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1.  The Epilepsy Phenome/Genome Project (EPGP) informatics platform 
The Epilepsy Phenome/Genome Project (EPGP) is a large-scale, multi-institutional, collaborative network of 27 epilepsy centers throughout the U.S., Australia, and Argentina, with the objective of collecting detailed phenotypic and genetic data on a large number of epilepsy participants. The goals of EPGP are (1) to perform detailed phenotyping on 3750 participants with specific forms of non-acquired epilepsy and 1500 parents without epilepsy, (2) to obtain DNA samples on these individuals, and (3) to ultimately genotype the samples in order to discover novel genes that cause epilepsy. To carry out the project, a reliable and robust informatics platform was needed for standardized electronic data collection and storage, data quality review, and phenotypic analysis involving cases from multiple sites.
EPGP developed its own suite of web-based informatics applications for participant tracking, electronic data collection (using electronic case report forms/surveys), data management, phenotypic data review and validation, specimen tracking, electroencephalograph and neuroimaging storage, and issue tracking. We implemented procedures to train and support end-users at each clinical site.
Thus far, 3780 study participants have been enrolled and 20,957 web-based study activities have been completed using this informatics platform. Over 95% of respondents to an end-user satisfaction survey felt that the informatics platform was successful almost always or most of the time.
The EPGP informatics platform has successfully and effectively allowed study management and efficient and reliable collection of phenotypic data. Our novel informatics platform met the requirements of a large, multicenter research project. The platform has had a high level of end-user acceptance by principal investigators and study coordinators, and can serve as a model for new tools to support future large scale, collaborative research projects collecting extensive phenotypic data.
PMCID: PMC3655424  PMID: 22579394
EPGP; Informatics; Epilepsy; Research; Internet; Electronic data collection; Phenotyping
2.  Molecular programming of B cell memory 
Nature reviews. Immunology  2011;12(1):24-34.
The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information — resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes — has reshaped the conceptual landscape surrounding the generation of memory B cells. In this Review, we integrate this new information about each phase of antigen-specific B cell development to describe the newly unravelled molecular dynamics of memory B cell programming.
PMCID: PMC3947622  PMID: 22158414
3.  (±)3,4-Methylenedioxymethamphetamine (“Ecstasy”) Treatment Modulates Expression of Neurotrophins and Their Receptors in Multiple Regions of Adult Rat Brain 
The Journal of comparative neurology  2012;520(11):2459-2474.
(±)3,4-Methylenedioxymethamphetamine (MDMA), a widely used drug of abuse, rapidly reduces serotonin levels in the brain when ingested or administered in sufficient quantities, resulting in deficits in complex route-based learning, spatial learning, and reference memory. Neurotrophins are important for survival and preservation of neurons in the adult brain, including serotonergic neurons. In this study, we examined the effects of MDMA on the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their respective high-affinity receptors, tropomyosin receptor kinase (trk)B and trkC, in multiple regions of the rat brain. A serotonergic-depleting dose of MDMA (10 mg/kg × 4 at 2-hour intervals on a single day) was administered to adult Sprague-Dawley rats, and brains were examined 1, 7, or 24 hours after the last dose. Messenger RNA levels of BDNF, NT-3, trkB, and trkC were analyzed by using in situ hybridization with cRNA probes. The prefrontal cortex was particularly vulnerable to MDMA-induced alterations in that BDNF, NT-3, trkB, and trkC mRNAs were all upregulated at multiple time points. MDMA-treated animals had increased BDNF expression in the frontal, parietal, piriform, and entorhinal cortices, increased NT-3 expression in the anterior cingulate cortex, and elevated trkC in the entorhinal cortex. In the nigrostriatal system, BDNF expression was upregulated in the substantia nigra pars compacta, and trkB was elevated in the striatum in MDMA-treated animals. Both neurotrophins and trkB were differentially regulated in several regions of the hippocampal formation. These findings suggest a possible role for neurotrophin signaling in the learning and memory deficits seen following MDMA treatment.
