bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and Hg2+-Selective Ionophoric Properties of p-tert-Butylcalix[4]arene-aza-crown Ethers
Authors: Choi Mi Jung , Kim Mi Yee , Kim Joo Ryun , Chang Suk-Kyu
Published: June 2005

A series of new p-tert-butylcalix[4]arene aza-crown ethers has been prepared. They showed pronounced selective ionophoric properties in transport experiments toward Hg2+ ions among the heavy metal ions and Cu2+ ions among the transition metal ions surveyed. The calix[4]arene diaza-crown ethers are found to be relatively well optimized for the transport of Hg2+ ions.
The mystery of the wooden leg: vitamin C deficiency in East African prisons
Authors: Bennett M , Coninx R
Published: May 2005

Vitamin C deficiency (scurvy) is an uncommon disease in modern times, and therefore easily misdiagnosed when it appears. While visiting prisoners in East Africa, health delegates of the International Committee of the Red Cross (ICRC) encountered prisoners suffering from a hitherto undiagnosed 'mysterious' illness, consisting mainly of swollen and hard legs, that had not responded to various treatments given by the local health centre or hospital. The ICRC set out to investigate the nature of this disease and examined 133 prisoners with the suspected clinical symptoms described as 'wooden leg' syndrome in 10 different prisons. Serum ascorbic acid levels were measured and a food basket analysis done. The diagnosis of scurvy was confirmed. All patients responded to standard treatment with oral ascorbic acid.

The clinical presentation of scurvy in these East African prisons seems to be somewhat different from the classic descriptions, but is in line with historic records of the disease. Treatment is easy and cheap, and response to treatment is quick. Scurvy remains a problem in prisons in Africa and clinicians working in prisons need to be aware of its presence and its presentations.
Clinical predictors of malaria and other febrile illnesses in children under five on Pemba Island, Tanzania
Authors: Yacoub Sophie , Mohammed Mohammed Juma , Ramsan Mahdi , Albonico Marco
Published: May 2005

Under the current guidelines of presumptive treatment of all children with reported fever, the risk of over-prescribing antimalarial drugs and missing other important causes of fever, like acute respiratory tract infection (ARI), is substantial. Clinical algorithms have been shown to be useful in diagnosing malaria, but often with differing results, due to regional variations. We set out to explore the clinical features associated with malaria compared with other febrile illnesses and specifically severe malaria with ARI in children under five in Pemba. Two hundred and seven children aged six months to five years presenting to a hospital clinic with fever were studied in Pemba. Clinical findings were related to the presence of malaria parasitaemia. Malaria accounted for 67.7% of the febrile episodes investigated. Five symptoms and signs, including pallor, drowsiness, splenomegaly, fever duration and no chest crackles, could accurately predict a case of malaria with a sensitivity of 91.3% and specificity of 53% and positive predictive value of 80.3%. Several clinical features were found to differentiate severe malaria from ARI. These results confirm that clinical algorithms can increase the diagnostic accuracy of malaria, although not sufficiently to replace microscopy, and by promoting the use of clinical skills other treatable causes of febrile illnesses may be identified. These findings could have implications in optimizing treatment and malaria control in children on Pemba.
Determinants of tetanus toxoid immunization in pregnancy in rural Bihar
Authors: Thind Amardeep
Published: May 2005

In order to increase the uptake of tetanus toxoid (TT) vaccination, we need to understand the factors that underlie the decision of the pregnant woman to undergo vaccination, especially in rural areas, where 75% of India's population resides. This paper constructs a model from a data-set of 2398 women in order to understand the determinants of TT vaccine immunization by women during their most recent pregnancy and applies it to the National Family Health Survey-2 data. The object of the model is to predict the likelyhood of a pregnant woman receiving the recommended two doses of TT vaccine subject to other factors such as birth order, maternal education, prenatal care provider, household standard of living, health-care-seeking decision-maker and service availability. Policy implications of these findings are discussed.
Prevalence of HIV infection in pregnant women in remote rural areas of Maharastra State, India
Authors: Arole S , Premkumar R , Arole R , Mehendale S , Risbud A , Paranjape R
Published: May 2005

In a study of 304 pregnant women, the prevalence of HIV infection in remote rural areas of western India was 0.7% (confidence interval 0.08-2.3%). It is nearly 2½ times higher than the presumed prevalence for this part of the country.
Management and outcome of TB suspects admitted to the medical wards of a central hospital in Malawi
Authors: Friend Jeremy H , Mason Shirin , Harries Anthony D , Salaniponi Felix M , Neuhann Florian
Published: May 2005

In a study conducted in the medical wards of Lilongwe Central Hospital, Malawi, 84 (18%) of 470 medical admissions were TB suspects. Of these, 21 (25%) had the diagnosis confirmed; the median length of time between admission and starting anti-TB treatment was 10 days. Of the remaining TB suspects, 24 (29%) had another diagnosis made, principally pneumonia, and 39 (46%) had no diagnosis made, with half of these patients dying under investigation in hospital. Improved and more rapid ways of managing TB suspects need to be found.
A novel strategy to identify the location of necessary and sufficient cis-acting regulatory mRNA elements in trypanosomes
Authors: WEBB HELENA , BURNS ROISIN , KIMBLIN NICOLA , ELLIS LOUISE , CARRINGTON MARK
Published: June 2005

