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Cannabis use is common in young adulthood, yet little is known about the prevalence and patterns of multi-modal (i.e., use of more than one mode) cannabis use. Objective: We aimed to (1) determine the past 30-day prevalence of five modes (smoke, vape, edible, dab, other) of cannabis use, (2) describe the prevalence of multi-modal cannabis use (single vs. dual vs. poly-modal), and (3) identify socio-demographic correlates of multi-modal use among young adults. Method: Participants were 764 22–30-year-olds who currently used cannabis from Wave 9 (Spring 2019) of the Marketing and Promotions Across Colleges in Texas Project. Participants were 25.11 years old on average (SD = 1.81), 63.6% female, 38.7% identified as non-Hispanic white, 30.6% as Hispanic/Latino, 13.0% as Asian and 9.4% as Black, and 8.2% identified with two or more races or another race/ethnicity. Bivariate analyses and a multinomial regression were used to examine study questions. Results: Smoking was the most common mode of cannabis use followed by vaping and then edibles. Nearly 43% of participants reported single-modal cannabis use, 33% reported dual-modal use, and 24% reported poly-modal use. Males and those identifying as non-heterosexual were at a greater risk than their counterparts for using multiple modes of cannabis. Participants identifying as Black were at a reduced risk for poly-modal compared to single-modal use. Conclusion: Multi-modal use is common among young adults who currently use cannabis, indicating a need for universal efforts aimed at all young adults. Tailored interventions aimed toward those at elevated risk for multi-modal use also are needed.

Previous research has shown that job loss, financial strain, and/or loss of housing (JFH) in midlife elevate suicide risk. In this study based on the 2017–2019 National Violent Death Reporting System, we examined other suicide precipitants and contributors of decedents whose suicide was in part precipitated by JFH and the circumstances under which they died. First, we examined all adult decedents (N = 94,454; 74,042 males [78.4%] and 20,412 females [21.6%]) and then focused on decedents age 45–64 (N = 34,208; 25,640 males [75%] and 8568 females [25.0%]). The 45–64 age group had the highest rate of JFH (22.0% for males and 15.1% for females) as a suicide precipitant. The results of generalized linear models for all adult suicide decedents of both sexes showed that the 45–64 age group (IRR = 2.02, 95% CI = 1.89–2.16), compared to 65+ age group, and relationship problems, mental disorders, and alcohol problems were associated with significantly higher risk of JFH-precipitated suicide. In male decedents age 45–64, JFH was positively associated with depressed mood (IRR = 1.95, 95% CI = 1.85–2.06), alcohol problems (IRR = 1.14, 95% CI = 1.07–1.21), and number of crises (IRR = 1.48, 95% CI = 1.43–1.53). In female decedents age 45–64, JFH was positively associated with relationship problems (IRR = 1.19, 95% CI = 1.05–1.35), legal problems (IRR = 1.27, 95% CI = 1.06–1.54), depressed mood (IRR = 1.78, 95% CI = 1.59–1.99), and number of crises (IRR = 1.58, 95% CI = 1.48–1.68). In both sexes, the risk of JFH was also positively associated with a college education. In female decedents, JFH risk was higher among divorced or never-married individuals. Coroner/medical examiner and law enforcement agency reports show that some experienced depression and started misusing alcohol and/or other substances following a job loss, but others had these problems throughout life, which caused/contributed to JFH. These findings show the significance of suicide prevention approaches at both systemic (generous unemployment insurance, housing subsidies) and individual (treatment of depression and alcohol/substance misuse problems and social support/connection) levels.

Purpose: Acanthamoeba chorioretinitis is a rare manifestation of the parasitic infection, and reported cases often result in enucleation. Surgical removal of Acanthamoeba chorioretinitis has not been previously described. We report a surgical case of Acanthamoeba chorioretinitis spread from keratitis that ultimately resulted in a disease-free outcome. Observations: A healthy 80-year-old male with a history of keratoconus requiring a penetrating keratoplasty in the fellow eye presented with a severe corneal ulcer clinically consistent with Acanthamoeba keratitis. He ultimately required a penetrating keratoplasty and improved clinically until he developed vitritis on post-operative month 1 and was diagnosed with endophthalmitis. B-scan ultrasound demonstrated vitreous opacities and a large retinal mass that reduced in size following serial intravitreal injections of antibiotics, oral antibiotics, and a limited pars plana vitrectomy. He underwent a repeat pars plana vitrectomy 6 weeks later and a retinal mass in the mid-periphery with an associated tractional retinal detachment was noted. A localized retinectomy was performed around the lesion which was excised entirely, and silicone oil was instilled. Pathology of the lesion showed acute and chronic granulomatous necrotizing inflammation with the presence of several definitive amoebic organisms and numerous cells suspicious for amoebae. The patient was maintained on oral antibiotics by the Infectious Disease Service and was disease-free 1-year post-infection. Conclusions and importance: Acanthamoeba chorioretinitis is a rare, devastating disease and often leads to enucleation. We present a surgical case showing control of the infection utilizing a surgical retinectomy. Aggressive local therapy and a multidisciplinary approach with the Infectious Disease Service may lead to a successful outcome.

Purpose: To report a case of elevated intraocular pressure with retinal detachment. Observations: Liquid chromatography and tandem mass spectrometry was performed on the patient aqueous biopsy. Protein levels were analyzed with 1-way analysis of variance (ANOVA) and unbiased clustering. High levels of rod outer segment proteins were not detected, suggesting that this was not a case of Schwartz-Matsuo syndrome. Instead, elevated levels of Hepcidin (HEPC) and Cystatin C (CYTC; candidate biomarkers for primary open angle glaucoma) were detected, suggesting a different, unknown etiology. Conclusions and importance: Molecular diagnoses can differentiate between clinical diagnoses and point to common biomarkers or disease mechanisms.

Wetlands are often dominant features in low relief, depressional landscapes and provide an array of hydrologically driven ecosystem services. However, contemporary models do not adequately represent the role of spatially distributed wetlands in watershed-scale water storage and flows. Such tools are critical to better understand wetland hydrological, biogeochemical, and biological functions and predict management and policy outcomes at varying spatial scales. To develop a new approach for simulating depressional landscapes, we modified the Soil and Water Assessment Tool (SWAT) model to incorporate improved representations of depressional wetland structure and hydrological processes. Specifically, we refined the model to incorporate: (1) water storage capacity and surface flowpaths of individual wetlands and (2) local wetland surface and subsurface exchange. We utilized this model, termed SWAT-DSF (DSF for Depressional Storage and Flows), to simulate the ∼289 km2 Greensboro watershed within the Delmarva Peninsula of the US Coastal Plain. Model calibration and verification used both daily streamflow observations and remotely sensed surface water extent data (ca. 2-week temporal resolution), allowing us to assess model performance with respect to both streamflow and watershed inundation patterns. Our findings demonstrate that SWAT-DSF can successfully replicate distributed wetland processes and resultant watershed-scale hydrology. SWAT-DSF provides improved temporal and spatial characterization of watershed-scale water storage and flows in depressional landscapes, providing a new tool to quantify wetland functions at broad spatial scales. Keywords: Depressional wetlands, Delmarva Peninsula, Inundation mapping, Surface water extent, Agricultural ditches, Geographically isolated wetlands, Non-floodplain wetlands

