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1.  Neuronal Activity Promotes Oligodendrogenesis and Adaptive Myelination in the Mammalian Brain 
Science (New York, N.Y.)  2014;344(6183):1252304.
Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity–regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.
PMCID: PMC4096908  PMID: 24727982
2.  Enteric neural crest-derived cells promote their migration by modifying their microenvironment through tenascin-C production 
Developmental biology  2013;382(2):446-456.
The enteric nervous system (ENS) is derived from vagal and sacral neural crest cells that migrate, proliferate, and differentiate into enteric neurons and glia within the gut wall. The mechanisms regulating enteric neural crest-derived cell (ENCC) migration are poorly characterized despite the importance of this process in gut formation and function. Characterization of genes involved in ENCC migration is essential to understanding ENS development and could provide targets for treatment of human ENS disorders. We identified the extracellular matrix glycoprotein tenascin-C (TNC) as an important regulator of ENCC development. We find TNC dynamically expressed during avian gut development. It is absent from the cecal region just prior to ENCC arrival, but becomes strongly expressed around ENCCs as they enter the ceca and hindgut. In aganglionic hindguts, TNC expression is strong throughout the outer mesenchyme, but is absent from the submucosal region, supporting the presence of both ENCC-dependent and independent expression within the gut wall. Using rat-chick coelomic grafts, neural tube cultures, and gut explants, we show that ENCCs produce TNC and that this ECM protein promotes their migration. Interestingly, only vagal neural crest-derived ENCCs express TNC, whereas sacral neural crest-derived cells do not. These results demonstrate that vagal crest-derived ENCCs actively modify their microenvironment through TNC expression and thereby help to regulate their own migration.
PMCID: PMC3800188  PMID: 23958436
Enteric nervous system; extracellular matrix; neural crest cells; tenascin-C; Hirschsprung disease
3.  Invited Commentary: Broadening the Evidence for Adolescent Sexual and Reproductive Health and Education in the United States 
Journal of Youth and Adolescence  2014;43(10):1595-1610.
Scientific research has made major contributions to adolescent health by providing insights into factors that influence it and by defining ways to improve it. However, US adolescent sexual and reproductive health policies—particularly sexuality health education policies and programs—have not benefited from the full scope of scientific understanding. From 1998 to 2009, federal funding for sexuality education focused almost exclusively on ineffective and scientifically inaccurate abstinence-only-until-marriage (AOUM) programs. Since 2010, the largest source of federal funding for sexual health education has been the “tier 1” funding of the Office of Adolescent Health’s Teen Pregnancy Prevention Initiative. To be eligible for such funds, public and private entities must choose from a list of 35 programs that have been designated as “evidence-based” interventions (EBIs), determined based on their effectiveness at preventing teen pregnancies, reducing sexually transmitted infections, or reducing rates of sexual risk behaviors (i.e., sexual activity, contraceptive use, or number of partners). Although the transition from primarily AOUM to EBI is important progress, this definition of evidence is narrow and ignores factors known to play key roles in adolescent sexual and reproductive health. Important bodies of evidence are not treated as part of the essential evidence base, including research on lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) youth; gender; and economic inequalities and health. These bodies of evidence underscore the need for sexual health education to approach adolescent sexuality holistically, to be inclusive of all youth, and to address and mitigate the impact of structural inequities. We provide recommendations to improve US sexual health education and to strengthen the translation of science into programs and policy.
PMCID: PMC4162986  PMID: 25200033
4.  The TRIM-NHL Protein LIN-41 Controls the Onset of Developmental Plasticity in Caenorhabditis elegans 
PLoS Genetics  2014;10(8):e1004533.
