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1.  A Difference-In-Differences Study of the Effects of a New Abandoned Building Remediation Strategy on Safety 
PLoS ONE  2015;10(7):e0129582.
Vacant and abandoned buildings pose significant challenges to the health and safety of communities. In 2011 the City of Philadelphia began enforcing a Doors and Windows Ordinance that required property owners of abandoned buildings to install working doors and windows in all structural openings or face significant fines. We tested the effects of the new ordinance on the occurrence of crime surrounding abandoned buildings from January 2011 to April 2013 using a difference-in-differences approach. We used Poisson regression models to compare differences in pre- and post-treatment measures of crime for buildings that were remediated as a result of the ordinance (n = 676) or permitted for renovation (n = 241), and randomly-matched control buildings that were not remediated (n = 676) or permitted for renovation (n = 964), while also controlling for sociodemographic and other confounders measured around each building. Building remediations were significantly associated with citywide reductions in overall crimes, total assaults, gun assaults and nuisance crimes (p <0.001). Building remediations were also significantly associated with reductions in violent gun crimes in one city section (p <0.01). At the same time, some significant increases were seen in narcotics sales and possession and property crimes around remediated buildings (p <0.001). Building renovation permits were significantly associated with reductions in all crime classifications across multiple city sections (p <0.001). We found no significant spatial displacement effects. Doors and windows remediation offers a relatively low-cost method of reducing certain crimes in and around abandoned buildings. Cities with an abundance of decaying and abandoned housing stock might consider some form of this structural change to their built environments as one strategy to enhance public safety.
PMCID: PMC4496053  PMID: 26153687
2.  Linking Specialization and Seriousness in Criminal Careers 
Some research suggests that recidivistic criminal offending patterns typically progress in a stepping-stone manner from less to more serious forms of offending from childhood to adolescence to adulthood. Whether the progression into more serious types of offending reflects patterns of crime specialization is a matter of debate. Using data from 449 adolescent offenders who were interviewed at six time points between adolescence and adulthood, we present a new method for measuring crime specialization and apply it to an assessment of the link between specialization and offense seriousness. We measure specialization by constructing an empirical measure of how similar crimes are from each other based on the rate at which crimes co-occur within individual crime pathways over a given offender population. We then use these empirically-based population-specific offense similarities to assign a specialization score to each subject at each time period based on the set of crimes they self-report at that time. Finally, we examine how changes over time in specialization, within individuals, is correlated with changes in the seriousness of the offenses they report committing. Results suggest that the progression of crime into increasingly serious forms of offending does not reflect a general pattern of offense specialization. Implications for life course research are noted.
PMCID: PMC4240636  PMID: 25422597
criminal specialization; crime seriousness; criminal careers; longitudinal
3.  Fecal microbiota transplantation as novel therapy in gastroenterology: A systematic review 
AIM: To study the clinical efficacy and safety of Fecal microbiota transplantation (FMT). We systematically reviewed FMT used as clinical therapy.
METHODS: We searched MEDLINE, EMBASE, the Cochrane Library and Conference proceedings from inception to July, 2013. Treatment effect of FMT was calculated as the percentage of patients who achieved clinical improvement per patient category, on an intention-to-treat basis.
RESULTS: We included 45 studies; 34 on Clostridium difficile-infection (CDI), 7 on inflammatory bowel disease, 1 on metabolic syndrome, 1 on constipation, 1 on pouchitis and 1 on irritable bowel syndrome (IBS). In CDI 90% resolution of diarrhea in 33 case series (n = 867) was reported, and 94% resolution of diarrhea after repeated FMT in a randomized controlled trial (RCT) (n = 16). In ulcerative colitis (UC) remission rates of 0% to 68% were found (n = 106). In Crohn’s disease (CD) (n = 6), no benefit was observed. In IBS, 70% improvement of symptoms was found (n = 13). 100% Reversal of symptoms was observed in constipation (n = 3). In pouchitis, none of the patients (n = 8) achieved remission. One RCT showed significant improvement of insulin sensitivity in metabolic syndrome (n = 10). Serious adverse events were rare.
