bluuebunny/crossref_metadata_2025 huggingface dataset:
Precautionary wealth accumulation: evidence from Canadian microdata
Authors: Alan Sule
Published: November 2006

Abstract This paper estimates the effect of labour income uncertainty on wealth accumulation using two data sources. Wealth information is obtained from the master files of the new Canadian Survey of Financial Security 1999 (SFS). Labour income risk proxies are constucted by industry using the Canadian Survey of Labour and Income Dynamics (SLID) between 1996 and 2001. The empirical results suggest the presence of a strong precautionary saving motive among Canadian households for broad definitions of wealth. Furthermore, consistent with the buffer‐stock‐saving model, the level of precautionary funds significantly increases when households face liquidity constraints.
The changing role of dividends: a firm‐level study from the nineteenth to the twenty‐first century
Authors: Foerster Stephen R. , Sapp Stephen G.
Published: November 2006

Abstract We investigate the changes in dividend policy for one of North America's oldest banks (and Canada's first bank), Bank of Montreal, over time by considering the relationships between dividends, prices and earnings for this prominent firm. In the early part of the sample we find that annual dividend and earnings changes are highly variable, with dividend changes following changes in earnings and a larger portion of investors' returns coming from dividends. Since World War II dividend policy has been characterized by more stable and gradual increases in dividends, with more of investors' returns coming from capital gains. Overall, our results suggest that investors' perception of dividends has changed over time, allowing management to pay smaller dividends and reinvest funds in the firm.
Errors of aggregation and errors of specification in a consumer demand model: a theoretical note
Authors: Denton Frank T. , Mountain Dean C. , Spencer Byron G
Published: November 2006

Abstract Consumer demand models based on the concept of a representative or average consumer suffer from aggregation error. Misspecification of the underlying micro utility‐maximizing model, which is virtually inevitable, also results in error. This note provides a theoretical investigation of the relationship between the two types of error. Misspecified expenditure support functions for demand systems at the micro level induce the same misspecified structure in the corresponding expenditure functions at the macro level, and the errors at the two levels are shown to be of similar order.
The Electroanatomic Characteristics of the Cavotricuspid Isthmus: Implications for the Catheter Ablation of Atrial Flutter
Authors: CHANG SHIH‐LIN , TAI CHING‐TAI , LIN YENN‐JIANG , ONG MARY GERTRUDE , WONGCHAROEN WANWARANG , LO LI‐WEI , CHANG SHENG‐HSIUNG , HSIEH MING‐HSIUNG , CHEN SHIH‐ANN
Published: November 2006

Introduction: Radiofrequency ablation (RFA) of typical AFL is sometimes difficult because of the poor electroanatomic approach to the cavotricuspid isthmus (CTI). The aim of this study was to correlate the anatomy of the CTI between contact mapping (NavX) and right atrial angiography (RAG), and to investigate the impact of the electroanatomic characteristics of the CTI on the RFA of typical atrial flutter (AFL).

Methods: One hundred patients with typical AFL undergoing RFA were studied. The image‐guided group consisted of 50 consecutive patients with the guidance of NavX. NavX geometry and RAG were performed to investigate the morphology of the CTI. The bipolar voltages of the CTI were collected during sinus rhythm by a NavX. The control group consisted of 50 consecutive patients with the guidance of conventional fluoroscopy.

Results: There was a good correlation between the angiography and NavX for the anatomy of the CTI. The pouch type had a longer length of CTI than the flat type (33.4 ± 5.0 vs 22.6 ± 8.4 mm, P < 0.0001) and deeper depth than the concave type (6.5 ± 2.2 vs 3.7 ± 0.8 mm, P < 0.0001) on the angiography. The pouch‐type CTI had a longer ablation time and larger pulses of RFA than the other two types. The control group had a longer ablation time, fluoroscopy time, and larger pulses of RFA than image‐guided group.

Conclusions: The 3‐D mapping system provided a good reconstruction of CTI, which may help in the RFA in patients with a complex anatomy of the CTI.
Interleukin (IL)‐19, IL‐20 and IL‐24 are produced by and act on keratinocytes and are distinct from classical ILs
Authors: Kunz Stefanie , Wolk Kerstin , Witte Ellen , Witte Katrin , Doecke Wolf‐Dietrich , Volk Hans‐Dieter , Sterry Wolfram , Asadullah Khusru , Sabat Robert
Published: November 2006

Abstract:  Due to their structural similarity, interleukin (IL)‐19, IL‐20, IL‐22, IL‐24 and IL‐26 were combined with IL‐10 in the so‐called IL‐10 family. To expand the knowledge on IL‐19, IL‐20 and IL‐24, we systematically and quantitatively analysed the expression of these mediators and their receptor chains in vitro and in vivo under various conditions and in comparison with other IL‐10 family members. In vitro, IL‐19, IL‐20 and IL‐24 were produced not only by activated immune cells, particularly monocytes, but also to a similar extent by keratinocytes. IL‐1β increased the expression of these mediators 1000‐fold (IL‐19) and 10‐fold (IL‐20 and IL‐24) in keratinocytes. In vivo, these cytokines were expressed preferentially in inflamed tissues. The absence of either R1 chain for the two types of receptor complexes for these cytokines (IL‐20R1/IL‐20R2 and IL‐22R1/IL‐20R2) on immune cells implies that they cannot act on these cells. In fact, IL‐19, IL‐20 and IL‐24 did not induce activation of signal transducer and activator of transcription (STAT) molecules in immune cells. Instead, several tissues, particularly the skin, tissues from the reproductive and respiratory systems, and various glands appeared to be the main targets of these mediators. Keratinocytes expressed both receptor complexes; however, the expression of IL‐22R1 was 10 times higher than that of IL‐20R1. Interferon‐γ further increased the expression of IL‐22R1 and decreased that of IL‐20R1, suggesting that under T1 cytokine conditions these mediators primarily affect keratinocytes via the IL‐22R1/IL‐20R2 complex. In summary, these data support the notion that IL‐19, IL‐20 and IL‐24 are distinct from classical ILs and constitute a separate subfamily of mediators within the IL‐10 family.
Species-Specific Differences in the Activity of PrfA,the Key Regulator of Listerial VirulenceGenes
Authors: Mauder Norman , Ecke Regina , Mertins Sonja , Loeffler Daniela I. M. , Seidel Gerald , Sprehe Mareen , Hillen Wolfgang , Goebel Werner , Müller-Altrock Stefanie
Published: November 2006