The mechanisms controlling cell fate determination and reprogramming are fundamental for development. A profound reprogramming, allowing the production of pluripotent cells in early embryos, takes place during the oocyte-to-embryo transition. To understand how the oocyte reprogramming potential is controlled, we sought Caenorhabditis elegans mutants in which embryonic transcription is initiated precociously in germ cells. This screen identified LIN-41, a TRIM-NHL protein and a component of the somatic heterochronic pathway, as a temporal regulator of pluripotency in the germline. We found that LIN-41 is expressed in the cytoplasm of developing oocytes, which, in lin-41 mutants, acquire pluripotent characteristics of embryonic cells and form teratomas. To understand LIN-41 function in the germline, we conducted structure-function studies. In contrast to other TRIM-NHL proteins, we found that LIN-41 is unlikely to function as an E3 ubiquitin ligase. Similar to other TRIM-NHL proteins, the somatic function of LIN-41 is thought to involve mRNA regulation. Surprisingly, we found that mutations predicted to disrupt the association of LIN-41 with mRNA, which otherwise compromise LIN-41 function in the heterochronic pathway in the soma, have only minor effects in the germline. Similarly, LIN-41-mediated repression of a key somatic mRNA target is dispensable for the germline function. Thus, LIN-41 appears to function in the germline and the soma via different molecular mechanisms. These studies provide the first insight into the mechanism inhibiting the onset of embryonic differentiation in developing oocytes, which is required to ensure a successful transition between generations.
Author Summary
Reprogramming into a naïve, pluripotent state during the oocyte-to-embryo transition is directed by the oocyte cytoplasm. To understand how this reprogramming is controlled, we searched for C. elegans mutants in which the activation of embryonic genome, a landmark event demarcating the switch from a germline- to embryo-specific transcription, is initiated precociously in germ cells. This screen identified a novel function for LIN-41, a member of the TRIM-NHL protein family, in preventing a premature onset of embryonic-like differentiation and teratoma formation in developing oocytes, thus ensuring a successful passage between generations. This is the first example of such a regulator in cells that are poised for embryonic development. Interestingly, the majority of molecular “roadblocks” to reprograming that have been identified so far are epigenetic regulators. However, we propose that, at least in germ cells, LIN-41-like regulators may fulfill an analogous role in the cytoplasm, which has possible implications for the generation of human pluripotent stem cells.
PMCID: PMC4148191  PMID: 25167051
5.  Trigeminal Autonomic Cephalalgias: Beyond the Conventional Treatments 
The trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, and hemicrania continua. While the majority responds to conventional pharmacological treatments, a small but significant proportion of patients are intractable to these treatments. In these cases, alternative choices for these patients include oral and injectable drugs, lesional or resectional surgery, and neurostimulation. The evidence base for conventional treatments is limited, and the evidence for those used beyond convention is more so. At present, the most evidence exists for nerve blocks, deep brain stimulation, occipital nerve stimulation, sphenopalatine ganglion stimulation in chronic cluster headache, and microvascular decompression of the trigeminal nerve in short-lasting unilateral neuralgiform headache attacks.
PMCID: PMC4119587  PMID: 24974071
Trigeminal autonomic cephalalgias; Neurostimulation; Nerve blocks; Sphenopalatine ganglion stimulation; Occipital nerve stimulation; Deep brain stimulation
6.  COMBS: A Biosurveillance Ecosystem (BSVE) Prototype 
PMCID: PMC4050829
biosurveillance; public health; identify threats; analyst workbench
7.  Hypnosis: There’s an App for that. A systematic review of hypnosis apps 
The study systematically reviews the hypnosis apps available via iTunes that were compatible with iPhone or iPad. Of 1455 apps identified on iTunes, 407 met inclusion criteria and were further reviewed. Most common hypnosis app targets were: weight loss (23%), boosting self-esteem (20%), and relaxation/stress reduction (19%). 83% of apps delivered hypnosis via audio track, and 37% allowed tailoring. Less than 14% of apps reported disclaimers. None of the apps reported having been tested for efficacy, and none reported being evidence-based. Although apps have the potential to enhance hypnosis delivery, it seems as though technology has raced ahead of the supporting science. Recommendations from clinical researchers and policy makers are needed to inform responsible hypnosis app development and use.
PMCID: PMC3804912  PMID: 23957263
8.  Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity 
Human Molecular Genetics  2012;21(18):4084-4093.