CONCLUSION: FMT is highly effective in CDI, and holds promise in UC. As for CD, chronic constipation, pouchitis and IBS data are too limited to draw conclusions. FMT increases insulin sensitivity in metabolic syndrome.
PMCID: PMC4419078  PMID: 25954111
Fecal microbiota transplantation; Microbiota; Clostridium difficile infection; Inflammatory bowel disease; Metabolic syndrome
4.  Decomposing Racial Disparities in Prison and Drug Treatment Commitments for Criminal Offenders in California 
The Journal of legal studies  2014;43(1):155-187.
Blacks convicted of drug-related offenses in the U.S. have higher prison-commitment rates than Whites. Studies have been largely unsuccessful in explaining these disparities. This study uses administrative data from a random sample of individuals arrested for drug offenses in California to examine this issue. We use a decomposition model to estimate whether Black-White disparities in commitments to prison or diversions to drug treatment are attributable to differences in the characteristics of criminal cases and whether case characteristics are weighed differently by race. We also examine whether the influence of case characteristics changes after California implemented Proposition 36, which was a mandatory prison diversion program for eligible drug offenders. Our results suggest that Black-White differences in prison commitments are fully explained by criminal case characteristics, but that a significant portion of the differences in treatment diversions remain unexplained. The unexplained variation in drug treatment also does not change after Proposition 36. These findings suggest that case characteristics play a larger role in explaining prison commitments for drug offenders than the discretion of prosecutors and judges. By contrast, diversion to drug treatment appears to be driven more by the discretion of court officials and Black-White disparities remain prominent.
PMCID: PMC4219536  PMID: 25382877
5.  Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer 
Investigational new drugs  2013;31(5):1142-1150.
Previously, we reported on the anti-tumor activities of two designed calix[4]arene-based topomimetics (PTX008 and PTX009) of the amphipathic, angiostatic peptide Anginex. Here, we chemically modified the hydrophobic and hydrophilic faces of PTX008 and PTX009, and discovered new calixarene compounds that are more potent, cytotoxic anti-tumor agents. One of them, PTX013, is particularly effective at inhibiting the growth of several human cancer cell lines, as well as drug resistant cancer cells. Mechanistically, PTX013 induces cell cycle arrest in sub-G1 and G0/G1 phases of e.g. SQ20B cells, a radio-resistant human head and neck carcinoma model. In the syngeneic B16F10 melanoma tumor mouse model, PTX013 (0.5 mg/Kg) inhibits tumor growth by about 50-fold better than parent PTX008. A preliminary pharmacodynamics study strongly suggests that PTX013 exhibits good in vivo exposure and a relatively long half-life. Overall, this research contributes to the discovery of novel therapeutics as potentially useful agents against cancer in the clinic.
PMCID: PMC4242102  PMID: 23392775
Calixarenes; Galectin-1; Structure-activity relationships; Therapeutics
6.  Trans-National Scale-Up of Services in Global Health 
PLoS ONE  2014;9(11):e110465.
Scaling up innovative healthcare programs offers a means to improve access, quality, and health equity across multiple health areas. Despite large numbers of promising projects, little is known about successful efforts to scale up. This study examines trans-national scale, whereby a program operates in two or more countries. Trans-national scale is a distinct measure that reflects opportunities to replicate healthcare programs in multiple countries, thereby providing services to broader populations.
Based on the Center for Health Market Innovations (CHMI) database of nearly 1200 health programs, the study contrasts 116 programs that have achieved trans-national scale with 1,068 single-country programs. Data was collected on the programs' health focus, service activity, legal status, and funding sources, as well as the programs' locations (rural v. urban emphasis), and founding year; differences are reported with statistical significance.
This analysis examines 116 programs that have achieved trans-national scale (TNS) across multiple disease areas and activity types. Compared to 1,068 single-country programs, we find that trans-nationally scaled programs are more donor-reliant; more likely to focus on targeted health needs such as HIV/AIDS, TB, malaria, or family planning rather than provide more comprehensive general care; and more likely to engage in activities that support healthcare services rather than provide direct clinical care.