PrfA, the master regulator of LIPI-1, is indispensable for the pathogenesis of the human pathogenListeria monocytogenesand the animal pathogenListeria ivanovii. PrfA is also present in the apathogenic speciesListeria seeligeri, and in this study, we elucidate the differences between PrfA proteins from the pathogenic and apathogenic species of the genusListeria. PrfA proteins ofL. monocytogenes(PrfALmand PrfA*Lm),L. ivanovii(PrfALi), andL. seeligeri(PrfALs) were purified, and their equilibrium constants for binding to the PrfA box of thehlypromoter (PhlyLm) were determined by surface plasmon resonance. In addition, the capacities of these PrfA proteins to bind to the PrfA-dependent promoters Phlyand PactAand to form ternary complexes together with RNA polymerase were analyzed in electrophoretic mobility shift assays, and their abilities to initiate transcription in vitro starting at these promoters were compared. The results show that PrfALiresembled the constitutively active mutant PrfA*Lmmore than the wild-type PrfALm, whereas PrfALsshowed a drastically reduced capacity to bind to the PrfA-dependent promoters Phlyand PactA. In contrast, the efficiencies of PrfALm, PrfA*Lm, and PrfALiforming ternary complexes and initiating transcription at Phlyand PactAwere rather similar, while those of PrfALswere also much lower. The low binding and transcriptional activation capacities of PrfALsseem to be in part due to amino acid exchanges in its C-terminal domain (compared to PrfALmand PrfALi). In contrast to the significant differences in the biochemical properties of PrfALm, PrfALi, and PrfALs, the PrfA-dependent promoters ofhly(PhlyLm, PhlyLi, and PhlyLs) andactA(PactALm, PactALi, and PactALs) of the threeListeriaspecies did not significantly differ in their binding affinities to the various PrfA proteins and in their strengths to promote transcription in vitro. The allelic replacement ofprfALmwithprfALsinL. monocytogenesleads to low expression of PrfA-dependent genes and to reduced in vivo virulence ofL. monocytogenes, suggesting that the altered properties of PrfALsprotein are a major cause for the low virulence ofL. seeligeri.
Salmonella enterica
Serovar Typhimurium Periplasmic Superoxide Dismutase SodCI Is a Member of the PhoPQ Regulon and Is Induced in Macrophages
Authors: Golubeva Yekaterina A. , Slauch James M.
Published: November 2006

Salmonella enterica
serovar Typhimurium replicates within host macrophages during the systemic stage of infection. In the macrophage, the bacteria must survive the respiratory burst that produces superoxide. Serovar Typhimurium strain 14028 produces two periplasmic superoxide dismutases, SodCI and SodCII, but only SodCI contributes to virulence. Although we have shown that this is primarily due to differences in the two proteins, evidence suggests differential regulation of the two genes. Using transcriptional
sodCI-
and
sodCII-lac
fusions, we show that
sodCII
is under the control of the RpoS sigma factor, as was known for the
Escherichia coli
ortholog,
sodC
. In contrast, we show that
sodCI
is transcriptionally controlled by the PhoPQ two-component regulatory system, which regulates an array of virulence genes required for macrophage survival. Introduction of a
phoP
-null mutation into the
sodCI
fusion strain resulted in a decrease in transcription and loss of regulation. The
sodCI
-
lac
fusion showed high-level expression in a background containing a
phoQ
constitutive allele. The
sodCI
gene is induced 15-fold in bacteria recovered from either the tissue culture macrophages or the spleens of infected mice. Induction in macrophages is dependent on PhoP. The
sodCII
fusion was induced three- to fourfold in macrophages and animals; this induction was unaffected by loss of PhoP. Thus,
sodCI
, which is horizontally transferred by the Gifsy-2 phage, is regulated by PhoPQ such that it is induced at the appropriate time and place to combat phagocytic superoxide.
The Ser/Thr Protein Kinase PknB Is Essential for Sustaining Mycobacterial Growth
Authors: Fernandez Pablo , Saint-Joanis Brigitte , Barilone Nathalie , Jackson Mary , Gicquel Brigitte , Cole Stewart T. , Alzari Pedro M.
Published: November 2006