The zinc metalloprotease ZMPSTE24 plays a critical role in nuclear lamin biology by cleaving the prenylated and carboxylmethylated 15-amino acid tail from the C-terminus of prelamin A to yield mature lamin A. A defect in this proteolytic event, caused by a mutation in the lamin A gene (LMNA) that eliminates the ZMPSTE24 cleavage site, underlies the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). Likewise, mutations in the ZMPSTE24 gene that result in decreased enzyme function cause a spectrum of diseases that share certain features of premature aging. Twenty human ZMPSTE24 alleles have been identified that are associated with three disease categories of increasing severity: mandibuloacral dysplasia type B (MAD-B), severe progeria (atypical ‘HGPS’) and restrictive dermopathy (RD). To determine whether a correlation exists between decreasing ZMPSTE24 protease activity and increasing disease severity, we expressed mutant alleles of ZMPSTE24 in yeast and optimized in vivo yeast mating assays to directly compare the activity of alleles associated with each disease category. We also measured the activity of yeast crude membranes containing the ZMPSTE24 mutant proteins in vitro. We determined that, in general, the residual activity of ZMPSTE24 patient alleles correlates with disease severity. Complete loss-of-function alleles are associated with RD, whereas retention of partial, measureable activity results in MAD-B or severe progeria. Importantly, our assays can discriminate small differences in activity among the mutants, confirming that the methods presented here will be useful for characterizing any new ZMPSTE24 mutations that are discovered.
PMCID: PMC3428156  PMID: 22718200
9.  The red ear syndrome 
Red Ear Syndrome (RES) is a very rare disorder, with approximately 100 published cases in the medical literature. Red ear (RE) episodes are characterised by unilateral or bilateral attacks of paroxysmal burning sensations and reddening of the external ear. The duration of these episodes ranges from a few seconds to several hours. The attacks occur with a frequency ranging from several a day to a few per year. Episodes can occur spontaneously or be triggered, most frequently by rubbing or touching the ear, heat or cold, chewing, brushing of the hair, neck movements or exertion. Early-onset idiopathic RES seems to be associated with migraine, whereas late-onset idiopathic forms have been reported in association with trigeminal autonomic cephalalgias (TACs). Secondary forms of RES occur with upper cervical spine disorders or temporo-mandibular joint dysfunction. RES is regarded refractory to medical treatments, although some migraine preventative treatments have shown moderate benefit mainly in patients with migraine-related attacks. The pathophysiology of RES is still unclear but several hypotheses involving peripheral or central nervous system mechanisms have been proposed.
PMCID: PMC3850925  PMID: 24093332
Red ear syndrome; Migraine; Trigemino-autonomic reflex; Trigeminal autonomic cephalalgias; Parasympathetic system; Erythromelalgia
10.  Genetic and epigenetic alterations of steroidogenic factor-1 in ovarian tumors 
International Journal of Oncology  2012;42(2):627-634.
Steroidogenic factor-1 (SF-1), the product of the NR5A1 gene, is an essential transcription factor that is known to regulate steroidogenesis in ovarian epithelia, including the synthesis of progesterone, a suppressor of ovarian cancer. Expression of the SF-1 protein, a potential ovarian tumor suppressor, has been demonstrated in normal OSE cells, but is lost in most ovarian tumors and ovarian tumor cell lines. We examined loss of heterozygosity (LOH) and promoter methylation as potential mechanisms that may explain the loss of SF-1 protein in ovarian tumor tissues. Genotyping of three NR5A1 SNPs in matched tumor/normal tissues identified LOH in 16/36 (44%) of the ovarian tumors successfully analyzed, and somatic mutations (gain of allele) in 10% of the tumors. Furthermore, a methylation-sensitive restriction enzyme method was used to demonstrate statistically significant (p<0.0001) increase in the frequency of NR5A1 gene methylation in ovarian tumors (36/46; 78%) versus normal ovaries (1/11; 9%). These data suggest that the SF-1 encoding gene exhibits frequent genetic (LOH/base substitution) and epigenetic (methylation) somatic alterations in ovarian tumors. These data also present novel molecular mechanisms that may explain the loss of SF-1 protein in ovarian tumors, and its potential role in ovarian carcinogenesis.
PMCID: PMC3583749  PMID: 23291911
somatic; mutation; ovarian; carcinogenesis; steroidogenesis
Children with autism may struggle in developing conditional discrimination repertoires. Saunders and Spradlin (1989, 1990, 1993) arranged “blocked” teaching trials in which they presented the same sample stimulus repeatedly across trials (in lieu of randomly alternating targets across trials) and then faded the number of trials in each block. We replicated the effects of this blocked-trials procedure in teaching identity matching to a child with autism and evaluated the necessity of fading. Arranging blocked trials facilitated the acquisition of identity matching, but fading the block size was not necessary to maintain discriminated performance.