This work, based on a large data set of health programs, reports on trans-national scale with comparison to single-country programs. The work is a step towards understanding when programs are able to replicate their services as they attempt to expand health services for the poor across countries and health areas. A subset of these programs should be the subject of case studies to understand factors that affect the scaling process, particularly seeking to identify mechanisms that lead to improved health outcomes.
PMCID: PMC4222765  PMID: 25375328
8.  Interaction of Acetylcholinesterase with Neurexin-1β regulates Glutamatergic Synaptic stability in Hippocampal neurons 
Molecular Brain  2014;7:15.
Excess expression of acetylcholinesterase (AChE) in the cortex and hippocampus causes a decrease in the number of glutamatergic synapses and alters the expression of neurexin and neuroligin, trans-synaptic proteins that control synaptic stability. The molecular sequence and three-dimensional structure of AChE are homologous to the corresponding aspects of the ectodomain of neuroligin. This study investigated whether excess AChE interacts physically with neurexin to destabilize glutamatergic synapses.
The results showed that AChE clusters colocalized with neurexin assemblies in the neurites of hippocampal neurons and that AChE co-immunoprecipitated with neurexin from the lysate of these neurons. Moreover, when expressed in human embryonic kidney 293 cells, N-glycosylated AChE co-immunoprecipitated with non-O–glycosylated neurexin-1β, with N-glycosylation of the AChE being required for this co-precipitation to occur. Increasing extracellular AChE decreased the association of neurexin with neuroligin and inhibited neuroligin-induced synaptogenesis. The number and activity of excitatory synapses in cultured hippocampal neurons were reduced by extracellular catalytically inactive AChE.
Excessive glycosylated AChE could competitively disrupt a subset of the neurexin–neuroligin junctions consequently impairing the integrity of glutamatergic synapses. This might serve a molecular mechanism of excessive AChE induced neurodegeneration.
PMCID: PMC3973991  PMID: 24594013
Protein interaction; Glycosylation; Neurodegeneration; Synaptic apoptosis
9.  Iodinated contrast–induced thyrotoxicosis 
PMCID: PMC3563887  PMID: 23148056
10.  Recent Progress in Understanding Subtype Specific Regulation of NMDA Receptors by G Protein Coupled Receptors (GPCRs) 
G Protein Coupled Receptors (GPCRs) are the largest family of receptors whose ligands constitute nearly a third of prescription drugs in the market. They are widely involved in diverse physiological functions including learning and memory. NMDA receptors (NMDARs), which belong to the ionotropic glutamate receptor family, are likewise ubiquitously expressed in the central nervous system (CNS) and play a pivotal role in learning and memory. Despite its critical contribution to physiological and pathophysiological processes, few pharmacological interventions aimed directly at regulating NMDAR function have been developed to date. However, it is well established that NMDAR function is precisely regulated by cellular signalling cascades recruited downstream of G protein coupled receptor (GPCR) stimulation. Accordingly, the downstream regulation of NMDARs likely represents an important determinant of outcome following treatment with neuropsychiatric agents that target selected GPCRs. Importantly, the functional consequence of such regulation on NMDAR function varies, based not only on the identity of the GPCR, but also on the cell type in which relevant receptors are expressed. Indeed, the mechanisms responsible for regulating NMDARs by GPCRs involve numerous intracellular signalling molecules and regulatory proteins that vary from one cell type to another. In the present article, we highlight recent findings from studies that have uncovered novel mechanisms by which selected GPCRs regulate NMDAR function and consequently NMDAR-dependent plasticity.
PMCID: PMC3958896  PMID: 24562329
NMDA receptor; G protein coupled receptor; protein kinase A; protein kinase C; cyclic AMP
11.  Diarylamidines: High potency inhibitors of acid-sensing ion channels 
Neuropharmacology  2010;58(7):10.1016/j.neuropharm.2010.01.011.
