorder related to inflammation of paranasal sinuses and nasal cavity mucosa. Herbal medicines could be an option in the treatment of rhinosinusitis due to their anti-inflammatory and anti-oxidative properties. The study aims to investigate the effect of intranasal Sambucus nigra L. subsp. nigra (SN) extract against inflammation, oxidative stress, and tissue remodeling in nasal and sinus mucosa, but also in serum, lungs, and brain, in Wistar rat model of subacute sinonasal inflammation induced by local administration of lipopolysaccharides (LPS), from Escherichia Coli. The cytokines (TNF-α, IL-1ß, IL-6) and oxidative stress (malondialdehyde) in nasal mucosa, blood, lungs, and brain were analyzed. In addition, a histopathological examination was performed, and NF-kB, MMP2, MMP9, TIMP1 expressions were also evaluated in nasal mucosa. Both doses of LPS increased the production of cytokines in all the investigated tissues, especially in the nasal mucosa and blood (p < 0.01 and p < 0.05), and stimulated their secretion in the lungs, and partially in the brain. Malondialdehyde increased in all the investigated tissues (p < 0.01 and p < 0.05). In parallel, upregulation of NF-kB and MMP2 expressions with downregulation of TIMP1, particularly at high dose of LPS, was observed. SN extract reduced the local inflammatory response, maintained low levels of IL-6, TNF-α, and IL-1ß. In lungs, SN reduced all cytokines levels while in the brain, the protective effect was noticed only on IL-6. Additionally, SN diminished lipid peroxidation and downregulated NF-kB in animals exposed to a low dose of LPS, with increased TIMP1 expression, while in animals treated with a high dose of LPS, SN increased NF-kB, MMP2, and MMP9 levels. In conclusion, SN extract diminished the inflammatory response, reduced generation of reactive oxygen species (ROS) and, influenced MMPs expressions, suggesting the benficial effect of SN extract on tissue remodeling in subacute rhinosinusitis and on systemic inflammatory response.

Biomarkers of pediatric obstructive sleep apnea syndrome and the assessment of quality of life before and after adenotonsillectomy.

The study aims to explore the inflammatory cytokines and oxidative stress in children with obstructive sleep apnea syndrome (OSAS) triggered by adenoids and/or tonsillar hypertrophy and their changes after adenotonsillectomy (AT) and to investigate the associated behavioral disorders in OSAS, before and after AT. Thirty patients with OSAS and 20 healthy children, aged 3 - 13 years were included in the study. According to apnea-hypopnea index (AHI), OSAS children were classified into 3 groups: mild (n = 19), moderate (n = 5), and severe OSAS (n = 6). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, malondialdehyde (MDA) and antioxidant enzymes activities were assessed in serum, preoperative and 6 weeks after AT. TNF-α, IL-6 and malondialdehyde levels were also estimated in adenoid and tonsils tissues. A Pediatric Sleep Questionnaire was completed by the parents before and after AT. As a result of the study, we obtained the following results: TNF-α, IL-6 and malondialdehyde evaluated preoperative increased in serum and tissues in OSAS, especially in severe disease compared to mild and moderate forms. Six weeks after AT, AHI diminished significantly in OSAS, as well as the inflammatory markers and malondialdehyde, in parallel with significant improvement of antioxidant enzymes activities. Daytime sleepiness, hyperactivity and attention deficit in OSAS, even in mild disease were present, with significant improvements of obstructive symptoms after AT. We conclude that OSAS caused by adenoids and/or tonsillar hypertrophy led to changes in the blood parameters, with significant improvement after AT. Postoperatively, a significant improvement in sleep quality and behavior in OSAS patients was also observed.

Quercetin attenuates naso-sinusal inflammation and inflammatory response in lungs and brain on an experimental model of acute rhinosinusitis in rats.