PMCID: PMC3469304  PMID: 23060677
autism; blocked trials; children; conditional discrimination; identity matching
12.  Synthesis of Unsymmetrical 3,4-Diaryl-3-pyrrolin-2-ones Utilizing Pyrrole Weinreb Amides 
The Journal of organic chemistry  2011;76(20):8203-8214.
A regiocontrolled synthesis of unsymmetrical 3,4-diaryl-3-pyrrolin-2-ones has been achieved in three steps from 1,2-diaryl-1-nitroethenes with pyrrole-2-carboxamides (pyrrole Weinreb amides) serving as the key linchpin intermediates. Two different methods for the preparation of the requisite nitroalkenes were investigated: (1) modified Henry reaction between arylnitromethanes and arylimines; and (2) Suzuki-Miyaura cross-coupling reaction of 2-aryl-1-bromo-1-nitroethenes with arylboronic acids. Some difficulty was encountered in the preparation of arylnitromethanes, thus leading to the exploration of a cross-coupling strategy that proved more useful. A Barton-Zard pyrrole cyclocondensation reaction between 1,2-diaryl-1-nitroethenes and N-methoxy-N-methyl-2-isocyanoacetamide gave the corresponding pyrrole Weinreb amides, which were then converted into the desired 3-pyrrolin-2-ones in two steps. Overall, this method allowed for the construction of 3,4-diaryl-3-pyrrolin-2-ones with complete regiocontrol of the substituents with respect to the lactam carbonyl. The utility of this synthetic methodology was demonstrated by the preparation of eight unsymmetrical and symmetrical 3,4-diaryl-3-pyrrolin-2-ones including the N-H lactam analog of the selective COX-II inhibitor, rofecoxib.
PMCID: PMC3193567  PMID: 21913662
13.  Three distinct amine receptors operating at different levels within the locomotory circuit are each essential for the serotonergic modulation of chemosensation in Caenorhabditis elegans 
Serotonin modulates behavioral plasticity in both vertebrates and invertebrates and in Caenorhabditis elegans regulates key behaviors, including locomotion, aversive learning and olfaction through at least four different 5-HT receptors. In the present study, we examined the serotonergic stimulation of aversive responses to dilute octanol in animals containing null alleles of these 5-HT receptors. Both ser-1 and mod-1 null animals failed to increase sensitivity to dilute octanol on food/5-HT, in contrast to wild-type, ser-4 or ser-7 null animals. 5-HT sensitivity was restored by the expression of MOD-1 and SER-1 in the AIB or potentially the AIY, and RIA interneurons of mod-1 and ser-1 null animals, respectively. Since none of these 5-HT receptors appear to be expressed in the ASH sensory neurons mediating octanol sensitivity, we identified a 5-HT6-like receptor, F16D3.7(SER-5), that was required for food/5-HT dependent increases in octanol sensitivity. ser-5 null animals failed to increase octanol sensitivity in the presence of food/5-HT and sensitivity could be restored by expression of SER-5 in the ASHs. Similarly, the RNAi knockdown of ser-5 expression in the ASHs of wild-type animals also abolished 5-HT dependent increases in octanol sensitivity, suggesting that SER-5 modulates the octanol responsiveness of the ASHs directly. Together, these results suggest that multiple amine receptors, functioning at different levels within the locomotory circuit, are each essential for the serotonergic modulation of ASH-mediated aversive responses.
PMCID: PMC3418693  PMID: 19193891
ASH neuron; G-protein coupled receptors; locomotion; plasticity; reversals; serotonin (5-HT)
14.  The Therapeutic Relationship in E-Therapy for Mental Health: A Systematic Review 
E-therapy is defined as a licensed mental health care professional providing mental health services via e-mail, video conferencing, virtual reality technology, chat technology, or any combination of these. The use of e-therapy has been rapidly expanding in the last two decades, with growing evidence suggesting that the provision of mental health services over the Internet is both clinically efficacious and cost effective. Yet there are still unanswered concerns about e-therapy, including whether it is possible to develop a successful therapeutic relationship over the Internet in the absence of nonverbal cues.
Our objective in this study was to systematically review the therapeutic relationship in e-therapy.
We searched PubMed, PsycINFO, and CINAHL through August 2011. Information on study methods and results was abstracted independently by the authors using a standardized form.