Background: Bangladesh has implemented school-based mass drug administration (MDA) bi-annually since 2008 aimed to control soil-transmitted helminth (STH) infection. Despite several rounds of MDA, the government is still facing challenges to achieve the target coverage and utilization of the intervention. This study was done to explore and explain the barriers and gaps that hinder the utilization and coverage of MDA for STH. Methods: This research was a mixed method study, was conducted in two selected districts of Bangladesh. A total of 160 questionnaire surveys, 12 in-depth interviews, 8 focus group discussion, and 2 key-informant interviews were done among 238 study participants which included school-age children with relevant parents, school teachers, health workers, community leaders and MDA program managers. Descriptive statistical analysis was used to analyze the quantitative data while thematic analysis was applied for the qualitative data. Results: It was revealed that the participants have positive attitudes towards MDA but they pointed out the limitations in reaching all target population especially non-school going children. The level of knowledge regarding STH and MDA were found different among the study population. The evaluated coverage of MDA was also found lower than that reported. Some major barriers associated with MDA coverage found in this study were drug distribution policy, accessibility to schools, poor record keeping, follow-up, and information dissemination. Inadequate information about population dynamics and rumors about side effects of MDA drugs adversely affected the compliance of the intervention. Insufficient training of drug distributors and poor motivation among stakeholders also added to the barriers. Conclusion: There is the need to re-strategize drug distributing methods and create effective policies to include all targeted population. Use of local channels for community sensitization, adding local distribution points, regular monitoring and follow-up and promotion of health education can possibly enhance both treatment coverage and program infrastructure. Keywords: Barriers, Utilization, Coverage, Mass drug administration, Soil-transmitted helminth

This article describes a dataset of facial electromyography and subjective liking data from 70 New Zealand participants used in the study “An unfamiliar presence reduces facial disgust responses to food stimuli” by Nath, Cannon and Philipp [1]. Participants’ facial muscle activity from zygomaticus major, corrugator supercilii, and levator labii superioris was recorded as they viewed and rated food images, and tasted samples of chocolate. Half of the participants were seated alone, and the other half was seated in the presence of the researcher. The data allows for investigations into the effect of social context on hedonic ratings and facial responses to food, and an exploration into the individual factors contributing to differences in facial reactivity. The data includes raw EMG files generated by Acqknowledge 4.2, raw subjective liking files generated by PsychoPy, a table of participant information, the food images stimuli, the PsychoPy code used for stimuli presentation, and the R scripts used to filter, aggregate and analyse the data. Keywords: Facial electromyography, Food preference, Food liking, Social context, Implicit emotion

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) are prone to anoikis after single cell dissociation. The small molecule, Y-27632 is known to increase survival of hESCs and hiPSCs by inhibiting the Rho-associated protein kinase (ROCK). However, the underlying mechanisms are still unclear. Here, we thoroughly screened small molecules to investigate the adhesion and survival of hESCs in adherent culture. Y-27632 provided higher adhesion and survival of hESCs by increased cell migration and preventing cell blebbing in single dissociated cells. The combination of Matrigel with poly-d-lysine increased the attachment and survival of dissociated cells via actin filament and microtubule spreading in Y-27632-treated cells. Although Y-27632 prevented apoptosis by suppressing actin filament contraction, microtubule bundling, and blebbing, prolonged Y-27632 treatment presented a different morphology in the attached growing hESC colony. It induced apoptosis of cells by promoting cytoplasmic spread, E-cadherin structural change, and increased detachment. It also induced actin cytoskeleton disruption, combined with microtubule and intermediate filament elongation. For optimal hPSC culture, our research suggests that Y-27632 should be removed shortly after passaging. Keywords: Cytoskeletal changes, ROCK inhibitor, Apoptosis, Human embryonic stem cells, Adhesion, Extracellular matrices

T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC 50 0.171 µM) and 11h (IC 50 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay. Furthermore, a molecular dynamic simulation of 11h was carried out to assess the stability to form a complex with the L858R/T790M EGFR Kinase domain, which demonstrated that complex was stable for the 100 ns and form strong crucial covalent binding contacts with the thiol group of Cys797 residue. Finally, satisfactory in silico pharmacokinetics properties of 2i, 11h and 11i compounds were predicted. The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Insulin/insulin receptor signaling is involved in cognitive functions. Clinical studies have shown that intranasal insulin administration improves memory functions. However, the molecular mechanisms associated with improvement in memory functions are largely unexplored. Therefore, we investigated the protective effect of intranasal insulin in intracerebroventricular (ICV) streptozotocin (STZ) induced memory impairment in rats., Main Methods: Rats were injected with STZ (3mg/kg, ICV) bilaterally twice, on days 1 and 3 and intranasal insulin (2IU/rat/day) was given for 14days. Memory was assessed by Morris water maze test. Cerebral blood flow (CBF) was measured by laser-Doppler flowmetry. The biochemical and molecular studies were done in cortex and hippocampus of rat brain., Key Findings: STZ (ICV) administration caused memory impairment along with the reduction of CBF, ATP level, and Nrf-2 expression. Treatment with intranasal insulin significantly improved memory functions as well as restored CBF, ATP content and Nrf-2 expression in STZ injected rats. STZ administration stimulated oxidative-nitrosative stress as evidenced by a significant increase in ROS, malondialdehyde, NO level and inducible nitric oxide synthase expression and the decrease in glutathione level; which was normalized by intranasal insulin delivery. STZ-induced cholinergic dysfunction (AChE activity and α7-nAChR expression), and mitochondrial hypofunction was largely prevented by treatment with intranasal insulin. Intranasal insulin delivery successfully restored BDNF level and pCREB expression in STZ injected rats., Significance: The study shows the beneficial effects of intranasal insulin against STZ-induced memory impairment, which attributed to improved CBF, cholinergic function, brain energy metabolism, BDNF, Nrf-2 expression and antioxidative action., (Copyright © 2016. Published by Elsevier Inc.)