This study aimed to investigate the effect of quercetin without intranasal inflammation and oxidative stress in nasal and sinus mucosa, but also in serum, lungs and brain in a rat model of acute nasal and sinus inflammation induced by administration of lipopolysaccharides (LPS) (from Escherichia coli). Wistar rats were divided into five groups of 10 animals each. The control group received an intranasal saline solution once/day, for seven consecutive days. Rats in groups 2 and 3, received low-dose (5 µg) and high-dose (10 µg) of LPS, once/day, for seven consecutive days. Rats in groups 4 and 5, received low-dose (5 µg) and high-dose (10 µg) of LPS and after 2 h, 80 mg/kg of quercetin, once/day for seven consecutive days was administered. After the treatment period, the histopathological examination of nasal and sinus mucosa was performed and levels of cytokines (tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6)) and oxidative stress in the blood, nasal mucosa, lungs and brain were also analyzed. High dose of LPS increased TNF-α, IL-6 and IL-1ß levels in serum, nasal mucosa, and lungs homogenates while in brain, this effect was only on TNF-α levels. IL-1ß enhanced significantly in serum and mucosa, especially after administration of a high dose of LPS (P < 0.01 and P < 0.05). Histopathological and immunofluorescence analysis revealed acute inflammatory reaction in rats treated with both doses of LPS without significant changes of lipid peroxidation in the studied tissues. Quercetin administration diminished the exudate and degree of inflammation in lamina propria of nasal and sinusal areas, parallel with the decreased secretion of TNF-α (40.2% reduction after the low dose of LPS, and 35.4% reduction after the high dose of LPS) and IL-6 (21.4% reduction after the low dose of LPS and 35.8% reduction after the high dose of LPS). In lungs, quercetin reduced TNF-α (43.3%) and IL-6 levels (24.5%), and in the brain, the protective effect was noticed only on TNF-α (46.5%). The intranasal LPS administration successfully induced acute rhinosinusitis in a rat model and also generated an inflammatory response in the lungs and brain. Intranasal administration of quercetin diminished the nasal inflammation and also exerted protective effect on lungs and partially on brain inflammatory reaction.

PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration.

PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

Antiangiogenic gene therapy for cancer via systemic administration of adenoviral vectors expressing secretable endostatin.

A growing number of antiangiogenesis strategies have been investigated for the treatment of cancer and other angiogenesis-dependent diseases. One of the most promising strategies is to systemically administer one or more antiangiogenic proteins frequently enough to achieve a sufficient long-term steady state level of the protein(s) to achieve the maximum beneficial effect. However, the utility of this strategy is limited because of many technical difficulties, including obtaining both the quantity and quality of the protein(s) necessary for optimal therapeutic benefit. To overcome these difficulties, we hypothesized that a single administration of a replication-defective adenoviral vector expressing a secretable antiangiogenic protein could achieve an optimal long-term systemic concentration. We constructed a recombinant adenoviral vector, Av3mEndo, which encodes a secretable form of murine endostatin. We demonstrated secretion of endostatin from several cell lines transduced with Av3mEndo. Partially purified endostatin secreted from Av3mEndo-transduced mammalian cells was shown to potently inhibit endothelial cell migration in vitro. A single intravenous administration of Av3mEndo in mice was shown to result in (1) prolonged and elevated levels of circulating endostatin, (2) partial inhibition of VEGF-induced angiogenesis in a VEGF implant angiogenesis model, and (3) prolonged survival and in 25% of mice the complete prevention of tumor growth in a prophylactic human colon/liver metastasis xenograft murine model. These results support our contention that adenoviral vector-mediated expression of an antiangiogenic protein(s) represents an attractive therapeutic approach to cancer and other angiogenesis-dependent diseases.

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

Inhibitors of the renin-angiotensin system lower blood pressure of spontaneously hypertensive rats, although plasma renin is not elevated. To test the hypothesis that the actions of angiotensin II within the kidney may contribute to the high blood pressure in spontaneously hypertensive rats, we infused valsartan, a subtype 1 angiotensin II receptor antagonist, via the suprarenal artery into the right kidney of conscious, freely moving, unilaterally nephrectomized (left) spontaneously hypertensive rats (12 to 14 weeks old). Valsartan (0.3 mg/kg per day for 48 hours) lowered blood pressure (change in blood pressure, -7 +/- 3, -19 +/- 4, and -26 +/- 4 mm Hg, n = 11, at 12, 24, and 48 hours) after intrarenal administration but had no significant effect on blood pressure after intravenous administration (change in blood pressure, 1 +/- 5, -3 +/- 4, and 10 +/- 5 mm Hg, n = 7, at 12, 24, and 48 hours). Infusion of vehicle (0.9% saline) intrarenally had no significant effect on blood pressure (change in blood pressure, 2 +/- 5, -1 +/- 6, and 0 +/- 7 mm Hg, n = 11, at 12, 24, and 48 hours). The maximum fall in blood pressure reached after intrarenal administration of this dose of valsartan was similar to the maximum fall induced after intravenous administration of higher doses (change in blood pressure, -14 +/- 5, -27 +/- 4, and -32 +/- 5 mm Hg, n = 7, at 12, 24, and 48 hours after 3 mg/kg per day i.v.). Thus, endogenous angiotensin II acting within the kidney appears to play an important role in the maintenance of high blood pressure in spontaneously hypertensive rats.