From the 840 reviewed studies, only 11 (1.3%) investigated the therapeutic relationship. The majority of the reviewed studies were focused on the therapeutic alliance—a central element of the therapeutic relationship. Although the results do not allow firm conclusions, they indicate that e-therapy seems to be at least equivalent to face-to-face therapy in terms of therapeutic alliance, and that there is a relationship between the therapeutic alliance and e-therapy outcome.
Overall, the current literature on the role of therapeutic relationship in e-therapy is scant, and much more research is needed to understand the therapeutic relationship in online environments.
PMCID: PMC3411180  PMID: 22858538
e-Therapy; therapeutic relationship; therapeutic alliance; common factors in psychotherapy
15.  The acute and preventative treatment of episodic migraine 
Annals of Indian Academy of Neurology  2012;15(Suppl 1):S33-S39.
Episodic migraine is a common debilitating condition with significant worldwide impact. An effective management plan must include acute treatment to relieve the pain and potential disability associated with the attacks and may also include preventative treatments with an aim of decreasing attack frequency and severity in the longer term. Acute treatments must be limited to a maximum of 2-3 days a week to prevent medication overuse headache and focus on simple analgesia, non-steroidal anti-inflammatory drugs and triptans. Preventative treatments are numerous and should be considered when migraine attacks are frequent and or disabling, acute medication is failing, in special circumstances such as hemiplegic migraines or if the patient requests them. All preventative medications must be given at therapeutic doses for at least 6-8 weeks before an adequate trial can be judged ineffective. The most important factor in choosing drugs is the patient and the clinical features of their attack and treatment should be tailored to these. Relative co-morbidities will influence drug choice, as will the side effect profile and the efficacy of the drug. First line preventative drugs include ß-blockers, amitriptyline and anti-epileptic drugs such as topiramate and valproate. Drugs with lower efficacy or poorer side effect profiles include selective serotonin reuptake inhibitors (SSRIs), calcium channel antagonists, gabapentin and herbal medicines.
PMCID: PMC3444218  PMID: 23024562
Acute; migraine; preventative; prophylaxis; treatment
16.  Retrospective Audit of Medication Order Turnaround Time after Implementation of Standardized Definitions 
Standardizing the interpretation of “stat”, “emergent”, “urgent”, and “now” medication orders can improve patient safety. However, the effect of implementing standardized definitions on the turnaround time for medication orders in hospital pharmacy dispensaries has not been studied.
To examine the effects of using formal definitions for “stat”, “emergent”, “urgent”, and “now” on turnaround time for medication orders within a pharmacy dispensary.
Definitions for “stat”, “emergent”, “urgent”, and “now” orders, as well as for “turnaround time”, were developed from the formal literature and the grey literature. The definitions were implemented by educating all pharmacy staff. Retrospective audits of turnaround time were conducted at baseline (for all orders over a 1-month period) and after implementation of the definitions (for a total of 28 days over a 3-month period). Health records and medication orders were used to calculate time from prescribing to administration (total turnaround time) and time from prescribing to departure from the dispensary (dispensary turnaround time). Differences between total and dispensary turnaround times were compared with nonparametric statistics.
During the baseline audit period, 84 (1.1%) of 7787 orders were identified as “stat”, “emergent”, “urgent”, or “now”. After implementation of the formal definitions, 142 (2.6%) of 5365 orders were identified by one of these terms. The percentage of orders meeting the target dispensary turnaround time of less than 15 min was at least 90% both at baseline (76/84 [90%]) and after implementation (129/142 [91%]) (p = 0.80). Median dispensary turnaround time for stat and emergent medication orders combined (10 versus 9 min, p = 0.27) and for urgent and now medication orders combined (10 versus 12 min, p = 0.09) did not change after implementation of formal definitions. Similarly, median total turnaround time did not change for stat and emergent medication orders combined (30 versus 45 min, p = 0.32), but it increased for urgent and now orders combined (35 versus 45 min, p = 0.041).
Implementing standardized definitions for “stat”, “emergent”, “urgent”, and “now” had no significant effect on dispensary turnaround time. However, the majority of orders with these designations met the expected target for dispensary turnaround time. Further interventions aimed at other health care professionals may be needed to reduce total turnaround time. This research supports the concept of interdisciplinary interventions for reducing total turnaround time.