Expression of nearly all protein coding genes in trypanosomes is regulated post-transcriptionally, predominantly at the level of mRNA half-life. The identification of cis-acting elements involved in mRNA stability has been hindered by a lack of ability to screen for loss-of-regulation mutants. The method described in this article allows the region containing the necessary and sufficient elements within a mRNA to be identified and uses antibiotic resistance genes as both selectable markers and reporters. In the case of unstable mRNAs, the strategy can be extended by performing a screen for spontaneous loss-of-function mutants in regulatory parts of a mRNA. The method was validated by using the GPI-PLC mRNA, which is unstable in procyclic form trypanosomes and showed that the 3′UTR of the GPI-PLC mRNA contains all elements required for developmentally regulated instability. Loss-of-instability mutants all contained deletions within the 2300-nucleotide-long 3′UTR, and their analysis showed that a deletion including the last 800 nt of the gene stabilized the mRNA. The method is nonpresumptive, allows far more rapid screening for cis-elements than existing procedures, and has the advantage of identifying functional mutants. It is applicable to all eukaryotes using polycistronic transcription.
The pseudouridine synthase RluD is required for normal ribosome assembly and function in Escherichia coli
Authors: GUTGSELL NANCY S. , DEUTSCHER MURRAY P. , OFENGAND JAMES
Published: June 2005

RluD is the pseudouridine synthase responsible for the formation of Ψ1911, Ψ1915, and Ψ1917 in Escherichia coli 23S rRNA. Previous work from our laboratory demonstrated that disruption of the rluD gene and/or loss of the pseudouridine residues for which it is responsible resulted in a severe growth phenotype. In the current work we have examined further the effect of the loss of the RluD protein and its product pseudouridine residues in a deletion strain lacking the rluD gene. This strain exhibits defects in ribosome assembly, biogenesis, and function. Specifically, there is a deficit of 70S ribosomes, an increase in 50S and 30S subunits, and the appearance of new 62S and 39S particles. Analysis of the 39S particles indicates that they are immature precursors of the 50S subunits, whereas the 62S particles are derived from the breakdown of unstable 70S ribosomes. In addition, purified mutant 70S ribosomes were found to be somewhat less efficient than wild type in protein synthesis. The defect in ribosome assembly and resulting growth phenotype of the mutant could be restored by expression of wild-type RluD and synthesis of Ψ1911, Ψ1915, and Ψ1917 residues, but not by catalytically inactive mutant RluD proteins, incapable of pseudouridine formation. The data suggest that the loss of the pseudouridine residues can account for all aspects of the mutant phenotype; however, a possible second function of the RluD synthase is also discussed.
Weighted sequence motifs as an improved seeding step in microRNA target prediction algorithms
Authors: SÆTROM OLA , SNØVE OLA , SÆTROM PÅL
Published: June 2005

We present a new microRNA target prediction algorithm called TargetBoost, and show that the algorithm is stable and identifies more true targets than do existing algorithms. TargetBoost uses machine learning on a set of validated microRNA targets in lower organisms to create weighted sequence motifs that capture the binding characteristics between microRNAs and their targets. Existing algorithms require candidates to have (1) near-perfect complementarity between microRNAs’ 5′ end and their targets; (2) relatively high thermodynamic duplex stability; (3) multiple target sites in the target’s 3′ UTR; and (4) evolutionary conservation of the target between species. Most algorithms use one of the two first requirements in a seeding step, and use the three others as filters to improve the method’s specificity. The initial seeding step determines an algorithm’s sensitivity and also influences its specificity. As all algorithms may add filters to increase the specificity, we propose that methods should be compared before such filtering. We show that TargetBoost’s weighted sequence motif approach is favorable to using both the duplex stability and the sequence complementarity steps. (TargetBoost is available as a Web tool from http://www.interagon.com/demo/.)
Epidemiology, Comparative Methods of Detection, and Preventability of Adverse Drug Events
Authors: Al-Tajir Ghada K , Kelly William N
Published: June 2005

BACKGROUND

Adverse drug events (ADEs) continue to be of concern to all health professionals. Even serious ADEs are underreported in all patient-care environments.

OBJECTIVE

To discover the incidence and the best detection methods and preventability for ADEs at Al Qassimi Hospital, a 360-bed facility in the United Arab Emirates.

METHODS

During the first and fourth quarters of 2003, data collection for ADEs was limited to spontaneous reporting. During the second and third quarters, active monitoring for ADEs took place in the adult, pediatric medical, and intensive care wards. ADEs were assessed for causality using the Naranjo algorithm and for severity and preventability. The incidence of ADEs was calculated and the detection methods were compared.

RESULTS

The incidence of ADEs detected through surveillance was significantly higher (p < 0.001) than for ADEs reported spontaneously for both inpatients (3.592 vs 0.068/100 patient days) and outpatients (0.299 vs 0.022/100 patient visits). Most ADEs were judged to be of mild to moderate severity. About 56% of ADEs were judged definite or probable and, of these, 13.8% were consistently judged preventable. The most prevalent drugs implicated were central nervous system (23.6%), antiinfective (17.1%), and cardiovascular (16.5%) agents. The best ADE detection method was using physicians' notes.