Acid-sensing ion channels (ASICs) are proton-gated cation channels that are predominantly expressed in the nervous system. ASICs are involved in a number of neurological diseases such as pain, ischemic stroke and multiple sclerosis but limited tools are available to target these channels and provide probes for their physiological functions. Here we report that the anti-protozoal diarylamidines, 4′,6-diamidino-2-phenylindole (DAPI), diminazene, hydroxystilbamidine (HSB) and pentamidine potently inhibit ASIC currents in primary cultured hippocampal neurons with apparent affinities of 2.8 µM, 0.3 µM, 1.5 µM and 38 µM, respectively. These four compounds (100 µM) failed to block ENaC channels expressed in oocytes. Sub-maximal concentrations of diminazene also strongly accelerated desensitization of ASIC currents in hippocampal neurons. Diminazene blocked ASIC1a, -1b -2a, and -3 currents expressed in CHO cells with a rank order of potency 1b > 3 > 2a ≥ 1a. Patchdock computational analysis suggested a binding site of diarylamidines on ASICs. This study indicates diarylamidines constitute a novel class of non-amiloride ASIC blockers and suggests that diarylamidines may be developed as therapeutic agents in treatment of ASIC-involved diseases.
PMCID: PMC3846926  PMID: 20114056
ASIC; Diarylamidines; Channel blockers; Pain
12.  Optogenetics and synaptic plasticity 
Acta Pharmacologica Sinica  2013;34(11):1381-1385.
The intricate and complex interaction between different populations of neurons in the brain has imposed limits on our ability to gain detailed understanding of synaptic transmission and its integration when employing classical electrophysiological approaches. Indeed, electrical field stimulation delivered via traditional microelectrodes does not permit the targeted, precise and selective control of neuronal activity amongst a varied population of neurons and their inputs (eg, cholinergic, dopaminergic or glutamatergic neurons). Recently established optogenetic techniques overcome these limitations allowing precise control of the target neuron populations, which is essential for the elucidation of the neural substrates underlying complex animal behaviors. Indeed, by introducing light-activated channels (ie, microbial opsin genes) into specific neuronal populations, optogenetics enables non-invasive optical control of specific neurons with milliseconds precision. These approaches can readily be applied to freely behaving live animals. Recently there is increased interests in utilizing optogenetics tools to understand synaptic plasticity and learning/memory. Here, we summarize recent progress in applying optogenetics in in the study of synaptic plasticity.
PMCID: PMC4006463  PMID: 24162508
synaptic plasticity; optogenetics; opsin; channelrhodopsin; halorhodopsin; LTP; LTD; learning and memory
13.  Acute 5-HT7 receptor activation increases NMDA-evoked currents and differentially alters NMDA receptor subunit phosphorylation and trafficking in hippocampal neurons 
Molecular Brain  2013;6:24.
N-methyl-D-aspartate (NMDA) receptors are regulated by several G protein-coupled receptors (GPCRs) as well as receptor tyrosine kinases. Serotonin (5-HT) type 7 receptors are expressed throughout the brain including the thalamus and hippocampus. Long-term (2–24 h) activation of 5-HT7 receptors promotes the expression of neuroprotective growth factor receptors, including the platelet-derived growth factor (PDGF) β receptors which can protect neurons against NMDA-induced neurotoxicity.
In contrast to long-term activation of 5-HT7 receptors, acute (5 min) treatment of isolated hippocampal neurons with the 5-HT7 receptor agonist 5-carboxamidotryptamine (5-CT) enhances NMDA-evoked peak currents and this increase in peak currents is blocked by the 5-HT7 receptor antagonist, SB 269970. In hippocampal slices, acute 5-HT7 receptor activation increases NR1 NMDA receptor subunit phosphorylation and differentially alters the phosphorylation state of the NR2B and NR2A subunits. NMDA receptor subunit cell surface expression is also differentially altered by 5-HT7 receptor agonists: NR2B cell surface expression is decreased whereas NR1 and NR2A surface expression are not significantly altered.
In contrast to the negative regulatory effects of long-term activation of 5-HT7 receptors on NMDA receptor signaling, acute activation of 5-HT7 receptors promotes NMDA receptor activity. These findings highlight the potential for temporally differential regulation of NMDA receptors by the 5-HT7 receptor.