This paper describes the use of an agile text mining platform (Linguamatics' Interactive Information Extraction Platform, I2E) to extract document-level cardiac risk factors in patient records as defined in the i2b2/UTHealth 2014 challenge. The approach uses a data-driven rule-based methodology with the addition of a simple supervised classifier. We demonstrate that agile text mining allows for rapid optimization of extraction strategies, while post-processing can leverage annotation guidelines, corpus statistics and logic inferred from the gold standard data. We also show how data imbalance in a training set affects performance. Evaluation of this approach on the test data gave an F-Score of 91.7%, one percent behind the top performing system., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hypertension is a risk factor for cognitive impairment. Furthermore, neuroinflammation and neurodegeneration are intricately associated with memory impairment. Therefore, the present study aimed to explore the involvement of hypertension and angiotensin system in neurodegeneration and memory dysfunction in the presence of neuroinflammatory stimulus. Memory impairment was induced by chronic neuroinflammation that was developed by repeated intracerebroventricular (ICV) injections of lipopolysaccharide (LPS) on the 1st, 4th, 7th, and 10th day. Memory functions were evaluated by the Morris water maze (MWM) test on days 13-15, followed by biochemical and molecular studies in the cortex and hippocampus regions of rat brain. LPS at the dose of 25μg ICV caused memory impairment in spontaneously hypertensive rats (SHRs) but not in normotensive Wistar rats (NWRs). Memory deficit was obtained with 50μg of LPS (ICV) in NWRs. Control SHRs already exhibited increased angiotensin converting enzyme (ACE) activity and expression, neuroinflammation (increased TNF-α, GFAP, COX-2 and NF-kB), oxidative stress (increased iNOS, ROS and nitrite levels), TLR-4 expression and TUNEL positive cells as compared to control NWRs. Further, LPS (25μg ICV) exaggerated inflammatory response, oxidative stress and apoptosis in SHRs but similar effects were witnessed at 50μg of LPS (ICV) in NWRs. Oral administration of perindopril (ACE inhibitor), at non-antihypertensive dose (0.1mg/kg), for 15days attenuated LPS induced deleterious changes in both NWRs and SHRs. Our data suggest that susceptibility of the brain for neurodegeneration and memory impairment induced by neuroinflammation is enhanced in hypertension, and that can be protected by ACE inhibition., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The present study was conducted to investigate the effect of the neurotoxins 6-hydroxydopamine and lipopolysaccharide on astrocytes. Rat astrocyte C6 cells were treated with different concentration of 6-hydroxydopamine (6-OHDA)/lipopolysaccharides (LPS) for 24 h. Both neurotoxins significantly decreased the viability of astrocytes, augmented the expression of inducible nitric oxide synthase (iNOS) and the astrocyte marker--glial fibrillar acidic protein. A significantly decreased mitochondrial dehydrogenase activity, mitochondrial membrane potential, augmented reactive oxygen species (ROS) level, caspase-3 mRNA level, chromatin condensation and DNA damage was observed in 6-OHDA/LPS treated astroglial cells. 6-OHDA/LPS treatment also caused the significantly increased expression of iNOS and nitrite level. Findings showed that 6-OHDA/LPS treatment caused mitochondrial dysfunction mediated death of astrocytes, which significantly involve the nitric oxide. Since we have observed significantly increased level of iNOS along with mitochondrial impairment and apoptotic cell death in astrocytes, therefore to validate the role of iNOS, the cells were co-treated with iNOS inhibitor aminoguanidine (AG, 100 μM). Co-treatment of AG significantly attenuated the 6-OHDA/LPS induced cell death, mitochondrial activity, augmented ROS level, chromatin condensation and DNA damage. GFAP and caspase-3 expression were also inhibited with co-treatment of AG, although the extent of inhibition was different in both experimental sets. In conclusion, the findings showed that iNOS mediated increased level of nitric oxide acts as a key regulatory molecule in 6-OHDA/LPS induced mitochondrial dysfunction, DNA damage and apoptotic death of astrocytes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-α indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIα and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-α, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Oxidative stress plays an important role in the pathophysiology of Parkinson's disease (PD) but its mechanism is still not properly explored. Cyclooxygenase-2 (COX-2) inhibition has also been known a major neuroprotective strategy in the various 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) induced models of Parkinson's disease (PD) but its role in astrocytes is still not properly understood. The present study demonstrated that, guggulipid and nimesulide (preferentially selective COX-2 inhibitor) treatment of rat astrocytoma cells, C6 for 24 h significantly decreased MPTP (400 μM) induced nitrative and oxidative stress and intracellular calcium ion (Ca(2+)) level. Guggulipid and nimesulide also deactivated MPTP-induced P-p38 MAPK (Phosphorylated p38 mitogen-activated protein kinase) and down regulated expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and CHOP (C/EBP, homologous protein 10). At transcriptional level of inflammatory cytokine genes, guggulipid and nimesulide down regulated MPTP-induced tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mRNA expressions with up regulations in interleukin-6 (IL-6) and interleukin-1α (IL-1α) mRNA expressions. In addition to this, guggulipid and nimesulide inhibited translocation of nuclear factor kappa-B (NF-κB) from cytosol to nucleus. In conclusion, our findings elucidated the potential antioxidant and anti-neuroinflammatory effect of guggulipid and nimesulide in rat astrocytoma cells C6, which may suggest the use of these drugs in the management of neuroinflammation associated pathophysiology of PD., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aims: The aim of the present study is to investigate the status of proinflammatory cytokine in the brain of intracerebroventricular (i.c.v.) okadaic acid (OKA) induced memory impaired rat., Main Methods: OKA (200 ng) intracerebroventricular (i.c.v.) was administered in rats. Memory was assessed by Morris water maze test. Biochemical marker of neuroinflammation (TNF-α, IL-β), total nitrite, mRNA (RT PCR) and protein expression (WB) of iNOS and nNOS were estimated in rat brain areas., Key Findings: OKA caused memory-impairment in rats with increased expression of proinflammatory cytokine TNF-α and IL-1β and total nitrite in brain regions hippocampus and cortex. The expression of mRNA and protein of iNOS was increased while; the expressions were decreased in case of nNOS. Pretreatment with antidementic drugs donepezil (5 mg/kg, p.o.) and memantine (10 mg/kg, p.o) for 13 days protected i.c.v. OKA induced memory impairment and changes in level of TNF-α, IL-β, total nitrite and expressions of iNOS and nNOS in OKA treated rat., Significance: This study suggests that neuroinflammation may play a vital role in OKA induced memory impairment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Mitochondrial abnormalities have been identified in a large proportion of neurodegenerative diseases. Recently we have reported that intracerebroventricular (ICV) administration of okadaic acid (OKA) causes memory impairment in rat. However involvement of mitochondrial function in OKA induced memory impairment and neuronal damage has not been determined. OKA (200 ng) was administered by ICV route. After 13th day of OKA administration memory function was evaluated by Morris Water Maze test. Following completion of behavioral studies on 16th day, mitochondrial membrane potential, Ca(2+) and reactive oxygen species were evaluated in mitochondrial preparation of cortex, hippocampus, striatum and cerebellum of rat brain. While ATP, mitochondrial activity, lipid peroxidation and nitrite were investigated in synaptosomal preparation of rat brain areas. The activities and mRNA expression of apoptotic factors, caspase-3 and caspase-9, were studied in rat brain regions. The neuronal damage was also confirmed by histopathological study. OKA treated rats showed memory impairment including increased Ca(2+) and reactive oxygen species and decreased mitochondrial membrane potential, ATP and mitochondrial activity in mitochondrial preparation. There was a significant increase in lipid peroxidation and nitrite in synaptosomal preparations. Preventive treatment daily for 13 days with antidementic drugs, donepezil (5 mg/kg, p.o) and memantine (10 mg/kg, p.o), significantly attenuated OKA induced mitochondrial dysfunction, apoptotic cell death, memory impairment and histological changes. Mitochondrial dysfunction appeared as a key factor in OKA induced memory impairment and apoptotic cell death. This study indicates that clinically used antidementic drugs are effective against OKA induced adverse changes at behavioral, cellular, and histological levels and mitochondrial dysfunction., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Piracetam is a nootropic drug that protects neurons in neuropathological and age-related diseases and the activation and modulation of peripheral blood cells in patients with neuropathological conditions is well known. Therefore, in the present study, in vivo, ex vivo, and in vitro tests were conducted to investigate the effect of piracetam on leukocytes and macrophages. Lipopolysaccharide (LPS) causes oxidative DNA damage; thus, in the present study, LPS was used as a tool to induce DNA damage. In vivo experiments were conducted on Sprague Dawley rats, and piracetam (600mg/kg, oral) was provided for five consecutive days. On the fifth day, a single injection of LPS (10mg/kg, i.p.) was administered. Three hours after LPS injection, blood leukocytes and peritoneal macrophages were collected and processed, and a variety of different assays were conducted. Ex vivo treatments were performed on isolated rat blood leukocytes, and in vitro experiments were conducted on rat macrophage cell line J774A.1. Cell viability and the level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and DNA damage were estimated in untreated (control) and piracetam-, LPS- and LPS+piracetam-treated leukocytes and macrophages. In vivo experiments revealed that rats pretreated with piracetam were significantly protected against LPS-induced increases in ROS levels and DNA damage. Ex vivo isolated leukocytes and J774A.1 cells treated with LPS exhibited augmented ROS levels and DNA damage, which were attenuated with piracetam treatment. Thus, the present study revealed the salutary effect of piracetam against LPS-induced oxidative stress and DNA damage in leukocytes and macrophages., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Brain insulin receptors (IRs) have been suggested as an important regulatory factor for cognitive functions but the involvement of IR signaling in memory deficit associated with neurodegenerative conditions is not yet explored. In the present study, IR gene expression was studied by RT-PCR and signaling pathways by immunoblotting in CA1, DG and CA3 subregions of hippocampus in intracerebroventricular (ICV) administered streptozotocin (STZ, 3mg/kg twice) induced memory deficit model in rat. The effect of pre- and post-treatment of donepezil (5mg/kg po) and melatonin (20mg/kg po) on signaling pathways were studied. Effect of LY294002 (ICV), a PI3 Kinase inhibitor, was also investigated on memory functions and Akt phosphorylation. An increased IR expression (both gene and protein), phosphorylation of Shc, Erk1/2, IRS-1 and Akt in CA1 and CA3 region of P2M fraction was observed after training as compared to control. STZ treated rats showed memory deficit and significant decrease in IR expression, phosphorylation of IRS-1 and Akt only in CA3 region as compared to trained group which were reversed by pre and post-treatment of melatonin but donepezil was effective only against memory deficit. LY294002 (3mM) treatment showed delayed learning and decrease in Akt phosphorylation. This study suggests that IR expression and its signaling pathways in hippocampal CA1 and CA3 regions are involved in memory functions and STZ (ICV) induced memory deficit. Hippocampal IR system might be playing an important role in regulation of memory functions, however only IR/IRS-1/Akt pathway in CA3 region is associated with STZ induced memory deficit., (Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.)