PMCID: PMC3891916  PMID: 22237931
BDNF; NT-3; trkB; trkC; MDMA; corticosterone
4.  Neurobehavioral phenotype of C57BL/6J mice prenatally and neonatally exposed to cigarette smoke 
Although maternal cigarette smoking during pregnancy is a well-documented risk factor for a variety of adverse pregnancy outcomes, how prenatal cigarette smoke exposure affects postnatal neurobehavioral/cognitive development remains poorly defined. In order to investigate the cause of an altered behavioral phenotype, mice developmentally exposed to a paradigm of ‘active’ maternal cigarette smoke is needed. Accordingly, cigarette smoke exposed (CSE) and air-exposed C57BL/6J mice were treated for 6 h per day in paired inhalation chambers throughout gestation and lactation and were tested for neurobehavioral effects while controlling for litter effects. CSE mice exhibited less than normal anxiety in the elevated zero maze, transient hypoactivity during a 1 h locomotor activity test, had longer latencies on the last day of cued Morris water maze testing, impaired hidden platform learning in the Morris water maze during acquisition, reversal, and shift trials, and impaired retention for platform location on probe trials after reversal but not after acquisition or shift. CSE mice also showed a sexually dimorphic response in central zone locomotion to a methamphetamine challenge (males under-responded and females over-responded), and showed reduced anxiety in the light-dark test by spending more time on the light side. No differences on tests of marble burying, acoustic startle response with prepulse inhibition, Cincinnati water maze, matching-to-sample Morris water maze, conditioned fear, forced swim, or MK-801-induced locomotor activation were found. Collectively, the data indicate that developmental cigarette smoke exposure induces subnormal anxiety in a novel environment, impairs spatial learning and reference memory while sparing other behaviors (route-based learning, fear conditioning, and forced swim immobility). The findings add support to mounting evidence that developmental cigarette smoke exposure has long-term adverse effects on brain function.
PMCID: PMC3593942  PMID: 23314114
behavior; cigarette smoke; tobacco; inhalation exposure; pregnancy; prenatal
5.  Hormone therapy and Alzheimer disease dementia 
Neurology  2012;79(18):1846-1852.
Observational studies suggest reduced risk of Alzheimer disease (AD) in users of hormone therapy (HT), but trials show higher risk. We examined whether the association of HT with AD varies with timing or type of HT use.
Between 1995 and 2006, the population-based Cache County Study followed 1,768 women who had provided a detailed history on age at menopause and use of HT. During this interval, 176 women developed incident AD. Cox proportional hazard models evaluated the association of HT use with AD, overall and in relation to timing, duration of use, and type (opposed vs unopposed) of HT.
Women who used any type of HT within 5 years of menopause had 30% less risk of AD (95% confidence interval 0.49–0.99), especially if use was for 10 or more years. By contrast, AD risk was not reduced among those who had initiated HT 5 or more years after menopause. Instead, rates were increased among those who began “opposed” estrogen-progestin compounds within the 3 years preceding the Cache County Study baseline (adjusted hazard ratio 1.93; 95% confidence interval 0.94–3.96). This last hazard ratio was similar to the ratio of 2.05 reported in randomized trial participants assigned to opposed HT.
Association of HT use and risk of AD may depend on timing of use. Although possibly beneficial if taken during a critical window near menopause, HT (especially opposed compounds) initiated in later life may be associated with increased risk. The relation of AD risk to timing and type of HT deserves further study.
PMCID: PMC3525314  PMID: 23100399
6.  Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to Poly IC 
Synapse (New York, N.y.)  2012;66(8):725-737.
Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero-maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, acoustic startle, or latent inhibition deficits reported in Poly IC-treated rats, but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction).
PMCID: PMC3370146  PMID: 22473973
Polyinosinic-polycytidylic acid; Poly IC; (+)-amphetamine-induced locomotor activity; prenatal immune activation; MK-801-induced locomotor activity; Morris water maze; Cincinnati water maze; rat; elevated zero-maze; marble burying; light-dark test; conditioned fear; latent inhibition; autism spectrum disorder
7.  Wernicke's Encephalopathy: An Unusual Consequence of the Acquired Immune Deficiency Syndrome—Case Report and Literature Review 
Case Reports in Medicine  2013;2013:709474.