CONCLUSIONS

Active surveillance for ADEs, with the aid of ADE trigger alerts, yields a significantly higher number of reports than spontaneous reporting. Such surveillance is useful in identifying areas where improvements in the safe use of drugs can be made.
Patterns of Potentially Inappropriate Medication Use Across Three Cohorts of Older Medicaid Recipients
Authors: Rigler Sally K , Jachna Carolyn M , Perera Subashan , Shireman Theresa I , Eng Marty L
Published: June 2005

BACKGROUND

Potentially inappropriate medication use is a serious quality concern, especially when it occurs in more vulnerable older adults or for extended durations.

OBJECTIVE

To characterize patterns of inappropriate medication use and duration among 3 cohorts with differing health status.

METHODS

We identified unconditionally inappropriate drug use, using Beers 1997 criteria, among 3185 older Kansas Medicaid beneficiaries. Claims from May 2000 to April 2001 provided data for 3 cohorts: nursing facility (NF) residents, recipients of home- and community-based services through the Frail Elderly (FE) program, and persons with neither NF/FE care (Ambulatory). Duration, categorized as short-term (≤1 month's supply), extended (>1–9 mo), or chronic (>9–12 mo), was determined for each drug and cohort. Drug–disease associations were explored.

RESULTS

Any inappropriate medication use occurred in 21%, 48%, and 38% of Ambulatory, FE, and NF cohorts, respectively. Inappropriate analgesics, antihistamines, antidepressants, muscle relaxants, and oxybutynin were most common, but prevalence and duration varied by cohort. Short-term analgesic and antihistamine use was common. FE cohort members had the highest use rates for all drugs. The NF cohort had less antidepressant and muscle relaxant use. Drug–disease associations were noted for amitriptyline use in diabetes mellitus, propoxyphene use in musculoskeletal and upper gastrointestinal conditions, and muscle relaxant use in musculoskeletal conditions.

CONCLUSIONS

Cross-sectional, one-year prevalence figures are comprised of both short- and long-term use that varies by drug and cohort. NF residence is associated with reduced use of drugs scrutinized during mandated medication review. Relevant diseases are associated with specific inappropriate prescribing. Future efforts should target extended and chronic duration of use and persons at highest risk for adverse effects, including recipients of home- and community-based care.
Evaluation of Presence of Aspirin-Related Warnings with Willow Bark
Authors: Clauson Kevin A , Santamarina Marile L , Buettner Christian M , Cauffield Jacintha S
Published: June 2005

BACKGROUND

The dietary supplement willow bark, also known simply as willow, contains salicylates that may present a safety risk to people. Current regulations do not require willow bark to include any cautions on its label.

OBJECTIVE

To evaluate the absence or presence of label warnings related to salicylates contained in willow bark to ascertain whether a potentially dangerous lack of information exists.

METHODS

The label of each willow supplement and willow-containing product was assessed for the presence or absence of 3 warnings: (1) aspirin allergy/sensitivity, (2) use of anticoagulants or “blood thinners,” and (3) children with flu-like symptoms or Reye's syndrome. Products from pharmacies and health food stores were targeted and their labels analyzed. A compilation of the identified products was used to conduct a similar evaluation of warnings from their Web sites.

RESULTS

A total of 58 willow bark–containing and 12 single-ingredient willow bark products were assessed. Of the 70 products evaluated, only 8.6% listed a warning. The warning regarding aspirin sensitivity was present on 4.3%, Reye's syndrome was 2.9%, and interactions with anticoagulants/“blood thinners” was 4.3%. One product was labeled as aspirin-free. Percentages were lower on Web sites.

CONCLUSIONS

There is a dearth of information regarding potential safety risks on the labels of willow bark and willow bark–containing products. Combination products containing willow bark may pose a greater danger to at-risk patients based on their sheer volume. Counseling of patients who take dietary supplements can improve the situation; however, it may ultimately take improved requirements for dietary supplement labeling to fully address this problem.
Polyploid Formation via Chromosome Duplication Induced by CTP:Phosphocholine Cytidylyltransferase Deficiency and Bcl-2 Overexpression: Identification of Two Novel Endogenous Factors
Authors: Shen You-Jun , DeLong Cynthia J. , Tercé Francois , Kute Timothy , Willingham Mark C. , Pettenati Mark J. , Cui Zheng
Published: May 2005

Polyploidy is a profound phenotype found in tumors and its mechanism is unknown. We report here that when B-cell lymphoma gene-2 (Bcl-2) was overexpressed in a Chinese hamster ovary cell line that was deficient in CTP:phosphocholine cytidylyltransferase (CT), cellular DNA content doubled. The higher DNA content was due to a permanent conversion from diploid cells to tetraploid cells. The mechanism of polyploid formation could be attributed to the duplication of 18 parental chromosomes. The rate of conversion from diploid to tetraploid was Bcl-2 dose dependent. The diploid genome was not affected by Bcl-2 expression or by CT deficiency alone. Endogenous CT or expression of recombinant rat liver CTα prior to Bcl-2 expression prevented the formation of polyploid cells. This conversion was irreversible even when both initiating factors were removed. In this study, we have identified Bcl-2 as a positive regulator and CTα as a negative regulator of polyploid formation.
The Double-Time Protein Kinase Regulates the Subcellular Localization of theDrosophilaClock Protein Period
Authors: Cyran Shawn A. , Yiannoulos Georgia , Buchsbaum Anna M. , Saez Lino , Young Michael W. , Blau Justin
Published: June 2005