PMCID: PMC3203827  PMID: 22479087
turnaround time; medication; stat; urgent; délai d’exécution; médicaments; stat; urgent
17.  Behavioral Signs of Schizoidia and Schizotypy in the Biological Parents of Social Anhedonics 
Behavior modification  2009;33(4):452-473.
A community sample of 88 putative schizotypes (48 social anhedonics, 40 controls), aged 18 to 19 years, and their biological parents (42 mothers of social anhedonics, 37 mothers of controls; 24 fathers of social anhedonics, 20 fathers of controls) receive videotaped diagnostic evaluations that serve as the basis for ratings of behavioral signs of schizoidia and schizotypy. Proband social anhedonics exhibit more atypical interpersonal behaviors characteristic of schizoid and schizotypal personality disorders than controls. Mothers of social anhedonics display more atypical interpersonal behaviors characteristic of schizotypal personality disorder than mothers of controls. In contrast, clinical symptom ratings of schizotypy do not differentiate mothers of social anhedonics from mothers of controls. Meaningful, though not statistically significant, effects are observed for behavioral sign ratings in the smaller sample of fathers of social anhedonics. Results provide preliminary support for the familiality of atypical interpersonal behavior in social anhedonics.
PMCID: PMC2849114  PMID: 19436072
schizotypy; anhedonia; schizophrenia; behavior; interpersonal; family
18.  Development and Experimental Validation of a Predictive Threshold Cycle Equation for Quantification of Virulence and Marker Genes by High-Throughput Nanoliter-Volume PCR on the OpenArray Platform▿ † 
Applied and Environmental Microbiology  2008;74(12):3831-3838.
Development of quantitative PCR (QPCR) assays typically requires extensive screening within and across a given species to ensure specific detection and lucid identification among various pathogenic and nonpathogenic strains and to generate standard curves. To minimize screening requirements, multiple virulence and marker genes (VMGs) were targeted simultaneously to enhance reliability, and a predictive threshold cycle (CT) equation was developed to calculate the number of starting copies based on an experimental CT. The empirical equation was developed with Sybr green detection in nanoliter-volume QPCR chambers (OpenArray) and tested with 220 previously unvalidated primer pairs targeting 200 VMGs from 30 pathogens. A high correlation (R2 = 0.816) was observed between the predicted and experimental CTs based on the organism's genome size, guanine and cytosine (GC) content, amplicon length, and stability of the primer's 3′ end. The performance of the predictive CT equation was tested using 36 validation samples consisting of pathogenic organisms spiked into genomic DNA extracted from three environmental waters. In addition, the primer success rate was dependent on the GC content of the target organisms and primer sequences. Targeting multiple assays per organism and using the predictive CT equation are expected to reduce the extent of the validation necessary when developing QPCR arrays for a large number of pathogens or other targets.
PMCID: PMC2446556  PMID: 18424532
19.  Effect of rhPDGF-BB Delivery on Mediators of Periodontal Wound Repair 
Tissue engineering  2006;12(6):1441-1450.
Growth factors such as platelet-derived growth factor (PDGF) exert potent effects on wound healing including the regeneration of tooth-supporting structures. This investigation examined the effect of the local delivery of PDGF-BB when combined with reconstructive periodontal surgery on local wound fluid (WF) levels of PDGF-AB, vascular endothelial growth factor (VEGF), and bone collagen telopeptide (ICTP) in humans with advanced periodontitis. Sixteen patients exhibiting localized periodontal osseous defects were randomized to one of three groups (β-TCP carrier alone, β-TCP + 0.3 mg/mL of recombinant human PDGF-BB [rhPDGF-BB], or β-TCP + 1.0 mg/mL of rhPDGF-BB) and monitored for 6 months. WF was harvested and analyzed for PDGF-AB, VEGF, and ICTP WF levels. Teeth contralateral to the target lesions served as controls. Increased levels of VEGF in the WF was observed for all surgical treatment groups with the 1.0 mg/mL rhPDGF-BB group showing the most pronounced difference at 3 weeks in the AUC analysis versus control (p < 0.0001). PDGF-AB WF levels were increased for the carrier alone group compared to both rhPDGF-BB groups. Low-dose rhPDGF-BB application elicited increases in ICTP at days 3–5 in the wound healing process, suggesting a promotion of bone turnover at early stages of the repair process (p < 0.02). These results demonstrate contrasting inducible expression patterns of PDGF-AB, VEGF, and ICTP during periodontal wound healing in humans.