The receptor-like protein kinase PknB from
Mycobacterium tuberculosis
is encoded by the distal gene in a highly conserved operon, present in all actinobacteria, that may control cell shape and cell division. Genes coding for a PknB-like protein kinase are also found in many more distantly related gram-positive bacteria. Here, we report that the
pknB
gene can be disrupted by allelic replacement in
M. tuberculosis
and the saprophyte
Mycobacterium smegmatis
only in the presence of a second functional copy of the gene. We also demonstrate that eukaryotic Ser/Thr protein kinase inhibitors, which inactivate PknB in vitro with a 50% inhibitory concentration in the submicromolar range, are able to kill
M. tuberculosis
H37Rv,
M. smegmatis
mc
2
155, and
Mycobacterium aurum
A+ with MICs in the micromolar range. Furthermore, significantly higher concentrations of these compounds are required to inhibit growth of
M. smegmatis
strains overexpressing PknB, suggesting that this protein kinase is the molecular target. These findings demonstrate that the Ser/Thr protein kinase PknB is essential for sustaining mycobacterial growth and support the development of protein kinase inhibitors as new potential antituberculosis drugs.
THE EFFECT OF Fe SUBSTITUTION ON THE STRUCTURAL TRANSITION OF LaMn1-xFexO3 MANGANITES: A RAMAN SPECTROSCOPY STUDY
Authors: VAN MINH NGUYEN , HOC NGUYEN QUANG , HA PHUONG L. T. , YANG IN-SANG
Published: November 2006

We present results of Raman scattering studies on LaMn 1-x Fe x O 3+δ manganite over a wide range of doping content (x = 0.1 - 0.75). There is no previous Raman work on the LaMn 1-x Fe x O 3+δ manganite system. The analysis of Raman spectra of various doping contents allows us to identify a clear spectroscopic signature of structural change from orthorhombic to rhombohedral at x = 0.4 as x increases. At x = 0.4, both phases coexist. This result is in good agreement with our XRD results. The resistance vs. temperature relation indicates that there is no metal-insulator transition in these samples in the range of observed temperatures. No abrupt change in the peak frequencies is observed across the measured temperatures. This indicates that the structural changes are not spatially coherent, but local in nature.
OPTICS WITH NANO-SIZED STRUCTURES MADE FROM SEMICONDUCTORS AND (NOBLE) METALS
Authors: KNOLL WOLFGANG , ZHONG XINHUA , STEFANI FERNANDO , ROBELEK RUDOLF , NIU LIFANG , ROCHHOLZ HEIKO , SHUMAKER-PARRY JENNIFER , KREITER MAX
Published: November 2006

We summarize some of our efforts in synthesizing and characterizing nanoscopic objects fabricated from semiconducting materials and noble metals. The optical properties of colloidal semiconductors (quantum dots) are analyzed, in particular, with respect to their spectral photoluminescence properties (bandgap engineering) and the characteristic emission blinking. The statistical evaluation of the on- and off-states seen in the time-dependent recordings of the photoluminescence emitted from a single nanoparticle confirmed the reported power-law probability distribution, however, with a superimposed decay of the on-state density (which is illumination intensity dependent). This results in a loss of fluorescence intensity upon extended illumination when these particles are used in biosensor assays. Next, a colloid particle-based template protocol for the fabrication of non-trivial Au nanostructures is described. The resulting nano-crescents can be varied in terms of their size and shape. It is demonstrated how their plasmonic resonance characteristics can thus be tuned with respect to the spectral position of their (multipole) absorbance peaks, and their polarization properties.
Serotonin Facilitates a Persistent Calcium Current in Motoneurons of Rats With and Without Chronic Spinal Cord Injury
Authors: Li X. , Murray K. , Harvey P. J. , Ballou E. W. , Bennett D. J.
Published: November 2006

In the months after spinal cord transection, motoneurons in the rat spinal cord develop large persistent inward currents (PICs) that are responsible for muscle spasticity. These PICs are mediated by low-threshold TTX-sensitive sodium currents (Na PIC) and L-type calcium currents (Ca PIC). Recently, the Na PIC was shown to become supersensitive to serotonin (5-HT) after chronic injury. In the present paper, a similar change in the sensitivity of the Ca PIC to 5-HT was investigated after injury. The whole sacrocaudal spinal cord from acute spinal rats and spastic chronic spinal rats (S2 level transection 2 mo previously) was studied in vitro. Intracellular recordings were made from motoneurons and slow voltages ramps were applied to measure PICs. TTX was used to block the Na PIC. For motoneurons of chronic spinal rats, a low dose of 5-HT (1 μM) significantly lowered the threshold of the Ca PIC from −56.7 ± 6.0 to −63.1 ± 7.1 mV and increased the amplitude of the Ca PIC from 2.4 ± 1.0 to 3.0 ± 0.73 nA. Higher doses of 5-HT acted similarly. For motoneurons of acute spinal rats, low doses of 5-HT had no significant effects, whereas a high dose (about 30 μM) significantly lowered the threshold of the L-Ca PIC from −58.5 ± 14.8 to −62.5 ± 3.6 mV and increased the amplitude of the Ca PIC from 0.69 ± 1.05 to 1.27 ± 1.1 nA. Thus Ca PICs in motoneurons are about 30-fold supersensitive to 5-HT in chronic spinal rats. The 5-HT–induced facilitation of the Ca PIC was blocked by nimodipine, not by the Ihcurrent blocker Cs+(3 mM) or the SK current blocker apamin (0.15 μM), and it lasted for hours after the removal of 5-HT from the nCSF, even increasing initially after removing 5-HT. The effects of 5-HT make motoneurons more excitable and ultimately lead to larger, more easily activated plateaus and self-sustained firing. The supersensitivity to 5-HT suggests the small amounts of endogenous 5-HT below the injury in a chronic spinal rat may act on supersensitive receptors to produce large Ca PICs and ultimately enable muscle spasms.
Distinct Roles for IFN Regulatory Factor (IRF)-3 and IRF-7 in the Activation of Antitumor Properties of Human Macrophages
Authors: Romieu-Mourez Raphaëlle , Solis Mayra , Nardin Alessandra , Goubau Delphine , Baron-Bodo Véronique , Lin Rongtuan , Massie Bernard , Salcedo Margarita , Hiscott John
Published: November 2006