Introduction. Wernicke's encephalopathy is a well-described syndrome characterized by the classic triad of confusion, ataxia, and ophthalmoplegia. Wernicke's encephalopathy results from thiamine (vitamin B1) deficiency. Common causes include alcoholism and gastric disorders. Wernicke's has been described in patients with acquired immune deficiency syndrome (AIDS); however, given these patients' immunosuppressed state, the diagnosis of Wernicke's encephalopathy is not apparent. Case Presentation. A 31-year-old previously healthy male presented to the ER complaining of progressive dyspnea. Workup revealed HIV/AIDS and PCP pneumonia. He was treated and improved. On day 14 he became confused and developed nystagmus and ataxia. Considering his immunocompromised state, infectious and neoplastic etiologies topped the differential diagnosis. CT head was negative. Lumbar puncture was unremarkable. Brain MRI revealed increased T2 signal in the medial thalamus bilaterally. Intravenous thiamine was administered resulting in resolution of symptoms. Discussion. The classic triad of Wernicke's encephalopathy occurs in 10% of cases. When immunosuppressed patients develop acute neurologic symptoms infectious or neoplastic etiologies must be excluded. However, given the relative safety of thiamine supplementation, there should be a low threshold for initiating therapy in order to reverse the symptoms and prevent progression to Korsakoff dementia, which is permanent.
PMCID: PMC3722985  PMID: 23935638
8.  Effects of Community-Based Cardiac Rehabilitation on Body Composition and Physical Function in Individuals with Stable Coronary Artery Disease: 1.6-Year Followup 
BioMed Research International  2013;2013:903604.
Objective. To examine long-term changes in physical function and body composition in coronary artery disease (CAD) patients participating in ongoing community-based cardiac rehabilitation (CR). Design. Thirty-four individuals (69.7 ± 8.2 years; 79% men) participated in this longitudinal observational study. Baseline and follow-up assessments included incremental shuttle walk, short physical performance battery, handgrip strength, chair stands, body composition, last year physical activity, and CR attendance. Results. Participants attended 38.5 ± 30.3% sessions during 1.6 ± 0.2 year followup. A significant increase in 30-second chair stands (17.0 ± 4.7 to 19.6 ± 6.4, P < 0.001), body weight (75.8 ± 11.1 to 77.2 ± 12.1 kg, P = 0.001), and body fat (27.0 ± 9.5 to 29.1 ± 9.6%, P < 0.001) and a decline in handgrip strength (36.4 ± 9.4 to 33.0 ± 10.6 kg·f, P < 0.001) and muscle mass (40.8 ± 5.6 to 39.3 ± 5.8%, P < 0.001) were observed during followup. There was no significant change in shuttle walk duration. CR attendance was not correlated to observed changes. Conclusions. Elderly CAD patients participating in a maintenance CR program improve lower-body muscle strength but experience a decline in handgrip strength and unfavourable changes in body composition, irrespective of CR attendance.
PMCID: PMC3707214  PMID: 23865071
9.  Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo(−/−) knockout mice 
Genes, brain, and behavior  2012;11(3):10.1111/j.1601-183X.2011.00762.x.
Organisms using oxygen for aerobic respiration require antioxidants to balance the production of reaction oxygen species during metabolic processes. Various species — including humans and other primates—suffer mutations in the GULO gene encoding L-gulono-γ-lactone oxidase; GULO is the rate-limiting enzyme in the biosynthesis of ascorbate, an important cellular antioxidant. Animals lacking the ability to synthesize vitamin C develop scurvy without dietary supplementation. The Gulo(−/−) knockout mouse requires oral supplemental vitamin C; without this supplementation the animal dies with a scorbutic condition within several weeks. Vitamin C is known to be most abundant in the brain, where it is believed to play important roles in neuroprotection, neurotransmission, and neuromodulation. We therefore hypothesized that ascorbate deficiency in Gulo(−/−) knockout mice might lead to an abnormal behavioral phenotype. We established the amount of ascorbate in the drinking water (220 ppm) necessary for generating a chronic low-ascorbate status in the brain, yet clinically the mice appeared healthy throughout 100 days postpartum at which time all behavioral-phenotyping tests were completed. Compared with Gulo(+/+) wild-type littermates, ascorbate-deficient Gulo(−/−) mice were found to be less active in moving in their environment; when in water, these mice swam more slowly in some tests, consistent with a mild motor deficit. We found no evidence of cognitive, anxiety, or sensorimotor-gating problems. Despite being less active, Gulo(−/−) mice exhibited exaggerated hyperactivity to the dopaminergic agonist methamphetamine. The subnormal movement, combined with hypersensitivity to a dopamine agonist, point to developmental ascorbate deficiency causing long-term striatal dysfunction.