Rotenone induces neurotoxicity but its correlation with biochemical and cerebral changes in rat brain regions are not well defined. In the present study rotenone was administered (3, 6 and12mug/mul) intranigrally in adult male SD rats and its effect was assessed on neuromuscular coordination and in different brain areas viz. striatum (STR), mid-brain (MB), frontal cortex (FC) and hippocampus (HP) cerebral and biochemical changes on 1st and 7th day after treatment. All the doses of rotenone significantly impaired neuromuscular coordination performance on Rota rod test on 1st and 7th day. TTC staining showed significant increase in cerebral injury volume on 1st and 7th day after rotenone treatment indicating mitochondrial enzyme deficiency but increase after 7th day was less that after 1st day. Rotenone treated rats showed significant decrease in GSH and increase in MDA in different brain regions though the pattern was varied. After 1 day of rotenone (6 and 12mug) treatment significant decrease in GSH was observed in STR and MB while MDA was significantly increased only in MB. The maximal effect on GSH and MDA was obtained in STR and MB on 7th day after treatment with 12mug dose of rotenone. Thus, based on the occurrence of changes, it may be suggested that impairment of neuromuscular coordination is inked to oxidative stress rather than mitochondrial enzyme deficiency, all the processes are correlated with each other with the progression of time. MB appeared as most sensitive brain area towards rotenone toxicity., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Curcumin, the principal curcuminoid of turmeric, exhibits beneficial role in several neurodegenerative disorders such as dementia of Alzheimer type. Recent evidences suggest the involvement of brain insulin receptors (IRs) in the pathophysiology of dementia disorders. Therefore, the present study was undertaken to investigate the effect of curcumin on memory functions, brain IRs, acetylcholinesterase (AChE) activity and oxidative stress in intracerebroventricular (ICV) administered streptozotocin (STZ) induced dementia in rats. Rats were injected with STZ (3 mg/kg, ICV) bilaterally twice, on day 1 and 3 and curcumin (200 mg/kg, po) was administered in pre- and post-treatment schedules. STZ (ICV) treated group had shown memory deficit as indicated by no significant decrease in latency time in Morris water maze test and significant decrease in IR protein level in both hippocampus and cerebral cortex. Pre- and post-treatment of curcumin in STZ (ICV) treated rats significantly restored the memory deficit and IR protein level in both the regions. Furthermore, STZ (ICV) resulted into enhanced AChE activity in hippocampus and cerebral cortex which was normalized by curcumin pre- and post-treatment. An increase in MDA level and decrease in GSH level were obtained in both hippocampus and cerebral cortex in STZ treated group, indicating state of oxidative stress, which was also attenuated by pre- and post-treatment of curcumin. The results suggest that besides the anticholinesterase and antioxidant activity, effect on brain IR may also be an important factor for protective effect of curcumin against STZ induced dementia model., (2010 Elsevier Ltd. All rights reserved.)

Aims: The aim of the present study is to investigate the effect of curcumin on cerebral blood flow (CBF), memory impairment, oxidative stress and cholinergic dysfunction in intracerebral (IC) streptozotocin (STZ) induced memory impairment in mice., Main Methods: Memory impairment was induced by STZ (0.5mg/kg, IC) administered twice with an interval of 48h in mice. Memory function was assessed by Morris water maze and passive avoidance test. CBF was measured by Laser Doppler Flowmetry (LDF). To study the preventive effect, curcumin (10, 20 and 50mg/kg, PO) was administered for 21days starting from the first dose of STZ. In another set of experiment, curcumin was administered for 7days from 19th day after confirming STZ induced dementia to observe its therapeutic effect. Biochemical parameters of oxidative stress and cholinergic function were estimated in brain on day 21., Key Findings: The major finding of this study is that STZ (IC) caused a significant reduction in CBF along with memory impairment, cholinergic dysfunction and enhanced oxidative stress. Curcumin dose dependently improved CBF in STZ treated mice together with amelioration of memory impairment both in preventive and therapeutic manner., Significance: The present study clearly demonstrates the beneficial effects of curcumin, the dietary staple of India, on CBF, memory and oxidative stress which can be exploited for dementia associated with age related vascular and neurodegenerative disorders., (Copyright 2009 Elsevier Inc. All rights reserved.)