PMCID: PMC2586965  PMID: 16846342
20.  Effect of rhPDGF-BB on bone turnover during periodontal repair 
Growth factors such as platelet-derived growth factor (PDGF) exert potent effects on wound healing including the regeneration of periodontia. Pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) is a well-known biomarker of bone turnover, and as such is a potential indicator of osseous metabolic activity. The objective of this study was to evaluate the release of the ICTP into the periodontal wound fluid (WF) following periodontal reconstructive surgery using local delivery of highly purified recombinant human PDGF (rhPDGF)-BB.
Forty-seven human subjects at five treatment centres possessing chronic severe periodontal disease were monitored longitudinally for 24 weeks following PDGF regenerative surgical treatment. Severe periodontal osseous defects were divided into one of three groups and treated at the time of surgery with either: β-tricalcium phosphate (TCP) osteoconductive scaffold alone (active control), β-TCP+0.3 mg/ml of rhPDGF-BB, or β-TCP+1.0 mg/ml of rhPDGF-BB. WF was harvested and analysed for local ICTP levels by radioimmunoassay. Statistical analysis was performed using analysis of variance and an area under the curve analysis (AUC).
The 0.3 and 1.0 mg/ml PDGF-BB treatment groups demonstrated increases in the amount of ICTP released locally for up to 6 weeks. There were statistically significant differences at the week 6 time point between β-TCP carrier alone group versus 0.3 mg/ml PDGF-BB group (p<0.05) and between β-TCP alone versus the 1.0 mg/ml PDGF-BB-treated lesions (p<0.03). The AUC analysis revealed no statistical differences amongst groups.
This study corroborates the release of ICTP as a measure of active bone turnover following local delivery of PDGF-BB to periodontal osseous defects. The amount of ICTP released from the WF revealed an early increase for all treatment groups. Data from this study suggests that when PDGF-BB is delivered to promote periodontal tissue engineering of tooth-supporting osseous defects, there is a direct effect on ICTP released from the wound.
PMCID: PMC2579262  PMID: 16441739
collagen telopeptides; growth factors; periodontal regeneration; periodontal wound repair; tissue engineering
21.  In Situ-Synthesized Virulence and Marker Gene Biochip for Detection of Bacterial Pathogens in Water▿ †  
Pathogen detection tools with high reliability are needed for various applications, including food and water safety and clinical diagnostics. In this study, we designed and validated an in situ-synthesized biochip for detection of 12 microbial pathogens, including a suite of pathogens relevant to water safety. To enhance the reliability of presence/absence calls, probes were designed for multiple virulence and marker genes (VMGs) of each pathogen, and each VMG was targeted by an average of 17 probes. Hybridization of the biochip with amplicon mixtures demonstrated that 95% of the initially designed probes behaved as predicted in terms of positive/negative signals. The probes were further validated using DNA obtained from three different types of water samples and spiked with pathogen genomic DNA at decreasing relative abundance. Excellent specificity for making presence/absence calls was observed by using a cutoff of 0.5 for the positive fraction (i.e., the fraction of probes yielding a positive signal for a given VMG). A split multiplex PCR design for simultaneous amplification of the VMGs resulted in a detection limit of between 0.1 and 0.01% relative abundance, depending on the type of pathogen and the VMG. Thermodynamic analysis of the hybridization patterns obtained with DNA from the different water samples demonstrated that probes with a hybridization Gibbs free energy of approximately −19.3 kcal/mol provided the best trade-off between sensitivity and specificity. The developed biochip may be used to detect the described bacterial pathogens in water samples when parallel and specific detection is required.
PMCID: PMC2292592  PMID: 18245235
22.  Money, Sex, and Drugs: A Case Study to Teach the Genetics of Antibiotic Resistance 
CBE Life Sciences Education  2008;7(3):302-309.