Continuous versus intermittent angiotensin converting enzyme inhibition in renal hypertensive rats.

Converting enzyme inhibitors impair renal function of the kidney beyond a stenosis of the renal artery in humans and induce histological lesions in the clipped kidney of renal hypertensive rats. In two-kidney, one clip hypertensive rats, we compared the time course and magnitude of the biochemical effects of angiotensin converting enzyme inhibition on the plasma renin-angiotensin system, cardiac hypertrophy, renal lesions, and 24-hour blood pressure decrease induced by either intermittent angiotensin converting enzyme inhibition administration (benazepril PO, 10 mg/kg once a day, n = 93) or continuous administration (benazeprilat, 3 mg/kg per day via osmotic pumps, n = 92). Control rats (n = 91) received the drug vehicle intermittently or continuously. Mortality was significantly reduced by both intermittent (n = 3/93) and continuous (n = 3/92) inhibition compared with controls (n = 18/91) (P < .001). Changes in the plasma renin-angiotensin system and blood pressure were parallel. A continuous suppression of the activity of the plasma renin-angiotensin system was associated with a 24-hour decrease in blood pressure with continuous inhibition, whereas intermittent inhibition induced a similar fall in blood pressure only for the first hours after gavage.(ABSTRACT TRUNCATED AT 250 WORDS)

Assays to measure nanomolar levels of the renin inhibitor CGP 38 560 in plasma.

A radioinhibitor binding assay and an enzyme inhibition assay have been developed to measure plasma levels of CGP 38 560, a potent human renin inhibitor. The detection limit of the assays was between 0.5 and 1 pmol/ml. There was a good correlation (r = 0.989) between the two assays for the measurement of human plasma spiked with CGP 38 560 in concentrations from 1.9 nM to 12 microM. Intra-assay variability was 6.1-17.3% and 4.4-27.2% for the radioinhibitor binding assay and the enzyme inhibition assay, respectively. Interassay variability was 6.0-28.2% and 3.8-28.4% for the radioinhibitor binding assay and the enzyme inhibition assay, respectively. Blood samples were collected during a pharmacological study performed in normotensive human volunteers on an unrestricted diet who were infused during a 30-minute period with CGP 38 560 A (50 micrograms/kg). Similar values for the concentrations of renin inhibitor in plasma were obtained with the radioinhibitor binding assay and the enzyme inhibitor assay, and there was a significant correlation between values obtained with the two different methodologies (r = 0.94). The plasma levels of renin inhibitor reached a maximum at the end of infusion and then decreased rapidly, indicating a short plasma half-life. The changes in biochemical parameters, plasma renin activity, and plasma concentration of active renin could be related to the concentrations of CGP 38 560 measured in the plasma.

Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences.

The present study examines the effects of prolonged angiotensin II antagonism in spontaneously hypertensive rats by using an angiotensin II receptor antagonist (DuP 753) that is devoid of agonistic properties and selective for the subtype 1 of the angiotensin II (AT1) receptor. The antihypertensive effects of DuP 753 and its effects on circulating parameters of the renin-angiotensin system were compared with those of a converting enzyme inhibitor (benazeprilat). To minimize any influence of differences in the pharmacokinetic properties of the two blockers, administration was by continuous intravenous infusion. The experiments were performed in conscious, freely moving rats with continuous 24-hour monitoring of blood pressure. DuP 753 (10 or 30 mg/kg/day) lowered mean arterial pressure to the same extent as benazeprilat (3 or 10 mg/kg/day) during a 48-hour period. The antihypertensive effect was sustained when the treatment was extended to 7 days (DuP 753, 10 mg/kg/day; benazeprilat, 3 mg/kg/day). Neither of the compounds affected the baseline or diurnal rhythm of heart rate. Plasma concentrations of renin and angiotensin II were increased sevenfold and 10-fold, respectively, in the rats treated with DuP 753. In rats treated with benazeprilat, plasma renin concentration increased threefold, whereas angiotensin II was unchanged. Heart weights were significantly reduced to a similar extent by DuP 753 and benazeprilat. Both compounds also induced a smaller but significant decrease in blood pressure in Wistar-Kyoto rats. Our results indicate that the antihypertensive effects of converting enzyme inhibitors in spontaneously hypertensive rats are mainly due to the blockade of the renin-angiotensin system. In this rat model, angiotensin II appears to play an important role in the maintenance of hypertension that is mediated via the AT1 receptor.