PMCID: PMC3325330  PMID: 22296218
acoustic startle response; ascorbic acid; elevated zero maze; L-gulono-γ-lactone oxidase; locomotor activity; methamphetamine challenge; Morris water maze; novel object recognition; oxidative stress in brain; vitamin C
10.  Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm(−/−) knockout mice 
Neurotoxicology and Teratology  2012;34(4):450-457.
Enhanced oxidative stress or deficient oxidative stress response in the brain is associated with neurodegenerative disorders and behavioral abnormalities. Previously we generated a knockout mouse line lacking the gene encoding γ-glutamylcysteine ligase modifier subunit (GCLM). Gclm(−/−) knockout (KO) mice are viable and fertile, yet exhibit only 9–35% of wild-type levels of reduced glutathione (GSH) in tissues, making them a useful model for chronic GSH depletion. Having the global absence of this gene, KO mice—from the time of conception and throughout postnatal life—experience chronic oxidative stress in all tissues, including brain. Between postnatal day (P) 60 and P100, we carried out behavioral phenotyping tests in adults, comparing male and female Gclm(−/−) with Gclm(+/+) wild-type (WT) littermates. Compared with WT, KO mice exhibited: subnormal anxiety in the elevated zero maze; normal overall exploratory open-field activity, but slightly more activity in the peripheral zones; normal acoustic startle and prepulse inhibition reactions; normal novel object recognition with increased time attending to the stimulus objects; slightly reduced latencies to reach a random marked platform in the Morris water maze; normal spatial learning and memory in multiple phases of the Morris water maze; and significantly greater hyperactivity in response to methamphetamine in the open field. These findings are in general agreement with two prior studies on these mice and suggest that the brain is remarkably resilient to lowered GSH levels, implying significant reserve capacity to regulate reactivity oxygen species—but with regional differences such that anxiety and stimulated locomotor control brain regions might be more vulnerable.
PMCID: PMC3404268  PMID: 22580179
acoustic startle response; elevated zero maze; GSH; reduced glutathione; locomotor activity; Morris water maze; novel object recognition
11.  Influence of comorbidities in idiopathic normal pressure hydrocephalus — research and clinical care. A report of the ISHCSF task force on comorbidities in INPH 
Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of ventriculomegaly, gait impairment, cognitive decline and incontinence that occurs in an elderly population prone to many types of comorbidities. Identification of the comorbidities is thus an important part of the clinical management of INPH patients. In 2011, a task force was appointed by the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders (ISHCSF) with the objective to compile an evidence-based expert analysis of what we know and what we need to know regarding comorbidities in INPH. This article is the final report of the task force. The expert panel conducted a comprehensive review of the literature. After weighing the evidence, the various proposals were discussed and the final document was approved by all the task force members and represents a consensus of expert opinions. Recommendations regarding the following topics are given: I. Musculoskeletal conditions; II. Urinary problems; III. Vascular disease including risk factors, Binswanger disease, and white matter hyperintensities; IV. Mild cognitive impairment and Alzheimer disease including biopsies; V. Other dementias (frontotemporal dementia, Lewy body, Parkinson); VI. Psychiatric and behavioral disorders; VII. Brain imaging; VIII. How to investigate and quantify. The task force concluded that comorbidity can be an important predictor of prognosis and post-operative outcome in INPH. Reported differences in outcomes among various INPH cohorts may be partly explained by variation in the rate and types of comorbidities at different hydrocephalus centers. Identification of comorbidities should thus be a central part of the clinical management of INPH where a detailed history, physical examination, and targeted investigations are the basis for diagnosis and grading. Future INPH research should focus on the contribution of comorbidity to overall morbidity, mortality and long-term outcomes.
PMCID: PMC3689166  PMID: 23758953
Hydrocephalus; Normal pressure; Comorbidity; Review; Guidelines; Task force
12.  Retracted manuscript 
Small GTPases  2013;4(2):61.
The following article from Small GTPases, “Scientific Yellow Journalism” by Anica Klockars and Michael J. Williams, published online on 20 September 2012  (doi: 10.4161/sgtp.22289; by Landes Bioscience and subsequently published in print in Small GTPases 2012 3(4):201 has been retracted by agreement between the authors and the journal’s Editor in Chief, Michael J. Williams (also an author of the paper). 
PMCID: PMC3747257  PMID: 23485921
Biochemical pharmacology  1991;41(10):1399-1410.