When properly activated, macrophages can be tumoricidal, thus making them attractive additions to standard cancer therapies. To this end, tolerance and activity of human autologous IFN-γ-activated macrophages, produced in large scale for clinical use (MAK cells), have been assessed in pilot trials in cancer patients. In the present study, we tested the hypothesis that activation of IFN regulatory factor (IRF)-3 and IRF-7, with subsequent type I IFN production, may be involved in the acquisition of new antitumor functions by macrophages. Adenoviral vectors were generated for the delivery of constitutively active forms of IRF-3 (Ad-IRF-3) or IRF-7 (Ad-IRF-7) into primary human macrophages. Cell death was observed in Ad-IRF-3-transduced macrophages, whereas Ad-IRF-7-transduced macrophages produced type I IFNs and displayed increased expression of genes encoding tumor necrosis factor (TNF)–related apoptosis-inducing ligand, interleukin (IL)-12, IL-15, and CD80, persisting for at least 96 hours. Expression of iNOS, TNF-α, FasL, IL-1, and IL-6 genes was unaltered by Ad-IRF-7 transduction. Interestingly, Ad-IRF-3 or Ad-IRF-7 transduction negatively regulated the transcription of protumorigenic genes encoding vascular endothelial growth factor and matrix metalloproteinase-2. Furthermore, Ad-IRF-7-transduced macrophages exerted a cytostatic activity on different cancer cell lines, including SK-BR-3, MCF-7, and COLO-205; the latter cells were shown previously to be insensitive to MAK cells. In conclusion, transduction of active forms of IRF-3 or IRF-7 differentially modulate the apoptotic and antitumor properties of primary macrophages, with active IRF-7 leading to the acquisition of novel antitumor effector functions. (Cancer Res 2006; 66(21): 10576-85)
Transgenic Mouse Model for Rapid Pharmacodynamic Evaluation of Antiandrogens
Authors: Ellwood-Yen Katharine , Wongvipat John , Sawyers Charles
Published: November 2006

Persistent androgen receptor signaling has been implicated as a critical factor in prostate cancer progression even at the hormone-refractory stage and provides strong rationale for developing novel androgen receptor antagonists. Traditional models for in vivo evaluation of antiandrogens are cumbersome because they rely on physiologic end points, such as the size of androgen-dependent tissues. Here, we describe a transgenic mouse (ARR2 Pb-Lux) that expresses luciferase specifically in the prostate in an androgen-dependent fashion. This signal is reduced by castration or by treatment with bicalutamide and can be quantified through noninvasive bioluminescent imaging. ARR2 Pb-Lux mice provide a novel method for rapid pharmacodynamic evaluation of novel pharmacologic compounds designed to inhibit androgen receptor signaling. (Cancer Res 2006; 66(21): 10513-6)
A Conserved RAS/Mitogen-Activated Protein Kinase Pathway Regulates DNA Damage–Induced Cell Death Postirradiation in Radelegans
Authors: Weidhaas Joanne B. , Eisenmann David M. , Holub Justin M. , Nallur Sunitha V.
Published: November 2006

Although the epidermal growth factor receptor (EGFR) signaling pathway is overactive in more than half of human cancers and mediates resistance to cytotoxic therapy, the molecular mechanisms of EGFR pathway–mediated resistance have remained elusive in cancer research. This difficulty partly stems from the lack of tissue models enabling clear separation of the many forms of cell death that the downstream signaling pathways of EGFR affect. We have created a model in Caenorhabditis elegans of radiation-induced reproductive cell death (“Radelegans”) in isolation of all other forms of cell death. We have employed Radelegans to genetically define the role of the EGFR signaling pathway in protection from reproductive cell death, the primary form of tumor stem or clonogen cell death postirradiation. We have found that the RAS/mitogen-activated protein kinase (MAPK) downstream signal transduction pathway of EGFR is critical for protection from reproductive cell death in Radelegans. In addition, we have shown that RAS/MAPK pathway signaling is genetically linear with the DNA damage response pathway and acts downstream of the DNA damage checkpoint in the radioresponse, implicating this pathway in DNA repair post-cytotoxic therapy. These findings support the hypothesis that enhanced repair is a mechanism of RAS/MAPK pathway–mediated resistance to cytotoxic therapy through its interaction with the DNA damage response pathway postirradiation. We postulate that these findings also help explain why current treatment strategies, based on the presumption that tumors have ineffective repair compared with normal tissues, are ineffective in EGFR/RAS/MAPK pathway–mediated tumors. Radelegans is a platform to further define the genetic basis of the radiation response in tissues. (Cancer Res 2006; 66(21): 10434-8)
Ras Induces Chromosome Instability and Abrogation of the DNA Damage Response
Authors: Abulaiti Adili , Fikaris Aphrothiti J. , Tsygankova Oxana M. , Meinkoth Judy L.
Published: November 2006