PMCID: PMC3661375  PMID: 23672716
5-HT7; NMDA; Hippocampus; Isolated neurons; Phosphorylation; Trafficking
14.  Failure to Adhere to Protocol Specified Radiation Therapy Guidelines Was Associated With Decreased Survival in RTOG 9704 - A Phase III Trial of Adjuvant Chemotherapy and Chemoradiotherapy for Patients with Resected Adenocarcinoma of the Pancreas 
In RTOG 9704, as previously published, patients with resected pancreatic adenocarcinoma received continuous infusion 5-FU and concurrent radiotherapy (5FU-RT). 5FU-RT treatment was preceded and followed by randomly assigned chemotherapy, either 5-FU or gemcitabine. This analysis explored whether failure to adhere to specified RT guidelines influenced survival and/or toxicity.
Methods and Materials
RT requirements were protocol specified. Adherence was scored as per protocol (PP) or less than per protocol (
RT was scored for 416 patients: 216 PP and 200
This is the first phase III, multi-center, adjuvant protocol for pancreatic adenocarcinoma to evaluate the impact of adherence to specified RT protocol guidelines on protocol outcomes. Failure to adhere to specified RT guidelines was associated with reduced survival and, for patients receiving gemcitabine, trend toward increased non-hematologic toxicity.
PMCID: PMC3133855  PMID: 21277694
Radiotherapy; quality assurance; pancreatic adenocarcinoma; adjuvant therapy; chemoradiotherapy
Scientific Reports  2013;3:926.
Group II metabotropic glutamate receptors (mGluR2/3) have emerged as important targets for the treatment of schizophrenia. Since hypofunction of N-methyl-D-aspartate receptors (NMDARs) has also been implicated in the etiology of schizophrenia, we examined whether postsynaptic mGluR2/3 regulate NMDAR function. Activation of mGluR2/3 significantly decreased the ratio of AMPA-to-NMDA excitatory postsynaptic currents at Schaffer Collateral-CA1 synapses and enhanced the peak of NMDA-evoked currents in acutely isolated CA1 neurons. The mGluR2/3-mediated potentiation of NMDAR currents was selective for GluN2A-containing NMDARs and was mediated by the Src family kinase Src. Activation of mGluR2/3 inhibited the adenylyl cyclase-cAMP-PKA pathway and thereby activated Src by inhibiting its regulatory C-terminal Src kinase (Csk). We suggest a novel model of regulation of NMDARs by Gi/o-coupled receptors whereby inhibition of the cAMP-PKA pathway via mGluR2/3 activates Src kinase and potentiates GluN2A-containing NMDAR currents. This represents a potentially novel mechanism to correct the hypoglutamatergic state found in schizophrenia.
PMCID: PMC3558700  PMID: 23378895
American Journal of Epidemiology  2011;174(11):1296-1306.
Greening of vacant urban land may affect health and safety. The authors conducted a decade-long difference-in-differences analysis of the impact of a vacant lot greening program in Philadelphia, Pennsylvania, on health and safety outcomes. “Before” and “after” outcome differences among treated vacant lots were compared with matched groups of control vacant lots that were eligible but did not receive treatment. Control lots from 2 eligibility pools were randomly selected and matched to treated lots at a 3:1 ratio by city section. Random-effects regression models were fitted, along with alternative models and robustness checks. Across 4 sections of Philadelphia, 4,436 vacant lots totaling over 7.8 million square feet (about 725,000 m2) were greened from 1999 to 2008. Regression-adjusted estimates showed that vacant lot greening was associated with consistent reductions in gun assaults across all 4 sections of the city (P < 0.001) and consistent reductions in vandalism in 1 section of the city (P < 0.001). Regression-adjusted estimates also showed that vacant lot greening was associated with residents’ reporting less stress and more exercise in select sections of the city (P < 0.01). Once greened, vacant lots may reduce certain crimes and promote some aspects of health. Limitations of the current study are discussed. Community-based trials are warranted to further test these findings.