A recent conference entitled Purines in Cell Signalling: Targets for New Drugs, held in Rockville, Maryland, in September, 1989, was one indication of the increasing interest in developing agonists and antagonists of P1-(adenosine) and P2-(ATP) purinoceptors [1] as potential therapeutic agents. Extracellular adenosine, acting at its membrane bound A1 and A2 receptors, is a ubiquitous modulator of cellular activity. The purine can arise from several sources including ATP hydrolysis by ectokinase activity in the region of the nerve terminal [2] and from S-adenosylhomocysteine [3] and ATP within the cell. Together with its more stable analogs, adenosine is a potent inhibitor of neurotransmitter release in both the central and peripheral nervous systems, and in cardiac, adipose and other tissues. Adenosine can also affect blood pressure and heart rate as well as modulate the function of the immune, inflammatory, gastrointestinal, renal and pulmonary systems, either via its effects on transmitter release or directly via receptor mechanisms altering intracellular transduction processes.
PMCID: PMC3561777  PMID: 2018549
14.  Neonatal citalopram treatment inhibits the 5-HT depleting effects of MDMA exposure in rats 
ACS chemical neuroscience  2011;3(1):12-21.
Neonatal exposure to 3,4-methylenedioxymethamphetamine (MDMA) produces long-term learning and memory deficits and increased anxiety-like behavior. The mechanism underlying these behavioral changes is unknown but we hypothesized that it involves perturbations to the serotonergic system as this is the principle mode of action of MDMA in the adult brain. During development 5-HT is a neurotrophic factor involved in neurogenesis, synaptogenesis, migration, and target region specification. We have previously showed that MDMA exposure (4×10 mg/kg/day) from P11-20 (analogous to human third trimester exposure) induces ~50% decreases in hippocampal 5-HT throughout treatment. To determine whether MDMA-induced 5-HT changes are determinative, we tested if these changes could be prevented by treatment with a selective serotonin reuptake inhibitor (citalopram: CIT). In a series of experiments we evaluated the effects of different doses and dose regimens of CIT on MDMA-induced 5-HT depletions in three brain regions (hippocampus, entorhinal cortex, and neostriatum) at three time-points (P12, P16, P21) during the treatment interval (P11-20) known to induce behavioral alterations when animals are tested as adults. We found that 5 mg/kg CIT administered twice daily significantly attenuated MDMA-induced 5-HT depletions in all three regions at all three ages but that the protection was not complete at all ages. Striatal dopamine was unaffected. We also found increases in hippocampal NGF and plasma corticosterone following MDMA treatment on P16 and P21, respectively. No changes in BDNF were observed. CIT treatment may be a useful means of interfering with MDMA-induced 5-HT reductions and thus permit tests of the hypothesis that the drug’s cognitive and/or anxiety effects are mediated through early disruptions to 5-HT dependent developmental processes.
PMCID: PMC3347712  PMID: 22582138
serotonin; dopamine; development; ecstasy; corticosterone; citalopram
15.  Neonatal Citalopram Treatment Inhibits the 5-HT Depleting Effects of MDMA Exposure in Rats 
ACS Chemical Neuroscience  2011;3(1):12-21.
Neonatal exposure to 3,4-methylenedioxymethamphetamine (MDMA) produces long-term learning and memory deficits and increased anxiety-like behavior. The mechanism underlying these behavioral changes is unknown, but we hypothesized that it involves perturbations to the serotonergic system as this is the principal mode of action of MDMA in the adult brain. During development, 5-HT is a neurotrophic factor involved in neurogenesis, synaptogenesis, migration, and target region specification. We have previously shown that MDMA exposure (4 × 10 mg/kg/day) from postnatal day (P)11–20 (analogous to human third trimester exposure) induces ∼50% decreases in hippocampal 5-HT throughout treatment. To determine whether MDMA-induced 5-HT changes are determinative, we tested if these changes could be prevented by treatment with a selective serotonin reuptake inhibitor (citalopram: CIT). In a series of experiments, we evaluated the effects of different doses and dose regimens of CIT on MDMA-induced 5-HT depletions in three brain regions (hippocampus, entorhinal cortex, and neostriatum) at three time points (P12, P16, P21) during the treatment interval (P11–20) known to induce behavioral alterations when animals are tested as adults. We found that 5 mg/kg CIT administered twice daily significantly attenuated MDMA-induced 5-HT depletions in all three regions at all three ages but that the protection was not complete at all ages. Striatal dopamine was unaffected. We also found increases in hippocampal NGF and plasma corticosterone following MDMA treatment on P16 and P21, respectively. No changes in BDNF were observed. CIT treatment may be a useful means of interfering with MDMA-induced 5-HT reductions and thus permit tests of the hypothesis that the drug’s cognitive and/or anxiety effects are mediated through early disruptions to 5-HT dependent developmental processes.