'An artefact gone awry': identification of the first case of nemaline myopathy by Dr R.D.K. Reye.

In 1963, Shy et al. (Brain 1963;86:793-810) and Conen et al. (Can Med Assoc J 1963;89:983-986) published the first description of a novel myopathy characterized by the aggregation of rods (nemaline bodies) in the muscle fibres. This disorder was subsequently known as nemaline myopathy. Dr Douglas Reye, an Australian pathologist, described a patient with 'rod myopathy' five years earlier, in 1958. Here we present Dr Reye's original description of nemaline myopathy, and details of the 'second opinion' which concluded that the rod were a 'processing artifact', so that the case was never published. Detailed histological and immunocytochemical studies of this original case demonstrate the typical features of nemaline myopathy, and a mutation in skeletal muscle alpha-actin has recently been identified in this patient. Not only was Dr Reye the first to use the term 'rod' in relation to muscle disease, he also made observations that are relevant to the pathogenesis of nemaline myopathy.

Concurrent and predictive validity of the Yale Children's Inventory: an instrument to assess children with attentional deficits and learning disabilities.

The Yale Children's Inventory rating scales for completion by parents were developed to improve the ability of clinicians and researchers to evaluate the school-related problems of children. The inventory consists of 11 narrow-band and two broad-band scales, the Behavioral and the Cognitive. The concurrent and predictive validity of the Yale Children's Inventory scales are reported in a school-based sample of 103 boys. External criterion variables were obtained from parents, teachers, and standardized tests administered to the children. We found that the Attention scale overlaps both broad-band domains, indicating the importance and the intrinsic relationship of attention to both behavioral and cognitive functions, which supports the Diagnostic and Statistical Manual of Mental Disorders, ed 3 nosology for disorders of attention and activity regulation. It also increases the number of children whose assessment may be enhanced by the availability of systematic parent report forms.

Measurement of intraocular pressure by telemetry in conscious, unrestrained rabbits.

PURPOSE: The aim of this study was to develop a system for the continuous recording of the intraocular pressure (IOP) in rabbits maintained in their normal environment. A telemetric system originally designed for the measurement of cardiovascular parameters in unrestrained, conscious laboratory animals was adapted for this purpose. METHODS: Experiments were performed in adult albino female rabbits. The transmitter was placed under the skin in the neck region. Its catheter was tunneled subcutaneously to the superior conjunctival sac and inserted into the midvitreous. Correlation with the IOP in the anterior chamber was performed by pneumatonography measurement and by manometric pressure perfusion in the implanted rabbits. Transitory increase in IOP was induced by a rapid intravenous injection of 20 ml/kg of 5% glucose. Timolol maleate (0.5%) or saline was administered (50 microliters) in the instrumented eye before the intravenous glucose injection. RESULTS: The intraocular catheter remained patent and was well tolerated for at least 2 months. A constant circadian rhythm of IOP was recorded as previously reported. Intraocular pressure measurements were highly correlated to pneumatonographic and to manometric measurements, indicating the accuracy and reliability of the recording system. A significant inhibition of the IOP increases following the intravenous injection of glucose was induced by 0.5% timolol treatment when compared to saline instillation. CONCLUSIONS: The continuous recording of IOP by our telemetric method represents a breakthrough for studying the effect of various pharmacologic agents in conscious, unrestrained rabbits under physiological conditions that have not been possible with previously described methods.

Frequent expression of the tumor necrosis factor receptor-associated factor 1 in latent membrane protein 1-positive posttransplant lymphoproliferative disease and HIV-associated lymphomas.