Ras mutations are frequent in thyroid tumors, the most common endocrine malignancy. The ability of Ras to transform thyroid cells is thought to rely on its mitogenic activity. Unexpectedly, acute expression of activated Ras in normal rat thyroid cells induced a DNA damage response, followed by apoptosis. Notably, a subpopulation of cells evaded apoptosis and emerged with features of transformation, including the loss of epithelial morphology, dedifferentiation, and the acquisition of hormone- and anchorage-independent proliferation. Strikingly, the surviving cells showed marked chromosomal instability. Acutely, Ras stimulated replication stress as evidenced by the induction of ataxia telangiectasia mutated and Rad3-related protein kinase (ATR) activity (Chk1 phosphorylation) and of γH2A.X, a marker of DNA damage. Despite the activation of a checkpoint, cells continued through mitosis in the face of DNA damage, resulting in an increase in cells harboring micronuclei, an indication of defects in chromosome segregation and other forms of chromosome damage. Cells that survived exposure to Ras continued to exhibit replication stress (ATR activation) but no longer exhibited γH2A.X or full activation of p53. When rechallenged with Ras or DNA-damaging agents, the surviving cells were more resistant to apoptosis than parental cells. These data show that acute expression of activated Ras is sufficient to induce chromosomal instability in the absence of other signals, and suggest that Ras-induced chromosomal instability arises as a consequence of defects in the processing of DNA damage. Hence, abrogation of the DNA damage response may constitute a novel mechanism for Ras transformation. (Cancer Res 2006; 66(21): 10505-12)
Norepinephrine Up-regulates the Expression of Vascular Endothelial Growth Factor, Matrix Metalloproteinase (MMP)-2, and MMP-9 in Nasopharyngeal Carcinoma Tumor Cells
Authors: Yang Eric V. , Sood Anil K. , Chen Min , Li Yang , Eubank Tim D. , Marsh Clay B. , Jewell Scott , Flavahan Nicholas A. , Morrison Carl , Yeh Peir-En , Lemeshow Stanley , Glaser Ronald
Published: November 2006

Recent studies using ovarian cancer cells have shown that the catecholamine hormones norepinephrine (norepi) and epinephrine (epi) may influence cancer progression by modulating the expression of matrix metalloproteinases (MMP) and vascular endothelial growth factor (VEGF). The purpose of this study is to determine if the stress hormone norepi can influence the expression of MMP-2, MMP-9, and VEGF in nasopharyngeal carcinoma (NPC) tumors by using three NPC tumor cell lines. The NPC cell lines HONE-1, HNE-1, and CNE-1 were treated with norepi. The effects of norepi on MMP-2, MMP-9, and VEGF synthesis were measured by ELISA; functional MMP activity was measured by the invasive potential of the cells using a membrane invasion culture system whereas functional activity of VEGF was analyzed using a human umbilical vein endothelial cell tube formation assay. Norepi treatment increased MMP-2, MMP-9, and VEGF levels in culture supernatants of HONE-1 cells, which could be inhibited by the β-blocker propranolol. Norepi induced the invasiveness of all NPC cell lines in a dose-dependent manner, which was blocked by CMT-3, an MMP inhibitor, and propranolol. Norepi stimulated the release of functional angiogenic VEGF by HONE-1 cells as well. Finally, HONE-1 cells were shown to express β-adrenergic receptors as did seven of seven NPC biopsies examined. The data suggest that catecholamine hormones produced by the sympathetic-adrenal medullary axis may affect NPC tumor progression, in part, through modulation of key angiogenic cytokines. (Cancer Res 2006; 66(21): 10357-64)
ATM deficiency disrupts Tcra locus integrity and the maturation of CD4+CD8+ thymocytes
Authors: Matei Irina R. , Gladdy Rebecca A. , Nutter Lauryl M. J. , Canty Angelo , Guidos Cynthia J. , Danska Jayne S.
Published: November 2006

Mutations in ATM (ataxia-telangiectasia mutated) cause ataxia-telangiectasia (AT), a disease characterized by neurodegeneration, sterility, immunodeficiency, and T-cell leukemia. Defective ATM-mediated DNA damage responses underlie many aspects of the AT syndrome, but the basis for the immune deficiency has not been defined. ATM associates with DNA double-strand breaks (DSBs), and some evidence suggests that ATM may regulate V(D)J recombination. However, it remains unclear how ATM loss compromises lymphocyte development in vivo. Here, we show that T-cell receptor β (TCRβ)–dependent proliferation and production of TCRβlow CD4+CD8+ (DP) thymocytes occurred normally in Atm−/− mice. In striking contrast, the postmitotic maturation of TCRβlow DP precursors into TCRβint DP cells and TCRβhi mature thymocytes was profoundly impaired. Furthermore, Atm−/− thymocytes expressed abnormally low amounts of TCRα mRNA and protein. These defects were not attributable to the induction of a BCL-2–sensitive apoptotic pathway. Rather, they were associated with frequent biallelic loss of distal Va gene segments in DP thymocytes, revealing that ATM maintains Tcra locus integrity as it undergoes V(D)J recombination. Collectively, our data demonstrate that ATM loss increases the frequency of aberrant Tcra deletion events, which compromise DP thymocyte maturation and likely promote the generation of oncogenic TCR translocations.
JAK/STAT signaling promotes regional specification by negatively regulatingwinglessexpression inDrosophila
Authors: Ekas Laura A. , Baeg Gyeong-Hun , Flaherty Maria Sol , Ayala-Camargo Aidee , Bach Erika A.
Published: November 2006