The Period (PER), Timeless (TIM), and Double-Time (DBT) proteins are essential components of one feedback loop in theDrosophilacircadian molecular clock. PER and TIM physically interact. Coexpression of PER and TIM promotes their nuclear accumulation and influences the activity of DBT: although DBT phosphorylates and destabilizes PER, this is suppressed by TIM. Experiments usingDrosophilacells in culture have indicated that PER can translocate to the nucleus without TIM and will repress transcription in a DBT-potentiated manner. In this study, we examined the control of PER subcellular localization inDrosophilaclock cellsin vivo.We found that PER can translocate to the nucleus intim01null mutants but only if DBT kinase activity is inhibited. We also found that nuclear PER is a potent transcriptional repressor indbtmutantsin vivowithout TIM. Thus,in vivo, DBT regulates PER subcellular localization, in addition to its previously documented role as a mediator of PER stability. However, DBT does not seem essential for transcriptional repression by PER. It was reported previously that overexpression of a second kinase, Shaggy (SGG)/Glycogen Synthase Kinase 3, accelerates PER nuclear accumulation. Here, we show that these effects of SGG on PER nuclear accumulation require TIM. We propose a revised clock model that incorporates this tight kinase regulation of PER and TIM nuclear entry.
Neuromagnetic Correlates of Streaming in Human Auditory Cortex
Authors: Gutschalk Alexander , Micheyl Christophe , Melcher Jennifer R. , Rupp André , Scherg Michael , Oxenham Andrew J.
Published: June 2005

The brain is constantly faced with the challenge of organizing acoustic input from multiple sound sources into meaningful auditory objects or perceptual streams. The present study examines the neural bases of auditory stream formation using neuromagnetic and behavioral measures. The stimuli were sequences of alternating pure tones, which can be perceived as either one or two streams. In the first experiment, physical stimulus parameters were varied between values that promoted the perceptual grouping of the tone sequence into one coherent stream and values that promoted its segregation into two streams. In the second experiment, an ambiguous tone sequence produced a bistable percept that switched spontaneously between one- and two-stream percepts. The first experiment demonstrated a strong correlation between listeners' perception and long-latency (>60 ms) activity that likely arises in nonprimary auditory cortex. The second demonstrated a covariation between this activity and listeners' perception in the absence of physical stimulus changes. Overall, the results indicate a tight coupling between auditory cortical activity and streaming perception, suggesting that an explicit representation of auditory streams may be maintained within nonprimary auditory areas.
Dejittered Spike-Conditioned Stimulus Waveforms Yield Improved Estimates of Neuronal Feature Selectivity and Spike-Timing Precision of Sensory Interneurons
Authors: Aldworth Zane N. , Miller John P. , Gedeon Tomás , Cummins Graham I. , Dimitrov Alexander G.
Published: June 2005

What is the meaning associated with a single action potential in a neural spike train? The answer depends on the way the question is formulated. One general approach toward formulating this question involves estimating the average stimulus waveform preceding spikes in a spike train. Many different algorithms have been used to obtain such estimates, ranging from spike-triggered averaging of stimuli to correlation-based extraction of “stimulus-reconstruction” kernels or spatiotemporal receptive fields. We demonstrate that all of these approaches miscalculate the stimulus feature selectivity of a neuron. Their errors arise from the manner in which the stimulus waveforms are aligned to one another during the calculations. Specifically, the waveform segments are locked to the precise time of spike occurrence, ignoring the intrinsic “jitter” in the stimulus-to-spike latency. We present an algorithm that takes this jitter into account. “Dejittered” estimates of the feature selectivity of a neuron are more accurate (i.e., provide a better estimate of the mean waveform eliciting a spike) and more precise (i.e., have smaller variance around that waveform) than estimates obtained using standard techniques. Moreover, this approach yields an explicit measure of spike-timing precision. We applied this technique to study feature selectivity and spike-timing precision in two types of sensory interneurons in the cricket cercal system. The dejittered estimates of the mean stimulus waveforms preceding spikes were up to three times larger than estimates based on the standard techniques used in previous studies and had power that extended into higher-frequency ranges. Spike timing precision was ∼5 ms.
Stimulus-Dependent γ (30-50 Hz) Oscillations in Simple and Complex Fast Rhythmic Bursting Cells in Primary Visual Cortex
Authors: Cardin Jessica A. , Palmer Larry A. , Contreras Diego
Published: June 2005

Oscillatory activity is generated by many neural systems. γ band (∼40 Hz) oscillations in the thalamus and cortex occur spontaneously and in response to sensory stimuli. Fast rhythmic bursting (FRB) cells (also called chattering cells) comprise a unique class of cortical neurons that, during depolarization by current injection, intrinsically generate bursts of high-frequency action potentials with an interburst frequency between 30 and 50 Hz. In the present study, we show for the first time that FRB cells in the primary visual cortex can be either simple or complex and are distributed throughout all cortical layers. Strikingly, both simple and complex FRB cells generate spike bursts at γ frequencies in response to depolarizing current pulses, but only simple FRB cells exhibit a selective, stimulus feature-dependent increase in γ oscillations in response to visual stimulation. In addition, we find that hyperpolarization does not reduce the relative power of visually evoked γ oscillations in theVmresponse of FRB cells. Our results thus indicate that visually evoked γ activity in individual simple and complex FRB cells is generated in large part by rhythmic synaptic input, rather than by depolarization-dependent activation of intrinsic properties. Finally, the presence of FRB cells in layer 6 suggests a role for corticothalamic feedback in potentiating thalamic oscillations and facilitating the generation of a corticothalamocortical oscillatory loop. We propose that rather than functioning as pacemakers, FRB cells amplify and distribute stimulus-driven γ oscillations in the neocortex.
Common Encoding of Novel Dynamic Loads Applied to the Hand and Arm
Authors: Davidson Paul R. , Wolpert Daniel M. , Scott Stephen H. , Flanagan J. Randall
Published: June 2005