The tumor necrosis factor receptor-associated factor 1 (TRAF1) participates in the signal transduction of various members of the tumor necrosis factor receptor (TNFR) family, including TNFR2, CD40, CD30, and the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). In vitro, TRAF1 is induced by LMP1, and previous studies have suggested that expression of TRAF1 is higher in EBV-associated tumors than in their EBV-negative counterparts. To determine whether this was the case in posttransplant lymphoproliferative disease (PTLD) and related disorders, we used immunohistochemistry to analyze expression of TRAF1 in a total of 42 such lesions arising in a variety of immunosuppressive states. The specimens consisted of 22 PTLD lesions, 18 acquired immunodeficiency syndrome-associated lymphomas, including 6 primary central nervous system lymphomas, and 2 cases of Hodgkin disease. The presence of latent EBV infection was determined by EBER in situ hybridization, and expression of EBV-LMP1 was detected by immunohistochemistry. Latent EBV infection, as determined by a positive EBER signal, was detected in 36 of 42 tumors. Of the EBER-positive specimens, 30 of 36 also expressed LMP1. Twenty-four of 30 LMP1-positive tumors, including both Hodgkin disease specimens, expressed TRAF1, compared with only 3 of 12 LMP1-negative tumors. This difference was statistically significant (P <.005). These results show frequent expression of TRAF1 at the protein level in LMP1-positive PTLD and related disorders and suggest an important role for LMP1-mediated TRAF1 signaling in the pathogenesis of EBV-positive tumors arising in immunosuppressive states.

Characterization of a new potent, in vivo neutralizing monoclonal antibody to human vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) is an important mediator of tumor-induced angiogenesis and represents a potential target for anticancer therapy. Therefore, we prepared a panel of monoclonal antibodies (mAb) against both the VEGF121 and VEGF165 isoforms. Three of them completely neutralized the mitogenic stimulation by VEGF of human umbilical vein endothelial cells at mAb concentrations below 0.1 microg/ml. The most potent one, with a dissociation constant (Kd) of 8 pM, inhibited, in a dose-dependent manner, VEGF-induced angiogenesis in a growth factor implant model in mice. A complete inhibition of the angiogenic response was obtained by daily intraperitoneal injections of 10 microg mAb/mouse. Angiogenesis induced by basic fibroblast growth factor was not inhibited by the mAb. Epitope mapping of the mAb, performed by competitive enzyme-linked immunosorbent assay and Western blot analysis, showed that it did not bind to the reduced and denatured monomer of VEGF. Substitutions of three residues (Q87R, G88K, Q89K), located on the major surface loop beta5 to beta6 of VEGF, resulted in the complete loss of binding (more than 400-fold reduction). The results suggest that the mAb binds primarily to a conformation-dependent epitope on the VEGF dimeric form, encompassing one of the loop regions involved in KDR receptor binding. The mAb with its strong neutralizing properties represents a useful agent for effective blocking of VEGF-mediated tumor neovascularization.

Are 'neutral cells' in the rostral ventro-medial medulla subtypes of on- and off-cells?

The classification of cells in the rostral ventromedial medulla (RVM) is based on the response pattern to noxious tail heat: on-cell activity increased, off-cell activity decreased, and activity of neutral cells is unaffected by noxious heat tail stimulation. It is generally assumed that on-, off- and neutral cells respond equally to noxious stimulation applied anywhere on the body surface, but so far this assumption has not been systematically examined. In the present study the effects of thermal and mechanical stimuli applied to the tail, the extremities and the orofacial region on the extracellularly recorded activity of 14 neutral cells were investigated in lightly anesthetized rats. Although the neutral cells did not respond to noxious tail heat, all of them responded to most of the other stimuli in an on- or off-manner. Especially cell responses to pinch stimuli applied to the skin of the ear, the forehead and the nose differed from the neutral behavior. The fact that the neutral cells in the present study responded in an off- or on-manner by applying noxious stimuli different from noxious tail heat suggests that these cells are possibly subtypes of on- and off-cells in the RVM.

Continuous intraocular pressure measurement by telemetry in alpha-chymotrypsin-induced glaucoma model in the rabbit: effects of timolol, dorzolamide, and epinephrine.