During development, a small number of conserved signaling molecules regulate regional specification, in which uniform populations of cells acquire differences and ultimately give rise to distinct organs. In the Drosophila eye imaginal disc, Wingless (Wg) signaling defines the region that gives rise to head tissue. JAK/STAT signaling was thought to regulate growth of the eye disc but not pattern formation. However, we show that the JAK/STAT pathway plays an important role in patterning the eye disc:it promotes formation of the eye field through repression of the wggene. Overexpression of the JAK/STAT activating ligand Unpaired in the eye leads to loss of wg expression and ectopic morphogenetic furrow initiation from the lateral margins. Conversely, tissue lacking stat92E, which cannot transduce JAK/STAT signals, is transformed from retinal tissue into head cuticle, a phenotype that is also observed with ectopic Wg signaling. Consistent with this, cells lacking stat92Eexhibit ectopic wg expression. Conversely, wg is autonomously repressed in cells with hyperactivated Stat92E. Furthermore, we show that the JAK/STAT pathway regulates a small enhancer in the wg3′ cis genomic region. As this enhancer is devoid of Stat92E-binding elements, we conclude that Stat92E represses wgthrough another, as yet unidentified factor that is probably a direct target of Stat92E. Taken together, our study is the first to demonstrate a role for the JAK/STAT pathway in regional specification by acting antagonistically to wg.
Plant development: new models and approaches bring progress
Authors: Long Jeff A.
Published: November 2006

In August 2006, plant biologists gathered at the FASEB `Mechanisms in Plant Development' meeting in Vermont, which was organized by Laurie Smith and Ueli Grossniklaus. A variety of plant developmental mechanisms were presented at this meeting and, although many talks focused on Arabidopsis thalianaas a primary model in which to study plant development, research in maize,tomato, Chlamydomonas and other plants also provided insight into various topics, such as cell-type specification, small RNA biosynthesis and action, hormone perception and transport, and cell and organ size.
Electron‐microscopic observations on the muscular coat of swell bodies in human nasal mucosa
Authors: Grevers G.
Published: November 2006

Morphology and function of so‐called nasal “swell bodies” or “cavernous tissue ” have been studied by many investigators during the past 140 years. However, many details of this interesting and peculiar tissue remained unsolved, even though this vascular system plays an important role in a variety of rhinologic disorders. The present study describes electron‐microscopic details of the muscular coat of the different venous structures that form human nasal swell bodies. The specimens were taken from patients requiring removal of conchal mucosa and septoplasty; semithin and ultrathin sections were obtained and examined with the optical and electron microscopes. The histologic evaluation showed differences in the venous wall structure depending on the location of the vessels. The muscular layers were significantly thinner in those parts of the swell bodies located adjacent to the epithelium. Electron‐microscopic studies enabled us to determine the cytoplasmic components of smooth muscle cells, i.e., thin filaments, glycogen granules, caveolar plasmalemmal areas, cytoplasmic dense bodies (CDB), and membrane‐associated dense bodies (MADB). Another interesting feature was the varying appearance of the basal lamina of smooth muscle cells of the cavernous tissue. Based on the findings of the present study, the morphologic peculiarities of nasal swell bodies are compared and discussed with the appropriate literature. Further immunohistochemical and molecular‐biological studies will have to be performed to understand the complex functional mechanism of this unique vascular system.
Absence of Tumor Necrosis Factor-α Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutations
Authors: Gowing Geneviève , Dequen Florence , Soucy Geneviève , Julien Jean-Pierre
Published: November 2006

An increase in the expression of the proinflammatory cytokine tumor necrosis factor α (TNF-α) has been observed in patients with amyotrophic lateral sclerosis (ALS) and in the mice models of the disease. TNF-α is a potent activator of macrophages and microglia and, under certain conditions, can induce or exacerbate neuronal cell death. Here, we assessed the contribution of TNF-α in motor neuron disease in mice overexpressing mutant superoxide dismutase 1 (SOD1) genes linked to familial ALS. This was accomplished by the generation of mice expressing SOD1G37Ror SOD1G93Amutants in the context of TNF-α gene knock out. Surprisingly, the absence of TNF-α did not affect the lifespan or the extent of motor neuron loss in SOD1 transgenic mice. These results provide compelling evidence indicating that TNF-α does not directly contribute to motor neuron degeneration caused by SOD1 mutations.
Panoramic Measurements of the Apex of the Cochlea
Authors: van der Heijden Marcel , Joris Philip X.
Published: November 2006

Our understanding of cochlear mechanics is impeded by the lack of truly panoramic data. Sensitive mechanical measurements cover only a narrow cochlear region, mostly in the base. The global spatiotemporal pattern of vibrations along the cochlea cannot be inferred from such local measurements but is often extrapolated beyond the measurement spot under the assumption of scaling invariance. Auditory nerve responses give an alternative window on the entire cochlea, but traditional techniques do not allow recovery of the effective vibration pattern. We developed a new analysis technique to measure cochlear amplitude and phase transfer of fibers with characteristic frequencies <5 kHz. Data from six cats yielded panoramic phase profiles along the apex of the cochlea for an ∼5 octave range of stimulus frequencies. All profiles accumulated systematic phase lags from base to apex. Phase accumulation was not gradual but showed a two-segment character: a steep segment (slow propagation) around the characteristic position of the stimulus, and a shallow segment (fast propagation) basal to it. The transition between the segments occurred in a narrow region and was smooth. Wavelength near characteristic position decreased from ∼3.5 to ∼1 mm for frequencies from 200 to 4000 Hz, corresponding to phase velocities of ∼0.5 to ∼5 m/s. The accumulated phase lag between the eardrum and characteristic position varied from ∼1 cycle at 200 Hz to ∼2.5 cycle at 4 kHz, invalidating scaling invariance. The generic character of our analysis technique and its success in solving the difficult problem of reconstructing the effective sensory input from neural recordings suggest its wider application as a powerful alternative to customary system analysis techniques.
Three-Dimensional Reconstruction and Quantitative Study of a Pyramidal Cell of a Cajal Histological Preparation
Authors: García-López Pablo , García-Marín Virginia , Freire Miguel
Published: November 2006

The year 2006 marks the centenary of the Nobel Prize for Physiology or Medicine awarded to Santiago Ramón y Cajal and Camilo Golgi. We commemorate this centenary with a three-dimensional reconstruction and a quantitative study of a pyramidal cell of a Cajal's histological preparation. This preparation is one of the 4529 histological preparations personally made by Ramón y Cajal and preserved in the Museum Cajal. The three-dimensional reconstruction of the neuron allows visualizing one important discovery of Ramón y Cajal that constitutes an active field of research in present-day neuroscience: dendritic spines.
Diabetes Mellitus Screening in Pediatric Primary Care
Authors: Anand Shikha G. , Mehta Supriya D. , Adams William G.
Published: November 2006

OBJECTIVE. The goal was to determine the rates of diabetes screening and the prevalence of screening abnormalities in overweight and nonoverweight individuals in an urban primary care clinic.