In manual action, the relationship between a given motor command and the ensuing movement depends on the dynamics of both the arm and hand-held objects. Skilled performance relies on the brain learning both these dynamics, and previous studies have examined how people adapt to novel loads applied to either the hand or the arm. In this study, we ask whether these different kinds of load are represented independently as a result of changes in cutaneous feedback and hand-arm coordination. We used a robotic apparatus that could either apply forces to an object held in the subject's hand or directly to the segments of the arm. We tested whether subjects could retain learning of a force field applied to the hand after subsequently experiencing the opposing field applied to the arm (or vice versa), or whether retrograde interference would be observed. In separate experiments, we used force fields and torque fields that were linearly related to either hand or joint velocities, respectively. Our finding of complete interference between opposing fields suggests that loads applied to the arm and hand are not represented independently by the sensorimotor system. This interference occurred despite markedly different cutaneous inputs that were directly related to the movement task. This result suggests that the brain represents dynamics independently of these sensory inputs. In addition, we found that the rate at which subjects adapted to a given force field, specified either in hand or joint coordinates, was independent of whether the forces were applied to the hand or arm segments.
Neuronal, Endocrine, and Anorexic Responses to the T-Cell Superantigen Staphylococcal Enterotoxin A: Dependence on Tumor Necrosis Factor-α
Authors: Rossi-George Alba , Urbach Daniella , Colas Danielle , Goldfarb Yael , Kusnecov Alexander W.
Published: June 2005

Staphylococcal enterotoxin A (SEA) is a microbial superantigen that activates T-lymphocytes and induces production of various cytokines, including tumor necrosis factor-α (TNFα). Previously, it was shown that SEA activates the hypothalamic-pituitary-adrenal axis and augments gustatory neophobic behaviors. In the present study, it was hypothesized that these effects involve neuronal activation in forebrain regions mediating fear and/or anxiety and are dependent on the production of TNFα. Male C57BL/6J mice were given intraperitoneal injections of 10 μg of SEA and 5 μg of lipopolysaccharide (LPS) or saline and perfused 2 h later for histochemical determination of brain c-Fos immunoreactivity (IR). The results showed increased c-Fos IR in the paraventricular nucleus, arcuate nucleus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and lateral septum. Challenge of TNF-/-mice with SEA did not produce a significant increase in brain c-Fos IR, although c-Fos was increased after exposure to a psychogenic stressor (i.e., open field). In additional experiments, the elevated corticosterone response to SEA was abrogated in TNF-/-mice and was shown to be corticotropin-releasing hormone dependent. Finally, the augmented reduction in novel food intake after SEA challenge was attenuated in TNF-/-mice as well as in wild-type mice administered antibody to TNFα. In conclusion, challenge with SEA recruits brain regions mediating stress and anxiety responses, an effect that requires endogenous TNFα. Whether this is indicative of all T-cell superantigens remains to be determined, although it stands in contrast to other models of neuroimmunomodulation (e.g., LPS) that involve multiple cytokine influences.
DNA Methylation Status ofSOX10Correlates with Its Downregulation and Oligodendrocyte Dysfunction in Schizophrenia
Authors: Iwamoto Kazuya , Bundo Miki , Yamada Kazuo , Takao Hitomi , Iwayama-Shigeno Yoshimi , Yoshikawa Takeo , Kato Tadafumi
Published: June 2005

Downregulation of oligodendrocyte-related genes, referred to as oligodendrocyte dysfunction, in schizophrenia has been revealed by DNA microarray studies. Because oligodendrocyte-specific transcription factors regulate the differentiation of oligodendrocytes, genes encoding them are prime candidates for oligodendrocyte dysfunction in schizophrenia. We found that the cytosine-guanine dinucleotide (CpG) island of sex-determining region Y-box containing gene 10 (SOX10), an oligodendrocyte-specific transcription factor, tended to be highly methylated in brains of patients with schizophrenia, correlated with reduced expression ofSOX10. We also found that DNA methylation status ofSOX10also was associated with other oligodendrocyte gene expressions in schizophrenia. This may be specific toSOX10, because the CpG island ofOLIG2, which encodes another oligodendrocyte-specific transcription factor, was rarely methylated in brains, and the methylation status of myelin-associated oligodendrocytic basic protein, which encodes structural protein in oligodendrocytes, did not account for their expressions or other oligodendrocyte gene expressions. Therefore, DNA methylation status of theSOX10CpG island could be an epigenetic sign of oligodendrocyte dysfunction in schizophrenia.
Impaired Motor Learning in Mice Expressing TorsinA with the DYT1 Dystonia Mutation
Authors: Sharma Nutan , Baxter Mark G. , Petravicz Jeremy , Bragg D. Cristopher , Schienda Alonna , Standaert David G. , Breakefield Xandra O.
Published: June 2005