PMCID: PMC3224254  PMID: 22079788
city planning; crime; geography; urban health; urban renewal; wounds and injuries
Lymph node status is an important predictor of survival in pancreatic cancer. We performed a secondary analysis of RTOG 9704, an adjuvant chemotherapy and chemoradiation trial, to determine the influence of lymph node factors-number of positive nodes (NPN), total nodes examined (TNE), and lymph node ratio (LNR-ratio of NPN to TNE)-on OS and disease-free survival (DFS).
Patient and Methods
Eligible patients from RTOG 9704 form the basis of this secondary analysis of lymph node parameters. Actuarial estimates for OS and DFS were calculated using Kaplan-Meier methods. Cox proportional hazards models were performed to evaluate associations of NPN, TNE, and LNR with OS and DFS. Multivariate Cox proportional hazards models were also performed.
There were 538 patients enrolled in the RTOG 9704 trial. Of these, 445 patients were eligible with lymph nodes removed. Overall median NPN was 1 (min-max, 0-18). Increased NPN was associated with worse OS (HR=1.06, p=0.001) and DFS (HR=1.05, p=0.01). In multivariate analyses, both NPN and TNE were associated with OS and DFS. TNE > 12, and >15, were associated with increased OS for all patients, but not for node-negative patients (n =142). Increased LNR was associated with worse OS (HR=1.01, p<0.0001) and DFS (HR=1.006, p=0.002).
In patients who undergo surgical resection followed by adjuvant chemoradiation, TNE, NPN, and LNR are associated with OS and DFS. This secondary analysis of a prospective, cooperative group trial supports the influence of these lymph node parameters on outcomes after surgery and adjuvant therapy using contemporary techniques.
PMCID: PMC3038247  PMID: 20934270
lymph node; nodal ratio; pancreatic cancer; radiation therapy; pancreaticoduodenectomy
Neurobiology of aging  2005;27(11):1613-1617.
The goal of the present study was to determine if there are global or regionally specific decreases in callosal area in early Alzheimer’s disease (AD) and mild cognitive impairment (MCI). In addition, this study examined the corpus callosum of healthy older adults who have subjective cognitive complaints (CC) but perform within normal limits on neuropsychological tests. We used a semi-automated procedure to examine the total and regional areas of the corpus callosum in 22 patients with early AD, 28 patients with amnestic MCI, 28 healthy older adults with cognitive complaints, and 50 demographically matched healthy controls (HC). The AD, MCI, and CC groups all showed a significant reduction of the posterior region (isthmus and splenium) relative to healthy controls. The AD group also had a significantly smaller overall callosum than the controls. The demonstration of callosal atrophy in older adults with cognitive complaints suggests that callosal changes occur very early in the dementing process, and that these earliest changes may be too subtle for detection by neuropsychological assessments, including memory tests.
PMCID: PMC3482483  PMID: 16271806
Alzheimer’s disease; Mild cognitive impairment; Cognitive complaints; Corpus callosum; Magnetic resonance imaging
Molecular Brain  2012;5:11.
Glutathione (GSH) plays an important role in neuronal oxidant defence. Depletion of cellular GSH is observed in neurodegenerative diseases and thereby contributes to the associated oxidative stress and Ca2+ dysregulation. Whether depletion of cellular GSH, associated with neuronal senescence, directly influences Ca2+ permeation pathways is not known. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+ permeable non-selective cation channel expressed in several cell types including hippocampal pyramidal neurons. Moreover, activation of TRPM2 during oxidative stress has been linked to cell death. Importantly, GSH has been reported to inhibit TRPM2 channels, suggesting they may directly contribute to Ca2+ dysregulation associated with neuronal senescence. Herein, we explore the relation between cellular GSH and TRPM2 channel activity in long-term cultures of hippocampal neurons.
In whole-cell voltage-clamp recordings, we observe that TRPM2 current density increases in cultured pyramidal neurons over time in vitro. The observed increase in current density was prevented by treatment with NAC, a precursor to GSH synthesis. Conversely, treatment of cultures maintained for 2 weeks in vitro with L-BSO, which depletes GSH by inhibiting its synthesis, augments TRPM2 currents. Additionally, we demonstrate that GSH inhibits TRPM2 currents through a thiol-independent mechanism, and produces a 3.5-fold shift in the dose-response curve generated by ADPR, the intracellular agonist for TRPM2.