PMCID: PMC3347712  PMID: 22582138
Serotonin; dopamine; development; ecstasy; corticosterone; citalopram
16.  Cellular mechanisms and behavioral consequences of Kv1.2 regulation in the rat cerebellum 
The Journal of Neuroscience  2012;32(27):9228-9237.
The potassium channel Kv1.2 alpha-subunit is expressed in cerebellar Purkinje cell (PC) dendrites where its pharmacological inhibition increases excitability (Khavandgar et al., 2005). Kv1.2 is also expressed in cerebellar basket cell (BC) axon terminals (Sheng et al., 1994), where its blockade increases BC inhibition of PCs (Southan and Robertson, 1998a). Secretin receptors are also expressed both in PC dendrites and BC axon terminals (reviewed in (Yuan et al.). The effect of secretin on PC excitability is not yet known, but, like Kv1.2 inhibitors, secretin potently increases inhibitory input to PCs (Yung et al., 2001). This suggests secretin may act in part by suppressing Kv1.2. Receptor-mediated endocytosis is a mechanism of Kv1.2 suppression (Nesti et al., 2004). This process can be regulated by protein kinase A (PKA) (Connors et al., 2008). Since secretin receptors activate PKA (Wessels-Reiker et al., 1993), we tested the hypothesis that secretin regulates Kv1.2 trafficking in the cerebellum. Using cell surface protein biotinylation of rat cerebellar slices, we found secretin decreased cell-surface Kv1.2 levels by modulating Kv1.2 endocytic trafficking. This effect was mimicked by activating adenylate cyclase (AC) with forskolin, and was blocked by pharmacological inhibitors of AC or PKA. Imaging studies identified the BC axon terminal and Purkinje cell dendrites as loci of AC-dependent Kv1.2 trafficking. The physiological significance of secretin regulated Kv1.2 endocytosis is supported by our finding that infusion into the cerebellar cortex of either the Kv1.2 inhibitor Tityustoxin-Kα, or of the Kv1.2 regulator secretin, significantly enhances acquisition of eyeblink conditioning in rats.
PMCID: PMC3400112  PMID: 22764231
17.  Effects of neonatal methamphetamine treatment on adult stress-induced corticosterone release in rats 
Neurotoxicology and Teratology  2011;34(1):136-142.
In rats neonatal (+)-methamphetamine (MA) exposure and maternal separation stress increase corticosterone during treatment and result in learning and memory impairments later in life. Early-life stress also changes later responses to acute stress. We tested the hypothesis that neonatal MA exposure would alter adult corticosterone after acute stress or MA challenge. Rats were treated with MA (10 mg/kg × 4/day), saline, or handling on postnatal (P) days 11–15 or 11–20 (days that lead to learning and memory impairments at this dose). As adults, corticosterone was measured before and after 15 min forced swim (FS) or 15 min forced confinement (FC), counterbalanced, and after an acute MA challenge (10 mg/kg) given last. FS increased corticosterone more than FC; order and stress type interacted but did not interact with treatment; treatment interacted with FS but not with FC. In the P11–15 regimen, MA-treated rats showed more rapid increases in corticosterone after FS than controls. In the P11–20 regimen, MA-treated rats showed a trend toward more rapid decrease in corticosterone after FS. No differences were found after MA challenge. The data do not support the hypothesis that neonatal MA causes changes in adult stress responsiveness to FS, FC, or an acute MA challenge.
PMCID: PMC3268879  PMID: 21856413
Methamphetamine; neonatal methamphetamine; stress; forced swim; corticosterone; forced confinement
18.  Differential Transcriptional Programming of Class-Specific B Cell Memory by T-bet and RORα 
Nature immunology  2012;13(6):604-611.