METHODS. This study was a retrospective chart review conducted in a hospital-based urban primary care setting. Deidentified data for patients who were 10 to 19 years of age and had ≥1 BMI measurement between September 1, 2002, and September 1, 2004, were extracted from the hospital electronic health record.

RESULTS. A total of 7710 patients met the study criteria. Patients were 73.0% black or Hispanic and 47.0% female; 42.0% of children exceeded normal weight, with 18.2% at risk for overweight and 23.8% overweight. On the basis of BMI, family history, and race, 8.7% of patients met American Diabetes Association criteria for type 2 diabetes mellitus screening, and 2452 screening tests were performed for 1642 patients. Female gender, older age group, and family history of diabetes were associated with screening. Increasing BMI percentile was associated with screening, exhibiting a dose-response relationship. Screening rates were significantly higher (45.4% vs 19.0%) for patients who met the American Diabetes Association criteria; however, less than one half of adolescents who should have been screened were screened. Abnormal glucose metabolism was seen for 9.2% of patients screened.

CONCLUSIONS. This study shows that, although pediatricians are screening for diabetes mellitus, screening is not being conducted according to the American Diabetes Association consensus statement. Point-of-care delivery of consensus recommendations could increase provider awareness of current recommendations, possibly improving rates of systematic screening and subsequent identification of children with laboratory evidence of abnormal glucose metabolism.
Medication Errors Related to Computerized Order Entry for Children
Authors: Walsh Kathleen E. , Adams William G. , Bauchner Howard , Vinci Robert J. , Chessare John B. , Cooper Maureen R. , Hebert Pamela M. , Schainker Elisabeth G. , Landrigan Christopher P.
Published: November 2006

OBJECTIVE. The objective of this study was to determine the frequency and types of pediatric medication errors attributable to design features of a computerized order entry system.

METHODS. A total of 352 randomly selected, inpatient, pediatric admissions were reviewed retrospectively for identification of medication errors, 3 to 12 months after implementation of computerized order entry. Errors were identified and classified by using an established, comprehensive, active surveillance method. Errors attributable to the computer system were classified according to type.

RESULTS. Among 6916 medication orders in 1930 patient-days, there were 104 pediatric medication errors, of which 71 were serious (37 serious medication errors per 1000 patient-days). Of all pediatric medication errors detected, 19% (7 serious and 13 with little potential for harm) were computer related. The rate of computer-related pediatric errors was 10 errors per 1000 patient-days, and the rate of serious computer-related pediatric errors was 3.6 errors per 1000 patient-days. The following 4 types of computer-related errors were identified: duplicate medication orders (same medication ordered twice in different concentrations of syrup, to work around computer constraints; 2 errors), drop-down menu selection errors (wrong selection from a drop-down box; 9 errors), keypad entry error (5 typed instead of 50; 1 error), and order set errors (orders selected from a pediatric order set that were not appropriate for the patient; 8 errors). In addition, 4 preventable adverse drug events in drug ordering occurred that were not considered computer-related but were not prevented by the computerized physician order entry system.

CONCLUSIONS. Serious pediatric computer-related errors are uncommon (3.6 errors per 1000 patient-days), but computer systems can introduce some new pediatric medication errors that are not typically seen in a paper ordering system.
Vitamin D Status in Children and Young Adults With Inflammatory Bowel Disease
Authors: Pappa Helen M. , Gordon Catherine M. , Saslowsky Tracee M. , Zholudev Anna , Horr Brian , Shih Mei-Chiung , Grand Richard J.
Published: November 2006

OBJECTIVES. Previous studies of vitamin D status in pediatric patients with inflammatory bowel disease have revealed conflicting results. We sought to report (1) the prevalence of vitamin D deficiency (serum 25-hydroxy-vitamin D concentration ≤15 ng/mL) in a large population with inflammatory bowel disease, (2) factors predisposing to this problem, and (3) its relationship to bone health and serum parathyroid hormone concentration.

PATIENTS AND METHODS. A total of 130 patients (8–22 years of age) with inflammatory bowel disease, 94 with Crohn disease and 36 with ulcerative colitis, had serum 25-hydroxy-vitamin D, intact parathyroid hormone, and lumbar spine bone mineral density (using dual-energy x-ray absorptiometry) measured at Children’s Hospital Boston.

RESULTS. The prevalence of vitamin D deficiency was 34.6%. Mean serum 25-hydroxy-vitamin D concentration was similar in patients with Crohn disease and ulcerative colitis, 52.6% lower among patients with dark skin complexion, 33.4% lower during the winter months (December 22 to March 21), and 31.5% higher among patients who were taking vitamin D supplements. Serum 25-hydroxy-vitamin D concentration was positively correlated with weight and BMI z score, disease duration, and serum albumin concentration and negatively correlated with erythrocyte sedimentation rate. Patients with Crohn disease and upper gastrointestinal tract involvement were more likely to be vitamin D deficient than those without it. Serum 25-hydroxy-vitamin concentration was not associated with lumbar spine bone mineral density z score or serum parathyroid hormone concentration.