The aim of this study was to set-up and validate the use of a radio-telemetry system in order to record IOP in chronic ocular hypertensive animals. The transmitter of a miniaturized radio-telemetry system was implanted in rabbits, and its catheter was tunnelled subcutaneously to the superior conjunctival sac and inserted into the midvitreous. Implantation was performed in chronic ocular hypertensive rabbits induced by an injection of alpha-chymotrypsin into the posterior chamber of the eye. The effects of 0.5% timolol maleate, 2% dorzolamide hydrochloride and 1% epinephrine were assessed and compared after topical administration in this model. Implanted radio-telemetric system into the vitreous allowed IOP measurement for more than 6 months. In this study, circadian IOP kinetic profiles were monitored in all animals over 24 h for 3 weeks. Timolol maleate was found significantly potent in reducing IOP, while changes depended on the nyctemeral period. Dorzolamide hydrochloride induced a very large IOP reduction and was found to be also well effective at night. We evidenced a biphasic time-dependent effect after topical epinephrine, with a long lasting IOP increase occurring after the administration. This change was found to be related to side effects resulting from a poor ocular tolerance of this drug in the rabbit, leading to either a complete eye closure or a higher blinking rate. By using our method, we confirmed the pressure pulses and undershoots occurring during blinking. Radio-telemetry in chronic glaucoma rabbits appears as a refined method to assess anti-glaucoma drug activity, 24 hours a day, for long-term periods in unrestrained animals, while also providing information on the ocular side effects of eye drops.

Effects of excitotoxins on free radical indices in mouse brain.

Excitotoxins and free radicals individually have been implicated in several neurological disorders including those associated with aging. We observed that systemically administered domoic acid enhanced mouse brain superoxide dismutase activity with either an associated decrease or no change in mouse brain lipid peroxidation. These findings reflect a state of adequately compensated oxidative stress induced by excitotoxins. In homogenates containing disrupted cells from various regions of mouse brain, however, kainic acid produced a 2 to 5-fold increase in lipid peroxidation. This suggests that excitotoxins cause lipid peroxidation possibly by acting at intracellular loci which become more accessible following disruption of cells in vitro and by extrapolation, possibly in vivo due to cellular permeability changes during the edematous stage of ischemic and other related neuropathological conditions.

Comparative pharmacokinetics of free muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) and liposomal MTP-PE.

The comparative pharmacokinetics of free MTP-PE (muramyl tripeptide phosphatidyl ethanolamine) and MTP-PE entrapped in negatively charged multilamellar liposomes (liposomal MPT-PE) was evaluated in rats at a bolus intravenous (i.v.) dose of 0.2 mg/kg and in dogs at a bolus i.v. dose of 0.1 mg/kg. Additional studies were performed with the free form in rats (1.4 mg/kg, bolus i.v.) and dogs (1 mg/kg, bolus i.v.) and with the liposomal form in dogs (0.5 mg/kg, bolus i.v.). Plasma samples were obtained at various times up to 48 h postinjection and assayed for the drug by a chemiluminescence immunoassay. The pharmacokinetic data regarding liposomal MTP-PE describe the distribution of free drug released from liposomes and total drug concentrations. The present studies demonstrate that the distribution characteristics of MTP-PE changed dramatically depending on the dosage form. The elimination kinetics of free MTP-PE from blood is substantially slower than that of the liposomal drug. For liposomal MTP-PE, free drug levels in plasma are very low compared with free MTP-PE. In rats at a dose of 0.2 mg/kg, 96% of MTP-PE contained in liposomes is removed from the plasma compartment 10 min after injection, and in dogs at a dose of 0.1 mg/kg, 100% of MTP-PE contained in liposomes is removed in the same time period. This rapid phase of liposome clearance is followed by a slower rate of clearance for the remainder of the liposomes in rats at a dose of 0.2 mg/kg and in dogs at a dose of 0.5 mg/kg.

Cannabis in the treatment of alcoholism.

Cannabis, alone or in conjunction with disulfiram, was not particularly effective in inducing alcoholics to enter or remain in treatment.

Yale Children's Inventory (YCI): an instrument to assess children with attentional deficits and learning disabilities. I. Scale development and psychometric properties.

The Yale Children's Inventory (YCI), a parent-based rating scale, and the scales derived from it have been developed to identify and measure multiple dimensions of learning disabilities with particular emphasis on attentional deficits. Scale construction was based on factor-analytic procedures. Measures of internal consistency, test-retest reliability, and coefficients of congruence support the reliability and stability of the 11 scales. A discriminant function classified normal and learning-disabled children with a relatively high rate of accuracy. The relationship and content of the three relevant YCI scales were compared to the DSM-III diagnostic categories for ADD. As operationalized, DSM-III criteria for hyperactivity formed a cohesive factor, while criteria for attention and impulsivity were not distinguishable from each other since they loaded together on a single factor. In contrast, the equivalent YCI scales for attention, impulsivity, and hyperactivity were found to be distinct.