Antibody class defines function in B cell immunity, but how class is propagated into B cell memory remains poorly understood. Here, we demonstrate that memory B cell subsets unexpectedly diverge across antibody class through the differential impact of major transcriptional regulators. Conditional genetic deletion of Tbx21 selectively blocks the formation and antigen-specific response of IgG2a memory B cells in vivo. Cell intrinsic T-bet expression regulates STAT1 expression, steady-state cell survival and IgG2a BCR transcription. In contrast, RORα was differentially expressed in IgA memory B cells with siRNA knockdown and chemical inhibition supporting its selective control in cell survival and IgA BCR transcription. Thus, divergent transcriptional regulators dynamically maintain subset integrity to promote specialized immune function within class-specific memory B cells.
PMCID: PMC3362691  PMID: 22561605
19.  Synthesis, Photophysical, Electrochemical, Tumor-Imaging and Phototherapeutic Properties of Purpurinimide-N-substituted Cyanine Dyes Joined with Variable Length of Linkers 
Bioconjugate chemistry  2011;22(11):2283-2295.
Purpurinimide methyl esters, bearing variable lengths of N-substitutions, were conjugated individually to a cyanine dye with a carboxylic acid functionality. The results obtained from in vitro and in vivo studies showed a significant impact of the linkers joining the phototherapeutic and fluorescence imaging moieties. The photosensitizer-fluorophore conjugate with a PEG linker showed the highest uptake in the liver, whereas the conjugate linked with two carbon units showed excellent tumor-imaging and PDT efficacy at 24 h postinjection. Whole body imaging and biodistribution studies at variable time points portrayed enhanced fluorescent uptake of the conjugates in the tumor compared to the skin. Interestingly the conjugate with the shortest linker and the one joining with two carbon units showed faster clearance from normal organs e. g., liver, kidney, spleen, lung compared to tumors. Both imaging and PDT efficacy of the conjugates were performed in BALB/c mice bearing Colon26 tumors. Compared to the others, the short linker conjugate showed poor tumor fluorescent properties and as a corollary does not exhibit the dual functionality of the photosensitizer-fluorophore conjugate. For this reason, it was not evaluated for in vivo PDT efficacy. However, in Colon26 tumor cells (in vitro), the short linker was highly effective. Among the conjugates with variable linkers, the rate of energy transfer from the purpurinimide moiety to the cyanine moiety increased with deceasing linker length, as examined by femtosecond laser flash photolysis measurements. No electron transfer from the purpurinimide moiety to the singlet excited state of the cyanine moiety or from the singlet excited state of the cyanine moiety to the purpurinimide moiety occurred as indicated by a comparison of transient absorption spectra with spectra of the one-electron oxidized and one-electron reduced species of the conjugate obtained by spectroelectrochemical measurements.
PMCID: PMC3229926  PMID: 21985310
20.  Low-Dose rt-PA Enhances Clot Resolution in Brain Hemorrhage: The Intraventricular Hemorrhage Thrombolysis Trial 
Background and Purpose
Patients with intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) have a reported mortality of 50–80%. We evaluated a clot lytic treatment strategy for these patients in terms of mortality, ventricular infection, and bleeding safety events and for its effect on the rate of intraventricular clot lysis.
48 Patients were enrolled at 14 centers and randomized to treatment with 3mg recombinant tissue plasminogen activator (rt-PA) or placebo. Demographic characteristics, severity factors, safety outcomes (mortality, infection, bleeding), and clot resolution rates were compared in the two groups.
Severity factors, including admission GCS, ICH volume, IVH volume and blood pressure, were evenly distributed, as were adverse events except for an increased frequency of respiratory system events in the placebo-treated group. Neither ICP nor Cerebral Perfusion pressure (CPP) differed substantially between treatment groups on presentation, with EVD closure, or during the active treatment phase. Frequency of death and ventriculitis was substantially lower than expected and bleeding events remained below the pre-specified threshold: mortality (18%, rt-PA; 23%, placebo); ventriculitis (8%, rt-PA; 9%, placebo); symptomatic bleeding (23%, rt-PA; 5% placebo, which approached statistical significance (p=0.1)). The median duration of dosing was 7.5 days for rt-PA and 12 days for placebo. There was a significant beneficial effect of rt-PA on rate of clot resolution
Low-dose rt-PA for the treatment of ICH with IVH has an acceptable safety profile compared to placebo and prior historical controls. Data from a well-designed Phase III clinical trial, such as CLEAR III, will be needed to fully evaluate this treatment.
Clinical Trial Registration Information
Participant enrollment began prior to July 1, 2005.