The goal of the work reported here was to help students expand their understanding of antibiotic resistance, the Central Dogma, and evolution. We developed a unit entitled “Ciprofloxacin Resistance in Neisseria gonorrhoeae,” which was constructed according to the principles of scientific teaching by a team of graduate students, science faculty, and instructors. A variety of activities and assessments were used, including a case study, short lectures, and group problem-solving. Implementation of “Ciprofloxacin Resistance in Neisseria gonorrhoeae” in a college freshman seminar suggests these materials are useful in increasing understanding of complex biological topics and improving problem-solving abilities.
PMCID: PMC2527979  PMID: 18765752
23.  Aligning Goals, Assessments, and Activities: An Approach to Teaching PCR and Gel Electrophoresis 
CBE Life Sciences Education  2008;7(1):96-106.
Polymerase chain reaction (PCR) and gel electrophoresis have become common techniques used in undergraduate molecular and cell biology labs. Although students enjoy learning these techniques, they often cannot fully comprehend and analyze the outcomes of their experiments because of a disconnect between concepts taught in lecture and experiments done in lab. Here we report the development and implementation of novel exercises that integrate the biological concepts of DNA structure and replication with the techniques of PCR and gel electrophoresis. Learning goals were defined based on concepts taught throughout the cell biology lab course and learning objectives specific to the PCR and gel electrophoresis lab. Exercises developed to promote critical thinking and target the underlying concepts of PCR, primer design, gel analysis, and troubleshooting were incorporated into an existing lab unit based on the detection of genetically modified organisms. Evaluative assessments for each exercise were aligned with the learning goals and used to measure student learning achievements. Our analysis found that the exercises were effective in enhancing student understanding of these concepts as shown by student performance across all learning goals. The new materials were particularly helpful in acquiring relevant knowledge, fostering critical-thinking skills, and uncovering prevalent misconceptions.
PMCID: PMC2262121  PMID: 18316813
24.  Age-related functional recruitment for famous name recognition: An event-related fMRI study 
Neurobiology of aging  2005;27(10):1494-1504.
Recent neuroimaging research shows that older adults exhibit recruitment, or increased activation on various cognitive tasks. The current study evaluated whether a similar pattern also occurs in semantic memory by evaluating age-related differences during recognition of Recent (since the 1990s) and Enduring (1950s to present) famous names. Fifteen healthy older and 15 healthy younger adults performed the name recognition task with a high and comparable degree of accuracy, although older adults had slower reaction time in response to Recent famous names. Event-related functional MRI showed extensive networks of activation in the two groups including posterior cingulate, right hippocampus, temporal lobe and left prefrontal regions. The Recent condition produced more extensive activation than the Enduring condition. Older adults had more extensive and greater magnitude of activation in 15 of 20 regions, particularly for the Recent condition (15 of 15; 7 of 15 also differed for Enduring); young adults did not show greater activation magnitude in any region. There were no group differences for non-famous names, indicating that age differences are task-specific. The results support and extend the existing literature to semantic memory tasks, indicating that older adult brains use functional recruitment to support task performance, even when task performance accuracy is high.
PMCID: PMC2078241  PMID: 16225965
Semantic memory; Event-related fMRI; Functional recruitment; Aging; Posterior cingulate; Frontal lobes; Neuroimaging; Cognition
25.  Temporally Graded Activation of Neocortical Regions in Response to Memories of Different Ages 
Journal of cognitive neuroscience  2007;19(7):1113-1124.
The temporally graded memory impairment seen in many neurobehavioral disorders implies different neuroanatomical pathways and/or cognitive mechanisms involved in storage and retrieval of memories of different ages. A dynamic interaction between medial-temporal and neocortical brain regions has been proposed to account for memory’s greater permanence with time. Despite considerable debate concerning its time-dependent role in memory retrieval, medial-temporal lobe activity has been well studied. However, the relative participation of neocortical regions in recent and remote memory retrieval has received much less attention. Using functional magnetic resonance imaging, we demonstrate robust, temporally graded signal differences in posterior cingulate, right middle frontal, right fusiform, and left middle temporal regions in healthy older adults during famous name identification from two disparate time epochs. Importantly, no neocortical regions demonstrated greater response to older than to recent stimuli. Our results suggest a possible role of these neocortical regions in temporally dating items in memory and in establishing and maintaining memory traces throughout the lifespan. Theoretical implications of these findings for the two dominant models of remote memory functioning (Consolidation Theory and Multiple Trace Theory) are discussed.
PMCID: PMC2078236  PMID: 17583988

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