In the present study the effect of melatonin on intracerebroventricularly administered streptozotocin (STZ)-induced neurodegeneration was investigated in rats. STZ (3mg/kg), administered twice with an interval of 48 h between the two doses, showed impairment in spatial memory tested by water maze test after 14 days of 1st dose. Administration of melatonin (2.5, 5.0 and 10mg/kg, i.p.) was started 1h prior to 1st dose of STZ and continued up to 14 days. Glutathione and malondialdehyde were used as biochemical markers of oxidative stress in different brain regions. Histopathological changes were examined by using hematoxylin and eosin stain. STZ administration caused significant decrease in glutathione and increase in malondialdehyde as compared to control and artificial Cerebrospinal Fluid treated rats indicating oxidative stress. Brain sections of STZ-treated rats showed increased vacuoles in the periventricular cortical area, damaged periventricular cells and damaged cells in the hippocampal CA4 region as compared to control and artificial Cerebrospinal Fluid treated groups. Melatonin treatment significantly attenuated the effect of STZ-induced oxidative stress and histopathological changes. The results indicate that melatonin is effective in providing protection against memory deficit, oxidative stress and neuronal damage induced by STZ.

Objective: The objective of the study was to characterize trends in gestational diabetes (GDM) by maternal age, race, and geographic region in the United States., Study Design: The National Hospital Discharge Survey, comprised of births in the United States between 1989 and 2004 (weighted n = 58,922,266), was used to examine trends in GDM, based on an International Classification of Diseases, Ninth Revision, Clinical Modification code of 648.8. We examined temporal trends by comparing GDM rates in the earliest (1989-1990) vs most recent (2003-2004) biennial periods. Relative risks, quantifying racial disparity (black vs white) in GDM, were derived through logistic regression models after adjusting for confounders. These analyses were further stratified by maternal age and geographic region., Results: Prevalence rates of GDM increased from 1.9% in 1989-1990 to 4.2% in 2003-2004, a relative increase of 122% (95% confidence interval [CI] 120%, 124%). Among whites, GDM increased from 2.2% in 1989-1990 to 4.2% in 2003-2004 (relative increase of 94% [95% CI 91%, 96%]), and this was largely driven by an increase in the 25-34 year age group. In contrast, the largest relative increase in GDM (260% [95% CI 243%, 279%]) among blacks between 1989-1990 (0.6%) and 2003-2004 (2.1%) occurred to women aged younger than 25 years. The black-white disparity in GDM rates widened markedly among women aged younger than 35 years in the 1997-2004 periods. The largest relative increases were seen in the West (182% [95% CI 177%, 187%]) followed by the South and Northeast. The observed increase in GDM rates in the Northeast, Midwest, and South regions most likely is due to increase in GDM prevalence rates among blacks., Conclusion: This study shows that the prevalence rate of GDM in the United States has increased dramatically between 1989 and 2004. The temporal increase and the widening black-white disparity in the rate of GDM deserves further investigation.

Objective: The purpose of this study was to evaluate the effect of maternal cigarette smoking on placental histology in women with abruption., Study Design: Data were derived from the New Jersey-Placental Abruption Study (NJ-PAS)--an ongoing, case-control study, conducted since August 2002 in 2 large hospitals in NJ. Abruption cases were identified based on a clinical diagnosis. Histologic evaluations were performed by 2 perinatal pathologists who were blinded to the abruption status. Maternal smoking during pregnancy was determined based on patient's self-report. Among abruption cases, histologic findings were compared between smokers and nonsmokers, and the association expressed as odds ratio (OR) with 95% confidence interval (CI). All analyses were adjusted for potential confounders., Results: A total of 189 abruption cases were available for analysis, of which 10.6% (n = 20) were smokers. Intervillous thrombus was more common in women who smoked (20%) than in nonsmokers (3.0%) (OR, 17.5; 95% CI, 3.1-99.4). However, placental infarcts were seen less frequently among smokers than nonsmokers (10.0% vs 32.5%; OR, 0.2; 95% CI, 0.1-0.8)., Conclusion: These findings suggest that different pathologic mechanisms may be responsible for the histologic findings between smokers and nonsmokers diagnosed with placental abruption.

Inflammation has been recently implicated in pathogenesis of dementia disorders. Effect of anti-dementia (Acetylcholinesterase inhibitor) drugs tacrine, rivastigmine and donepezil were studied on neuroinflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) in mice. Interleukin-2 (IL-2) and isoforms of acetylcholinesterase (AChE) were estimated in different brain areas as marker for neuroinflammation and cholinergic activity respectively. LPS significantly increased the level of IL-2 in all the brain areas while enhancement of AChE activity varied in brain areas. It was found that administration of tacrine, rivastigmine and donepezil in mice significantly attenuated the LPS induced increased levels of IL-2 along with the significant reduction of AChE activity predominantly in salt soluble (SS) fraction as compared to the detergent soluble (DS) fraction in a dose dependent manner. In vitro effect of LPS was also studied in different brain areas. LPS significantly increased the AChE activity in SS fractions but the significant increase was not found in DS fractions. The present study indicate that cholinesterase inhibitor anti-dementia drugs are effective against LPS induced neuroinflammation that may be linked to enhanced cholinergic activity.

Gugulipid, an ethyl acetate extract of the resin of plant Commiphora whighitii is an established hypolipidemic agent in clinical practice. The major constituent of gugulipid is guggulsterone [4, 17 (20)-pregnadiene-3, 16-dione]. It has been observed recently that patients receiving lipid-lowering drugs like statins have a reduced risk of dementia. Therefore, the present study was planned to explore the potential of gugulipid as cognitive enhancer. Gugulipid (12.5, 25 and 50 mg/kg, p.o.) showed dose dependent improvement in scopolamine-induced deficits in passive avoidance test. The maximal effective dose of gugulipid i.e. 50 mg/kg, p.o. was used for further studies on streptozotocin (STZ) model of dementia in mice. Gugulipid was investigated for its effect on learning and memory, parameters of oxidative stress (GSH and MDA) and acetylcholinesterase (AChE) activity in the STZ (ic)-treated mice. Intracerebral (ic) injections of STZ (0.5 mg/kg) on 1st and 3rd day caused significant deficit in memory in passive avoidance and Morris water maze test after the 14th day of first dose. In passive avoidance, transfer latency time (TLT) was not increased on retention trials in STZ (ic) group while gugulipid treatment resulted in significant increase in TLT on retention trials in STZ (ic)-treated mice. In Morris water maze test the latency time to reach platform in STZ (ic)-treated mice was significantly higher than control and vehicle (artificial CSF). Pre-treatment of gugulipid (50 mg/kg, p.o.) daily for 14 days started with the first dose of STZ (ic), significantly prevented STZ (ic)-induced memory deficit. Post-treatment i.e. after 14 days of first dose of STZ (ic) of gugulipid (50 mg/kg, p.o.) significantly decreased the latency time indicating anti-dementia activity. Effect of gugulipid and STZ in visible platform test was similar to those seen with hidden platform. Gugulipid and STZ-treated mice did not cause significant change in locomotor activity. Furthermore, STZ (ic) resulted into increase in AChE activity, low level of GSH and high concentration of MDA in brain on 21st day as compared to control. Gugulipid treatment caused significant decrease in AChE activity, low level of MDA and high concentration of GSH in brain following STZ (ic) as compared to vehicle administration in STZ (ic)-treated mice. The study demonstrated that gugulipid has significant protective affect against streptozotocin-induced memory deficits model of dementia that can be attributed to anti-oxidant and anti-AChE activity of gugulipid. These observations suggest gugulipid as a potential anti-dementia drug (CDRI, Lucknow has obtained US patent No. 6896901 for use of gugulipid as cognitive enhancer).