These results indicate that GSH plays a physiologically relevant role in the regulation of TRPM2 currents in hippocampal pyramidal neurons. This interaction may play an important role in aging and neurological diseases associated with depletion of GSH.
PMCID: PMC3352021  PMID: 22487454
TRPM2; Aging; Glutathione; Oxidative stress; Pyramidal neuron; Primary hippocampal culture
Neural Regeneration Research  2012;7(10):772-777.
As the major division of the basal ganglia, neostriatum forms mutual connections with multiple brain areas and is critically involved in motor control and learning/memory. Long-term synaptic plasticity has been widely studied in different species recently. However, there are rare reports about the short-term synaptic plasticity in neostratium. In the present study, using field excitatory postsynaptic potentials recording, we reported one form of short-term synaptic plasticity that is paired pulse depression in juvenile rat dorsal striatum slices induced by stimuli of the white matter. The field excitatory postsynaptic potentials could be abolished by α-amino-3-hydroxy-5-methylizoxazole-4-propionic acid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, but not by gamma-aminobutyric acid type A receptor antagonist bicuculline or dopamine D1 receptor antagonist SKF-81297. The paired pulse depression in the corticostratial pathway was different from paired pulse facilitation in the hippocampal CA1 synapse. In addition, the paired pulse depression was not affected by bath application of gamma-aminobutyric acid type A receptor antagonist or dopamine D1 receptor antagonist. However, low calcium and high magnesium could attenuate the paired pulse depression. These findings suggest a more complicated plasticity form in the dorsal striatum of juvenile rats that is different from that in the hippocampus, which is related with extracellular calcium.
PMCID: PMC4345660  PMID: 25737701
paired pulses depression; dorsal striatum; calcium; juvenile rats
Molecular Brain  2011;4:44.
Transient receptor potential melastatin 2 (TRPM2) is a calcium permeable non-selective cation channel that functions as a sensor of cellular redox status. Highly expressed within the CNS, we have previously demonstrated the functional expression of these channels in CA1 pyramidal neurons of the hippocampus. Although implicated in oxidative stress-induced neuronal cell death, and potentially in neurodegenerative disease, the physiological role of TRPM2 in the central nervous system is unknown. Interestingly, we have shown that the activation of these channels may be sensitized by co-incident NMDA receptor activation, suggesting a potential contribution of TRPM2 to synaptic transmission. Using hippocampal cultures and slices from TRPM2 null mice we demonstrate that the loss of these channels selectively impairs NMDAR-dependent long-term depression (LTD) while sparing long-term potentiation. Impaired LTD resulted from an inhibition of GSK-3β, through increased phosphorylation, and a reduction in the expression of PSD95 and AMPARs. Notably, LTD could be rescued in TRPM2 null mice by recruitment of GSK-3β signaling following dopamine D2 receptor stimulation. We propose that TRPM2 channels play a key role in hippocampal synaptic plasticity.
PMCID: PMC3298512  PMID: 22188973
TRPM2; GSK-3β; PSD-95; Long term depression; Metaplasticity; NMDA Receptors; AMPA Receptors
Futhan is a serine protease inhibitor and medicine in the treatment of disseminated intravascular coagulation (DIC) and acute pancreatitis. It is metabolized quickly in vivo. Here we show that Futhan reversibly inhibits NMDA receptors in hippocampal neurons and GABAA receptors both in hippocampal neurons and in A549 cells, a human alveolar epithelial cell line. The effect of Futhan on GABAA receptors in A549 cells is much more potent than its effect on GABAA receptors in hippocampal neurons (IC50: 0.9 μM V.S. 7.3 μM). Since GABAA receptors are also expressed in various non-neuronal tissues, particularly in airway epithelia and GABA promotes mucus production during asthma, our findings indicate that Futhan may be developed as a novel aerosolized therapeutic to treat asthma through blocking GABAA receptors in the lung.