PMCID: PMC3356690  PMID: 21868730
intracerebral hemorrhage; intraventricular hemorrhage; tissue plasminogen activator; thrombolysis
22.  Scientific yellow journalism 
Small GTPases  2012;3(4):201.
PMCID: PMC3520881  PMID: 22995950
23.  Neonatal methylphenidate does not impair adult spatial learning in the Morris water maze in rats 
Neuroscience letters  2011;502(3):152-156.
Methylphenidate (MPD) is the most prescribed drug for attention deficit hyperactivity disorder. Licit and illicit use also occurs during pregnancy, however the effects from this use on offspring development is unknown. To model late gestational exposure, Sprague-Dawley litters were treated with 0, 5, 10, 20, or 30 mg/kg × 4/day every 2 h with MPD on postnatal days 11–20 (within-litter design; days chosen to be comparable to human third trimester brain development). During treatment, body weights were decreased in MPD-treated groups; weight recovery occurred in all but the MPD-30 group by start of testing. MPD-treated rats showed no changes in anxiety (elevated zero maze), swimming ability (straight channel swimming), or spatial learning/reference memory (Morris water maze). MPD does not appear to pose a risk to these CNS functions after exposure during a stage of rat development analogous to third trimester human brain development.
PMCID: PMC3167480  PMID: 21798318
Methylphenidate; Morris water maze; spatial learning; reference memory; developmental exposure; elevated zero maze; anxiety; rats
24.  MicroRNAs in Insulin Resistance and Obesity 
Experimental Diabetes Research  2012;2012:484696.
MicroRNAs (miRNAs) are a class of short, single-stranded non-protein coding gene products which can regulate the gene expression through post-transcriptional inhibition of messenger RNA (mRNA) translation. They are known to be involved in many essential biological processes including development, insulin secretion, and adipocyte differentiation. miRNAs are involved in complex metabolic processes, such as energy and lipid metabolism, which have been studied in the context of diabetes and obesity. Obesity, hyperlipidemia (elevated levels of blood lipids), and insulin resistance are strongly associated with the onset of type 2 diabetes. These conditions are also associated with aberrant expression of multiple essential miRNAs in pancreatic islets of Langerhans and peripheral tissues, including adipose tissue. A thorough understanding of the physiological role these miRNAs play in these tissues, and changes to their expression under pathological conditions, will allow researchers to develop new therapeutics with the potential to correct the aberrant expression of miRNAs in type 2 diabetes and obesity.
PMCID: PMC3407629  PMID: 22851965
25.  Hydrodynamics of the Certas™ programmable valve for the treatment of hydrocephalus 
The new Certas™ shunt for the treatment of hydrocephalus has seven standard pressure settings that according to the manufacturer range from 36 to 238 mmH2O, and an additional “Virtual Off” setting with an opening pressure >400 mmH2O. Information on actual pressure response and reliability of shunt performance is important in clinical application, especially the “Virtual Off” setting as a non-surgical replacement for shunt ligation. The objective of this study was to evaluate the in-vitro hydrodynamic performance of the Certas™ shunt.
Six new Certas™ shunts with proximal and distal catheters were tested with an automated, computerized test system that raised the pressure from zero to a maximum pressure and back to zero at each valve setting. Opening pressure and flow resistance were determined.
For settings 1–7 the measured opening pressure range was 26 to 247 mmH2O, and the mean change in opening pressure for a one-step adjustment was between 33 and 38 mmH2O. For setting 8 (“Virtual Off”) the measured mean opening pressure was 494 ± 34 mmH2O (range 451 to 556 mmH2O). The mean outflow resistance was 7.0 mmHg/ml/min (outflow conductance 17.9 μl/s/kPa).
The six shunts had similar characteristics and closely matched the manufacturer’s specifications for opening pressure at settings 1–7. The opening pressure for the “Virtual Off” setting was nearly 500 mmH2O, which is 100 mmH2O higher than the manufacturer’s specification of “>400” and should be functionally off for most patients with communicating hydrocephalus. Clinical studies are needed to evaluate if the CSF dynamic profile persists after implantation in patients.
PMCID: PMC3386893  PMID: 22643114
Hydrocephalus; Normal pressure hydrocephalus; CSF; Cerebrospinal fluid; Shunt; Intracranial pressure; Outflow resistance; Conductance

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