Effect of acute, chronic-predictable and chronic-unpredictable stress on memory and acetylcholinesterase (AChE) was investigated in rats. The animals were subjected to 3 type of stressors--(1) acute immobilization stress, (2) chronic-predictable stress i.e., immobilization daily for 5 consecutive days and (3) chronic-unpredictable stress that included reversal of light/dark cycle, over-night fasting, forced-swimming, immobilization and forced exercise in random unpredictable manner daily for 5 consecutive days. Learning and memory function was studied by single trial Passive avoidance test. AChE activity was assayed spectrophotometrically in the detergent (DS) and salt (SS) soluble fractions in different brain regions. Learning was obtained in acute and chronic-predictable stress groups but not in chronic-unpredictable group. Acute, chronic-predictable and chronic-unpredictable stress caused significant decrease in AChE activity in the DS fraction of cortex, hippocampus and hypothalamus as compared to control. Results indicate that AChE in DS fraction is predominantly affected in stressed and stressed-trained group but cognition is affected only by chronic-unpredictable stress. In acute and chronic-predictable groups the decreased AChE activity in the hippocampal DS fraction during learning may be responsible to maintain cognitive function by enhancing the cholinergic activity.

Evolvulus alsinoides (EA) is well known for its memory enhancement, antiepileptic and immunomodulatory properties in the traditional Indian system of medicine, Ayurveda. In view of the increasing attention towards plants offering non-specific resistance (adaptogens) towards stress, we have evaluated crude ethanolic extract of EA for its adaptogenic and memory enhancing properties in rodents. Adaptogenic activity was assessed in rats subjected to acute and chronic unpredictable stress. Male Sprague-Dawley rats, weighing 180-200 g were immobilized for 150 min once only in acute stress (AS) model, whereas in chronic unpredictable stress (CUS) model rats were subjected to different types of stressors daily for 7 days. Stress exposure has induced gastric ulceration with increase in adrenal gland weight, plasma creatine kinase (CK), and corticosterone level in AS and CUS. However plasma glucose was increased only in AS. Rats were treated with graded doses of crude ethanolic extract of EA (100, 200 and 400 mg/kg p.o.) for 3 days and subjected to AS on 3 day after 45 min of last dose. In CUS, EA at a dose of 200 mg/kg p.o. found effective in acute studies was administered 45 min prior to stress regimen for 7 days. EA reduced the stress induced perturbations similar to Panax quinquefolium (PQ) (100 mg/kg p.o.), a well known adaptogen. EA (100 mg/kg) administered orally for 3 days in adult male Swiss mice, was effective in decreasing scopolamine induced deficit in passive avoidance test. The improvement in the peripheral stress markers and scopolamine induced dementia by EA in the present study indicates the adaptogenic and anti-amnesic properties of EA.

In the present study, activity of salt soluble (SS) G1 and detergent soluble (DS) G4 molecular isoforms of acetylcholinesterase (AChE) has been investigated in rat brain areas in trained (learned), scopolamine (amnesic) and Tacrine (anti-dementic) treated rats to find out their role in learning and memory functions. AChE was estimated spectrophotometrically at 412 nm in rat brain areas. Isolation and partial purification of molecular isoforms G1 and G4 of AChE was done by gel filtration chromatography. Passive avoidance was used to test learning and memory functions. AChE activity was altered in both the fractions SS and DS of different brain areas following passive avoidance in control, scopolamine treated, tacrine treated and tacrine treatment in scopolamine pretreated rats. The peak AChE activity obtained in the DS (fraction 9) and the SS (fraction 13) fraction following gel filtration chromatography. On the basis of molecular weight fraction 9 (DS) and 13 (SS) represent the G4 and G1, respectively. The pattern of changes in the AChE activity of G1 isoform (fraction 13 of SS) and G4 isoform (fraction 9 of DS) in brain areas were similar to those of SS and DS fraction, respectively. In hippocampus, AChE activity in the fraction G1 isoform (fraction 13 of SS) was decreased only in tacrine treated rats but AChE activity in the G4 isoform (fraction 9 of DS) was decreased in both trained and tacrine treated rats. Changes in activity of G4 isoform of AChE in hippocampus could be correlated with passive avoidance learning, scopolamine induced deficit in passive avoidance and reversal of scopolamine deficit by tacrine.

Bacopa monniera and Ginkgo biloba are well-known cognitive enhancers in Indian and Chinese traditional medicine systems. Standardized extracts of B. monniera and G. biloba were used to evaluate the antidementic and anticholinesterase activities in adult male Swiss mice. Antidementic activity was tested against scopolamine (3 mg/kg ip)-induced deficits in passive avoidance test. Three different extracts of B. monniera (30 mg/kg) and extract of G. biloba (15, 30 and 60 mg/kg) were administered postoperatively, daily for 7 days and 60 min after the last dose, i.e., on Day 7, first trial was conducted. In passive avoidance test, increased transfer latency time (TLT) and no transfer response (NTR) were taken as criteria for learning. TLT and NTR were significantly increased and decreased in second trial, 24 h after the first trial in control group and scopolamine-dementia group, respectively. The B. monniera- and G. biloba-treated groups produced significant increase in TLT and NTR on second trial (40-80%) after scopolamine treatment, thus, attenuating its antidementic effect. Both the extracts showed a dose (10-1000 microg)-dependent inhibitory effect on acetylcholinesterase (AChE) activity (in vitro), performed spectrophotometrically. IC(50) of G. biloba was 268.33 microg, whereas none of the extracts of B. monniera showed more than 50% inhibition. At a dose concentration of 30 and 60 mg/kg, extracts of G. biloba showed a cognitive enhancing property and, at the same time, a significant decrease in AChE-specific activity in both per se and scopolamine-dementia groups. These extracts possess a significant anticholinesterase and antidementic properties, which may be useful in the treatment of dementia.