Primary early-onset generalized dystonia is an autosomal dominant disorder caused by a deletion (ΔGAG) in the DYT1 gene encoding torsinA. The gene defect has incomplete penetrance, with ∼30% of carriers developing clinically evident dystonia. We describe lines of transgenic mice that express either human mutant torsinA (hMT) or human wild-type (hWT) torsinA. All mice demonstrated moderately increased levels of torsinA in the brain by Western blot analysis and normal subcellular distribution of torsinA in neurons by confocal microscopy. No animals had dystonic features. However, mice overexpressing hMT, but not hWT, torsinA displayed a reduced ability to learn motor skills in an accelerating rotarod paradigm. This pattern resembles the impaired motor sequence learning demonstrated in human nonmanifesting carriers of the ΔGAG mutation. Open-field testing showed no differences in spontaneous activity between transgenic mice and their nontransgenic littermates, indicating that mice overexpressing hMT torsinA did not develop overtly abnormal motor behavior. Together, these data suggest that these transgenic mice provide a useful model of the ΔGAG carrier state that can be used to probe genetic and environmental factors that can trigger the dystonic state.
Rapid Reversible Changes in Dendritic Spine StructureIn VivoGated by the Degree of Ischemia
Authors: Zhang Shengxiang , Boyd Jamie , Delaney Kerry , Murphy Timothy H.
Published: June 2005

Current therapeutic windows for effective application of thrombolytic agents are within 3-6 h of stroke. Although treatment can improve outcome, it is unclear what happens to synaptic fine structure during this critical periodin vivo. The relationship between microcirculation and dendritic spine structure was determined in mouse somatosensory neurons during stroke. Spines were, on average, 13 μm from a capillary and were supplied by ∼100 red blood cells per second. Moderate ischemia (∼50% supply) did not significantly affect spines within 5 h; however, severe ischemia (<10% supply) caused a rapid loss of spine and dendrite structure within as little as 10 min. Surprisingly, if reperfusion occurred within 20-60 min, dendrite and spine structure was mostly restored. These data suggest that the basic dendritic wiring diagram remains mostly intact during moderate ischemia and that affected synapses could potentially contribute to functional recovery. With severe ischemia, markedly deformed dendritic structure can partially recover if reperfusion occurs early.
The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration
Authors: Park So-Young , Ferreira Adriana
Published: June 2005

Recently, we have shown that the microtubule-associated protein tau is essential for β-amyloid (Aβ)-induced neurotoxicity in hippocampal neurons. However, the mechanisms by which tau mediates Aβ-induced neurite degeneration remain poorly understood. In the present study, we analyzed whether tau cleavage played a role in these events. Our results showed that pre-aggregated Aβ induced the generation of a 17 kDa tau fragment in cultured hippocampal neurons. The generation of this fragment was preceded by the activation of calpain-1. Conversely, inhibitors of this protease, but not of caspases, completely prevented tau proteolysis leading to the generation of the 17 kDa fragment and significantly reduced Aβ-induced neuronal death. Furthermore, the expression of this fragment in cultured hippocampal neurons induced the formation of numerous varicosity-bearing tortuous processes, as well as the complete degeneration of some of those neurite processes. These results suggest that Aβ-induced neurotoxicity may be mediated, at least in part, through the calpain-mediated generation of a toxic 17 kDa tau fragment. Collectively, these results provide insight into a novel mechanism by which tau could mediate Aβ-induced neurotoxicity.
The Neural Correlates of Motor Skill Automaticity
Authors: Poldrack Russell A. , Sabb Fred W. , Foerde Karin , Tom Sabrina M. , Asarnow Robert F. , Bookheimer Susan Y. , Knowlton Barbara J.
Published: June 2005

Acquisition of a new skill is generally associated with a decrease in the need for effortful control over performance, leading to the development of automaticity. Automaticity by definition has been achieved when performance of a primary task is minimally affected by other ongoing tasks. The neural basis of automaticity was examined by testing subjects in a serial reaction time (SRT) task under both single-task and dual-task conditions. The diminishing cost of dual-task performance was used as an index for automaticity. Subjects performed the SRT task during two functional magnetic imaging sessions separated by 3 h of behavioral training over multiple days. Behavioral data showed that, by the end of testing, subjects had automated performance of the SRT task. Before behavioral training, performance of the SRT task concurrently with the secondary task elicited activation in a wide network of frontal and striatal regions, as well as parietal lobe. After extensive behavioral training, dual-task performance showed comparatively less activity in bilateral ventral premotor regions, right middle frontal gyrus, and right caudate body; activity in other prefrontal and striatal regions decreased equally for single-task and dual-task conditions. These data suggest that lateral and dorsolateral prefrontal regions, and their corresponding striatal targets, subserve the executive processes involved in novice dual-task performance. The results also showed that supplementary motor area and putamen/globus pallidus regions showed training-related decreases for sequence conditions but not for random conditions, confirming the role of these regions in the representation of learned motor sequences.
Light Stimulates MSK1 Activation in the Suprachiasmatic Nucleus via a PACAP-ERK/MAP Kinase-Dependent Mechanism
Authors: Butcher Greg Q. , Lee Boyoung , Cheng Hai-Ying M. , Obrietan Karl
Published: June 2005