PMCID: PMC3230258  PMID: 22162781
Asthma; GABAA receptors; NMDA receptors; Futhan; ion channels
The built environment can constrain or facilitate physical activity. Most studies of the health consequences of the built environment suffer from problems of selection bias associated with confounding effects of residential choice and transportation decisions.
To examine the cross-sectional associations between objective and perceived measures of the built environment, BMI, obesity (BMI>30 kg/m2), and meeting weekly recommended physical activity (RPA) levels through walking and vigorous exercise. To assess effect of using light rail transit system (LRT) on changes in BMI, obesity, and meeting weekly RPA levels.
Data were collected on individuals before (July 2006–February of 2007) and after (March 2008–July 2008) completion of a light rail system in Charlotte, NC. BMI, obesity, and physical activity levels were calculated for a comparison of these factors pre- and post-LRT construction. A propensity score weighting approach adjusted for differences in baseline characteristics among LRT and non-LRT users. Data were analyzed in 2009.
More positive perceptions of one’s neighborhood at baseline were associated with a −0.36 (p<.05) lower BMI, 15% lower odds (95% CI=0.77, 0.94) of obesity, 9% higher odds (95% CI = 0.99, 1.20) of meeting weekly RPA through walking, and 11% higher odds (95% CI= 1.01, 1.22) of meeting RPA levels of vigorous exercise. The use of light rail transit to commute to work was associated with an average −1.18 reduction in BMI (p<0.05) and an 81% reduced odds (95% CI= 0.04, 0.92) of becoming obese over time.
The results of this study suggest that improving neighborhood environments and increasing the public’s use of LRT systems could provide improvements in health outcomes for millions of individuals.
PMCID: PMC2919301  PMID: 20621257
PLoS ONE  2011;6(7):e21970.
Together, acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) constitute the majority of voltage-independent sodium channels in mammals. ENaC is regulated by a chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show that ASICs were reversibly inhibited by activation of GABAA receptors in murine hippocampal neurons. This inhibition of ASICs required opening of the chloride channels but occurred with both outward and inward GABAA receptor-mediated currents. Moreover, activation of the GABAA receptors modified the pharmacological features and kinetic properties of the ASIC currents, including the time course of activation, desensitization and deactivation. Modification of ASICs by open GABAA receptors was also observed in both nucleated patches and outside-out patches excised from hippocampal neurons. Interestingly, ASICs and GABAA receptors interacted to regulate synaptic plasticity in CA1 hippocampal slices. The activation of glycine receptors, which are similar to GABAA receptors, also modified ASICs in spinal neurons. We conclude that GABAA receptors and glycine receptors modify ASICs in neurons through mechanisms that require the opening of chloride channels.
PMCID: PMC3138761  PMID: 21789198
The primary objective of this trial was to evaluate the response rate for trimetrexate (TMTX) in conjunction with 5FU and leucovorin (LV) (=TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting.
Patients with locally advanced, unresectable, or metastatic adenocarcinoma of the stomach received TMTX 110 mg/m2 IV over 60 minutes day 1, followed by 5-FU 500 mg/m2 IV bolus and LV 200 mg/m2 IV over 60 minutes day 2, followed by oral LV 15 mg every 6 hours × 7 doses, all weekly for 6 weeks followed by 2 weeks of rest, continued until progression.
Characteristics for 37 eligible patients: median age 63 (range 23 to 83); male/female: 69%/31%; performance status 0/1/2 15/20/1. The confirmed response rate was 19%, and median overall survival was 6 months. Two patients died as a result of therapy, one due to infection without significant neutropenia, and one due to perforation of a responding gastric lesion. 72% experienced Grades 3 and 4 toxicity, most commonly diarrhea, fatigue, and lymphopenia.
This regimen achieves response rates comparable to other 5FU-based regimens, when used in treatment of incurable gastric cancer. Toxicity appears manageable.
PMCID: PMC2967385  PMID: 19770625
trimetrexate; chemotherapy; gastric neoplasms

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