Effects of histaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with the food in the following dose schedule (in mg/kg given daily x days): 10 x 4, 20 x 4, 40 x 4, 80 x 4, and 120 x 7. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA), and audiogenic seizures. During the withdrawal period, the rats were divided into groups of 10 each. Control-withdrawal group did not receive any drug. The drugs (in mg/kg administered intramuscularly)--L-histidine (50), histamine-N-methyl (2), promethazine (10), pheniramine (10), astemizole (10), and thioperamide (1)--were given separately in other groups daily during the withdrawal period. The withdrawal signs in control group were hyperkinesia, hyperaggression, and audiogenic seizures. L-Histidine, precursor of histamine, and thioperamide, antagonist of H3 receptor, potentiated hyperkinesia, hyperaggression, and audiogenic seizures. Histamine-N-methyl, agonist of H3 receptor, and H1 receptor antagonists, promethazine and pheniramine, blocked all the withdrawal signs. Astemizole, a peripheral antagonist of H1 receptor, could not affect any withdrawal sign. It may be concluded that histamine H1 receptors are facilitatory and H3 receptors are inhibitory for benzodiazepine (BZD) withdrawal syndrome.

Inhibition of acetylcholinesterase (AChE)-metabolizing enzyme of acetylcholine, is presently the most important therapeutic target for development of cognitive enhancers. However, AChE activity in brain has not been properly evaluated on the basis of age and sex. In the present study, AChE activity was investigated in different brain areas in male and female Sprague-Dawley rats of adult (3 months) and old (18-22 months) age. AChE was assayed spectrophotometrically by modified Ellman's method. Specific activity (micromoles/min/mg of protein) of AChE was assayed in salt soluble (SS) and detergent soluble (DS) fractions of various brain areas, which consists of predominantly G1 and G4 molecular isoforms of AChE respectively. The old male rats showed a decrease (40-55%) in AChE activity in frontal cortex, striatum, hypothalamus and pons in DS fraction and there was no change in SS fraction in comparison to adult rats. In the old female rats the activity was decreased (25-40%) in frontal cortex, cerebral cortex, striatum, thalamus, cerebellum and medulla in DS fraction whereas in SS fraction the activity was decreased only in hypothalamus as compared to adult. On comparing with old male rats, old female rats showed increase in AChE activity in cerebral cortex, hippocampus and hypothalamus of DS fraction and decrease in hypothalamus of SS fraction. There was a significant increase in AChE activity in DS fraction of cerebral cortex, hippocampus, hypothalamus, thalamus and cerebellum in female as compared to male adult rats. However, no significant change in AChE activity was found in the SS fraction, except hypothalamus between these groups. Thus it appears that age alters AChE activity in different brain regions predominantly in DS fraction (G4 isoform) that may vary in male and female. These observations have significant relevance to age related cognitive deficits and its pharmacotherapy.

Various studies have shown that calcium channel blockers (CCB) affect the release of central neurotransmitters including noradrenaline (NA) and 5-hydroxytryptamine (5-HT), which are involved in depression. The behavioural despair test was used to investigate the effect of CCB on depression. The mice were treated acutely with CCB. Verapamil (5, 10, 20, and 40 mgkg(-1), i.p.) and diltiazem (10, 20, and 40 mgkg(-1), i.p.) produced a dose-dependent increase in immobility time, indicating the facilitation of depression, while nifedipine (12.5, 25, and 50 mgkg(-1), i.p.) significantly decreased the immobility time, indicating an antidepressant activity. Verapamil ( 40 mgkg(-1), i.p.) and diltiazem ( 40 mgkg(-1), i.p.) blocked the antidepressant effect of desipramine, clomipramine, mianserin, and tranylcypromine, indicating the involvement of various mechanisms in the facilitatory effect of verapamil and diltiazem on depression. The antidepressant effect of nifedipine may be attributed to the blockade of presynaptic alpha -2-receptors (autoreceptors), as nifedipine blocked the clonidine-induced facilitation of depression., (Copyright 2000 Academic Press.)

In the present study, the effect of acute and chronic immobilization stress on brain acetylcholinesterase (AChE) enzyme activity and cognitive function in mice was investigated. Mice were immobilized by strapping for 150 min. One group of mice were only immobilized once (acute stress) while in another group mice were immobilized (150 min) daily for 5 consecutive days (chronic stress). Specific AChE enzyme activity (micromol min(-1)mg(-1)) was estimated by a spectrophotometric method in the whole brain of mice subjected to acute and chronic stress. In the acute stress group, AChE activity (0.24922 +/- 0.011) in the detergent-soluble fraction was found to be significantly decreased in comparison to the control group (0.33561 +/- 0.022). Chronic stress did not cause any significant change in AChE activity in the detergent-soluble fraction. In the salt-soluble fraction, AChE activity was significantly decreased only in the chronic stress group (0.08791 +/- 0.011) as compared to the control group (0.12051 +/- 0.011). A passive avoidance test was used to assess cognitive function. The transfer latency time (TLT) from a light to dark chamber was recorded in the control and acute stress groups (30 min after immobilization is over) on day 1 (Trial I) and the following day (Trial II). The acute stress group showed an increase (178%) in TLT from Trial I to Trial II, which was significantly higher than that of the non-stress control group (75%). In the chronic stress group, Trial I was undertaken 30 min after the last immobilization, i.e. on day 5 and 24 hr later, Trial II. However, the chronically stressed mice showed an increase (70%) in TLT similar to the control group. Thus this study shows that acute immobilization stress may enhance cognitive function in mice which may be attributed to a decrease in AChE activity leading to an increase in cholinergic activity in the brain., (Copyright 2000 Academic Press.)

A possible relationship between change in dietary cholesterol absorption and plasma lipoprotein responsiveness was examined in 18 normal subjects fed low fat low cholesterol, high fat low cholesterol, and high fat high cholesterol diets. For the group, neither dietary cholesterol nor dietary fat affected the percentage dietary cholesterol absorption, whereas dietary cholesterol intake raised total and LDL-C and dietary fat raised total, LDL, and HDL-C. On a fixed diet there was approximately a 2-fold variation among subjects in percentage dietary cholesterol absorption. Subjects also varied in response to dietary cholesterol and fat with regard to dietary cholesterol absorption and plasma lipoprotein responsiveness. There was a U-shaped parabolic relationship between dietary cholesterol-induced percent change in LDL-C and the change in percentage dietary cholesterol absorption (R2 = 0.62, P = 0.005). A similar but weaker relationship characterized the responsiveness of HDL-C (R2 = 0.38, P = 0.05). For the group, increased cholesterol intake raised dietary cholesterol mass absorption from 1.6 to 4.6 mg/kg per day, but the range of increase was from 1 to 4.7 mg/kg per day. Increased fat intake also affected dietary cholesterol mass absorption with most subjects displaying a strong inverse relationship between fat intake and mass absorption (r = -0.77, P < 0.003). In summary: i) the percentage change in dietary cholesterol absorption in response to dietary cholesterol does appear to regulate diet responsiveness of LDL and HDL-C, and ii) the large variability in percent absorption and changes in percentage and mass absorption in response to dietary cholesterol suggest the presence of genetically determined differences among individuals in the regulation of dietary cholesterol absorption.