Signaling via the p42/44 mitogen-activated protein kinase (MAPK) pathway has been shown to be a key intracellular signaling event that couples light to entrainment of the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). Because many of the physiological effects of the MAPK pathway are mediated by extracellular signal-regulated kinase (ERK)-regulated kinases, it was of interest to identify kinase targets of ERK in the SCN. In this study, we examined whether mitogen- and stress-activated protein kinase 1 (MSK1) is a downstream target of ERK in the SCN and whether it couples to clock gene expression. Here we show that photic stimulation during the subjective night stimulates MSK1 phosphorylation at serine 360, an event required for robust kinase activation. Activated ERK and MSK1 were colocalized in SCN cell nuclei after photic stimulation. Thein vivoadministration of the MAP kinase kinase 1/2 inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene] attenuated MSK1 phosphorylation. MSK1 phosphorylation was more responsive to late-night than early-night photic stimulation, indicating that MSK1 may differentially contribute to light-induced phase advancing and phase delaying of the clock. The potential connection between pituitary adenylate cyclase-activating polypeptide (PACAP) (a regulator of clock entrainment) and MSK1 phosphorylation was examined. PACAP infusion stimulated MSK1 phosphorylation, whereas PACAP receptor antagonist infusion attenuated light-induced MSK1 phosphorylation in the SCN. In reporter gene assays, MSK1 was shown to couple to mPeriod1 via a cAMP response element-binding protein-dependent mechanism. Together, these data identify MSK1 as both a downstream target of the MAPK cascade within the SCN and a regulator of clock gene expression.
Cell-Cycle Reentry and Cell Death in Transgenic Mice Expressing Nonmutant Human Tau Isoforms
Authors: Andorfer Cathy , Acker Christopher M. , Kress Yvonne , Hof Patrick R. , Duff Karen , Davies Peter
Published: June 2005

Mutations in the microtubule-associated protein tau gene have been linked to neurofibrillary tangle (NFT) formation in several neurodegenerative diseases known as tauopathies; however, no tau mutations occur in Alzheimer's disease, although this disease is also characterized by NFT formation and cell death. Importantly, the mechanism of tau-mediated neuronal death remains elusive. Aged mice expressing nonmutant human tau in the absence of mouse tau (htau mice) developed NFTs and extensive cell death. The mechanism of neuron death was investigated in htau mice, and surprisingly, the presence of tau filaments did not correlate directly with death within individual cells, suggesting that cell death can occur independently of NFT formation. Our observations show that the mechanism of neurodegeneration involved reexpression of cell-cycle proteins and DNA synthesis, indicating that nonmutant tau pathology and neurodegeneration may be linked via abnormal, incomplete cell-cycle reentry.
ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTRand Sortilin
Authors: Teng Henry K. , Teng Kenneth K. , Lee Ramee , Wright Saundrene , Tevar Seema , Almeida Ramiro D. , Kermani Pouneh , Torkin Risa , Chen Zhe-Yu , Lee Francis S. , Kraemer Rosemary T. , Nykjaer Anders , Hempstead Barbara L.
Published: June 2005

Brain-derived neurotrophic factor (BDNF) is best characterized for critical roles in neuronal survival, differentiation, and synaptic modulation mediated by the TrkB receptor tyrosine kinase. Developmentally regulated death signaling by BDNF has also been demonstrated via activation of p75NTR. Because recent studies suggest that proNGF, the precursor form of NGF, is more active than mature NGF in inducing apoptosis after binding to p75NTRand a coreceptor, sortilin, we asked whether the precursor of BDNF (proBDNF) is also a proapoptotic ligand in the nervous system. proBDNF is secreted by cultured neurons, and recombinant proBDNF binds to sortilin. In sympathetic neurons coexpressing sortilin and p75NTR, we found that proBDNF is an apoptotic ligand that induces death at subnanomolar concentrations. In contrast, mature BDNF, but not proBDNF, is effective in inducing TrkB phosphorylation. proBDNF effects are dependent on cellular coexpression of both p75NTRand sortilin, because neurons deficient in p75NTRare resistant to proBDNF-induced apoptosis, and competitive antagonists of sortilin block sympathetic neuron death. Moreover, addition of preformed complexes of soluble sortilin and proBDNF failed to induce apoptosis of cells coexpressing both sortilin and p75NTR, suggesting that interaction of proBDNF with both receptors on the cell surface is required to initiate cell death. Together with our past findings, these data suggest that the neurotrophin family is capable of modulating diverse biological processes via differential processing of the proneurotrophins.
Nogo-A Interacts with the Nogo-66 Receptor through Multiple Sites to Create an Isoform-Selective Subnanomolar Agonist
Authors: Hu Fenghua , Liu Betty P. , Budel Stephane , Liao Ji , Chin Joanna , Fournier Alyson , Strittmatter Stephen M.
Published: June 2005

Nogo is a myelin-derived protein that limits axonal regeneration after CNS injury. A short hydrophilic Nogo-66 loop between two hydrophobic domains of Nogo binds to a Nogo-66 receptor (NgR) to inhibit axonal outgrowth. Inhibition of axon outgrowth and cell spreading by a second Nogo domain, termed Amino-Nogo-A, is thought to be mediated by a distinct receptor complex. Here, we define a novel Nogo-A-specific domain in Amino-Nogo that binds to NgR with nanomolar affinity. This second domain of 24 amino acids does not alter cell spreading or axonal outgrowth. Fusion of the two NgR-binding Nogo-A domains creates a ligand with substantially enhanced affinity for NgR and converts a NgR antagonist peptide to an agonist. Thus, NgR activation by Nogo-A involves multiple sites of interaction between Nogo-A and NgR.
Psychosocial Risk Associated With Newborn Screening for Cystic Fibrosis: Parents’ Experience While Awaiting the Sweat-Test Appointment
Authors: Tluczek Audrey , Koscik Rebecca L. , Farrell Philip M. , Rock Michael J.
Published: June 2005

Background. The psychosocial effects on parents of infants with abnormal results in cystic fibrosis (CF) newborn screening (NBS) that uses genetic testing remain unclear.

Methods. Twenty-eight individuals representing 14 families participated in grounded theory interviews ∼6 months after their child’s positive NBS results for CF. Participants also completed the Center for Epidemiologic Studies Depression Scales (CES-D) at their infant’s sweat-test appointment (n = 51) and/or ∼6 months after the sweat test (n = 35).

Results. Most parents experienced high levels of emotional distress during their wait for the sweat-test appointment (CES-D score, mean ± SD: 16.5 ± 6.7; 43.1% in the clinical range; median wait: 7 days; range: 3–35 days). CES-D scores of these parents were also significantly higher than those of comparison parents. Interviews showed that parental cognitive uncertainty and emotional distress were influenced by the parents’ prior knowledge of NBS, CF, and their carrier status; parents’ adjustment to their new baby; and the physicians’ approach to informing parents. Parents’ coping strategies involved requesting a sweat test as soon as possible, searching for information, assessing the infant’s risk/health, seeking support, praying, or not talking with others.

Conclusions. The waiting period from notification regarding positive NBS results to diagnostic test results can be psychologically distressing to parents, causing depressive symptoms that vary depending on their perceptions about the likelihood that their infant has CF. Implications for future research examining psychosocial interventions for NBS are discussed.
Addressing Transition to Adult Health Care for Adolescents With Special Health Care Needs
Authors: Scal Peter , Ireland Marjorie
Published: June 2005

Objective. To determine the factors associated with addressing the transition from pediatric to adult-oriented health care among US adolescents with special health care needs.

Methods. Data for 4332 adolescents, 14 to 17 years of age, from the 2000–2001 National Survey of Children With Special Health Care Needs were used. The adequacy of transition services was determined by parent self-report. Explanatory variables, including parental education, family poverty status, race/ethnicity, measures of the severity and complexity of conditions, health insurance status, having a personal doctor, and the quality of the parent's relationship with the adolescent's doctor, were entered into a regression model.

Results. Overall, 50.2% of parents reported that they had discussed transition issues with their adolescent's doctor and 16.4% had discussed and developed a plan for addressing those needs. In a multivariate regression analysis, correlates of the adequacy of transition services included older age, female gender, complexity of health care needs, and higher quality of the parent-doctor relationship.

Conclusions. Among adolescents with special health care needs, those who were older and those with more complicated needs were more likely to have addressed the transition from a pediatric to adult-oriented system of care. Furthermore, this analysis demonstrated a strong association between a high-quality parent-provider relationship and the extent to which transition issues were addressed. The importance of transition services for adolescents with less complex needs and the overall impact of health care transition services were not assessed in this study and remain important questions for future investigations.
Evaluation of a Unique, Nurse-Inserted, Peripherally Inserted Central Catheter Program
Authors: Gamulka Beth , Mendoza Cristina , Connolly Bairbre
Published: June 2005

Background. Concerns regarding the safety and success of peripherally inserted central catheters (PICCs) placed at the bedside in the pediatric population initially precluded the development of a nurse-inserted PICC program at our pediatric center. Previously, all PICCs were inserted by interventional radiologists (IRs) with fluoroscopic guidance. A new nurse-inserted PICC program was initiated with collaboration between PICC nurses and IRs.

Methods. Three nurses participated in the project. Patients who met preestablished selection criteria were approached. All insertions were performed with sterile technique on the fluoroscopy table, with IRs available to support the PICC nurse. Veins were accessed visually or through palpation. Final tip position was confirmed in all cases with contrast material administration and fluoroscopy. Additional fluoroscopy was performed only if placement difficulties were encountered. All patients were monitored prospectively.

Results. Ninety-nine patients (age: 3–18 years; average age: 13.6 years) met the selection criteria. Two patients underwent primary insertion by an IR. The remaining 97 patients underwent an insertion attempt by a nurse. Sixty-nine PICCs (71.1%) were placed successfully by a nurse, 15 (15.5%) required minor assistance from an IR, and 13 (13.4%) were inserted by an IR after an unsuccessful nurse attempt. No insertion complications were noted. Insertion difficulties included difficulty advancing the catheter (19.6%), difficulty cannulating the vein (6.2%), and tip malposition (2.1%). Postinsertion complications occurred for 27.8% of PICCs, and 13.4% required removal before the end of therapy.

Conclusion. This novel, pediatric nurse-inserted PICC program has a good safety profile, high success rate, and low postprocedural complication rate.