The effect of calcium channel blockers on foot shock induced (aggression (FSA) were studied in mice. Verapamil, (10, 20 and 40 mg kg-1 i.p.) diltiazem (20 and 40 mg kg-1 i.p.) and nifedipine (25 and 50 mg kg-1 i.p.) significantly reduced fighting episodes. Diltiazem and nifedipine blocked the amphetamine induced facilitation of FSA, while verapamil blocked both amphetamine as well as physostigmine induced facilitation of FSA. These findings suggest that calcium channel blockers possess antiaggressive activity, which may be attributed to decrease in central dopaminergic and/or cholinergic mechanism.

A new met-enkephalin analogue (compound 82/205) was evaluated for its opioidergic activity in mice. The compound showed antinociception (warm water tail-flick test), tolerance, cross tolerance to morphine and physical dependence. The time course of antinociceptive effect of the compound was comparable to morphine. The antinociceptive ED50 (mumol kg-1, i.p.) values for the compound and morphine base were 5.31 and 7.59, respectively. Its antinociceptive effect was blocked by naloxone, beta-FNA (mu antagonist) and naloxonazine (mu1 antagonist) but not by ICI 174,864 (delta antagonist). Naloxone precipitated withdrawal jumpings were 2.6 times less in compound 82/205 treated mice than the morphine treated group. The new analogue compound 82/205 is a potent mu agonist antinociceptive with a possible weak dependence liability.

The effect of verapamil, a calcium channel blocker, was studied against stress (cold restraint), aspirin and pylorus ligation induced gastric ulcers in rats. Verapamil inhibited ulcerogenic response and ulcer index in all the three types of ulcers. Verapamil also decreased total and free gastric acidity without changing gastric secretory volume.

The interaction of blood pressure, salt intake and the inhibition of angiotensin converting enzyme activity with cardiac hypertrophy were examined in the Dahl rat model. Eight-week-old salt sensitive and salt resistant rats were each separated into two colonies, one of which was maintained on a low salt and the other on a high salt diet for three weeks, at the end of which time both salt sensitive colonies were hypertensive. Each colony was then separated into two groups, one received no medication the other was given lisinopril until normotension was achieved. After 11 weeks of therapy, intra-arterial blood pressures and heart rates were recorded. The rats were sacrificed and heart weight to body weight ratios were determined. Both untreated salt sensitive groups displayed marked cardiac hypertrophy which correlated well with diastolic blood pressure irrespective of salt intake. Lisinopril therapy lowered blood pressures to normotensive levels in all groups except for salt sensitive rats ingesting a high salt diet where, despite a 10-fold increase in drug dose, normotension was not achieved. Significant cardiac regression accompanied lisinopril therapy in rats receiving low salt diets but high salt intake severely attenuated regression in both strains. There was no significant correlation between heart weight and blood pressure in the treated groups. The results suggest that cardiac regression appears to be mediated by other factors besides ventricular afterload pressure and that high salt intake adversely affects blood pressure and heart weight response to lisinopril therapy.

Phenytoin (DPH) was delivered to the brain by a dihydropyridine in equilibrium pyridinium salt redox system, which was evaluated for anticonvulsant activity. Following iv injection of the lipophilic delivery system of DPH (2) to rats, concentrations of DPH were lower but sustained and, after 30 min, essentially the same as the levels after equimolar administration of DPH. While 2 delivered the same levels of DPH to the brain as DPH did, it was twice as potent as DPH in rats (ED50 was 7.5 mumol/kg for 2 and 14.2 mumol/kg for DPH) and mice (2: 10.5; DPH: 23.9) against maximal electroshock seizures (MES), and seven times more potent in mice (2: 10.0, DPH: 70.6) against maximal pentylenetetrazole seizures (MPS). Moreover, 2 was active against pentylenetetrazole threshold seizures (PTS) in mice and rats (ED50 = 44.1 and 40.5 mumol/kg, respectively), while DPH was ineffective (up to a dose of 79.2 mumol/kg). After evaluation of acute neurological toxicity in rats, 2 was found to possess 1.5 times higher a protective index (for MES) than DPH. It appeared also that while DPH was 2.9 times less sensitive to MPS than to MES, 2 was equally potent to both types of convulsions. Thus, the data indicate that 2 delivered DPH more efficiently to the brain. The better anticonvulsant activity (quantitatively as well as qualitatively) of 2 can be explained on the basis of an improved distribution in the brain due to its higher lipophilicity, and by favorable regional differences in the rates of conversion of 2 to DPH at the convulsing foci.

The role of the central histaminergic system in depression was studied by using swimming despair test in mice - a behavioural model of depression. In this test, immobility of mice reflects a state of depression. Intracerebral (ic) injection of histamine (50-200 micrograms) increased significantly the immobility. The H1-receptor blocker mepyramine (2.5-20 mg/kg ip) had no effect while H2-receptor blocker cimetidine (100-200 micrograms ic) caused a significant decrease in immobility. The histamine induced facilitation was blocked completely by cimetidine and antidepressant drugs-imipramine and desipramine, but remained unaffected in mice pretreated with mepyramine or atropine. The H2 agonist impromidine (20-40 micrograms ic) also enhanced significantly, the immobility which was blocked by cimetidine and antidepressant drugs. It has been concluded that central H2-receptors facilitate depression and antidepressant drugs block central H2-receptors.

The antihypertensive efficacy of a single daily dose of bevantolol (200 mg) alone or in combination with hydrochlorothiazide (25 mg) has been compared against conventional twice daily propranolol (80 mg) therapy in a group of 22 hypertensive patients whose blood pressures did not respond to thiazide monotherapy. Addition of bevantolol to the diuretic resulted in a significant (P less than 0.001) fall in sitting blood pressures (144/97 to 137/90 mmHg), supine blood pressures (147/100 to 141/92 mmHg) and heart rate (83 to 73 beats/min) 24 h after administration. When the diuretic was withdrawn, heart rate and diastolic pressures remained unchanged and within normotensive limits but systolic pressures increased to pre-treatment levels. Substitution of propranolol for bevantolol gave results comparable to the combined bevantolol-diuretic regimen except that heart rate was still lower (66 beats/min). No significant adverse reactions were reported. In thiazide-resistant hypertensives, a once daily dose of 200 mg bevantolol effectively reduced diastolic blood pressures towards normotensive limits and to an extent comparable with twice daily propranolol therapy.

Today, American consumers believe they need more and better nutrients than their diets provide. Consequently, consumers spend approximately three billion dollars each year on vitamin and nutrition products. Vitamin and/or mineral supplements are relatively inexpensive and available without a prescription; therefore, it is understandable that they are used by a substantial portion of the population. However, the last 50 years have witnessed a steadily increasing understanding of vitamins and trace mineral biochemistry and its role in human nutrition and intermediary metabolism. It has not been shown conclusively that normal breastfed infants of well nourished mothers need any specific vitamin and mineral supplements, with the exception of iron and fluoride. The use of vitamin D supplements remains controversial. Preterm infants may require supplements of vitamin E, iron, and folic acid because of their rapid rate of growth and less complete, intestinal absorption.