CONCLUSIONS. Vitamin D deficiency is highly prevalent among pediatric patients with inflammatory bowel disease. Factors predisposing to the problem include having a dark-skin complexion, winter season, lack of vitamin D supplementation, early stage of disease, more severe disease, and upper gastrointestinal tract involvement in patients with Crohn disease. The long-term significance of hypovitaminosis D for this population is unknown at present and merits additional study.
Impact of Umbilical Cord Cleansing With 4.0% Chlorhexidine on Time to Cord Separation Among Newborns in Southern Nepal: A Cluster-Randomized, Community-Based Trial
Authors: Mullany Luke C. , Darmstadt Gary L. , Khatry Subarna K. , LeClerq Steven C. , Katz Joanne , Tielsch James M.
Published: November 2006

OBJECTIVE. Within a community-based, cluster-randomized study of the effects of 4.0% chlorhexidine on omphalitis and mortality risk, we aimed to describe the distribution of times to separation and the impact of topical chlorhexidine treatment on cord-separation times.

METHODS. Between November 2002 and March 2005, 15123 infants were assigned randomly within communities in southern Nepal to receive 1 of the following 3 cord-care regimens: cleansing with 4.0% chlorhexidine, cleansing with soap and water, or dry cord care. In intervention clusters, field workers cleansed the cord in the home on days 1, 2, 3, 4, 6, 8, and 10 after birth. Newborns were monitored throughout the newborn period for signs of omphalitis, and the time to cord separation was noted. Separation times were compared across treatment groups. Cord infection risk and a range of infant and household characteristics were assessed for their relationships to separation time.

RESULTS. The mean separation time was shorter in dry cord care (4.24 days) and soap/water (4.25 days) clusters than in chlorhexidine clusters (5.32 days; mean difference: 1.08 days). Cords of infants who received chlorhexidine were 3.6 times more likely to separate after 7 days. Separation time was not associated with omphalitis. Home-delivered topical antiseptics, facility-based birth, and birth attendant hand-washing were associated with greater likelihoods of cord separation after 7 days of age.

CONCLUSIONS. In this setting, the umbilical cord separated more rapidly than observed in hospital-based studies, and the impact of chlorhexidine cleansing on separation times was negligible. Increased cord-separation time attributable to topical chlorhexidine treatment should not be considered a factor in decision-making in settings where the baseline risk of omphalitis is high and chlorhexidine might reduce infection and mortality risks significantly.
Childhood Depressive Symptoms and Early Onset of Alcohol Use
Authors: Wu Ping , Bird Hector R. , Liu Xinhua , Fan Bin , Fuller Cordelia , Shen Sa , Duarte Cristiane S. , Canino Glorisa J.
Published: November 2006

OBJECTIVES. Few studies have assessed the relationship between depressive symptoms and early onset of alcohol use in children and early adolescents. We aimed to determine whether depressive symptoms in children are associated with subsequent initiation of alcohol use and, if so, whether this association is merely a result of demographic, parental, and/or individual risk factors shared by depression and alcohol use or independent of these shared risk factors.

METHODS. Analyses were based on a subsample of 10- to 13-year-old children (N = 1119) from the Boricua Youth Study, a longitudinal study of psychopathology among Puerto Rican children and early adolescents. Children in the study were assessed over 3 waves between 2000 and 2004. In-person structured interviews were conducted with both parents and children.

RESULTS. Depressive symptoms and alcohol use shared some significant risk and protective factors, such as parental psychopathology, parenting, child exposure to violence, and antisocial behaviors. After controlling for these factors, the association between depressive symptoms and alcohol use was reduced, but childhood depressive symptoms were still positively associated with subsequent alcohol use initiation. Children with medium or high levels of depressive symptoms were more than twice as likely to use alcohol as those with <2 depressive symptoms.

CONCLUSIONS. The finding of the current study that early life depressive symptoms may lead to earlier onset of alcohol use indicates the importance of identifying and treating depressive symptoms in preadolescent children. It also demonstrates the importance of examining shared risk and protective factors for understanding the relationship between depressive symptoms and alcohol use.
Acute Pediatric Rhabdomyolysis: Causes and Rates of Renal Failure
Authors: Mannix Rebekah , Tan Mei Lin , Wright Robert , Baskin Marc
Published: November 2006

OBJECTIVES. The goals were to (1) compare the causes, clinical presentation, and prevalence of acute renal failure in pediatric rhabdomyolysis with the published data for adults; (2) determine predictors of acute renal failure in pediatric patients with rhabdomyolysis; and (3) explore the relationship of acute renal failure with treatment modalities such as fluid and bicarbonate administration.

METHODS. We performed a retrospective chart review to identify patients with creatinine kinase levels of >1000 IU/L who were treated in the emergency department of a tertiary pediatric hospital between 1993 and 2003, and we constructed regression models.

RESULTS. Two hundred ten patients were studied. One hundred ninety-one patients met study eligibility (128 male and 63 female), with a median age of 11 years. The most common documented symptoms were muscle pain (45%), fever (40%), and symptoms of viral infection (39%). The most common causes of pediatric rhabdomyolysis were viral myositis (38%), trauma (26%), and connective tissue disease (5%). Six of 37 patients with creatinine kinase levels of ≥6000 IU/L had previously undiagnosed dermatomyositis or hereditary metabolic disease, compared with 10 of 154 patients with creatinine kinase levels of 1000 to 5999 IU/L. Nine of 191 patients developed acute renal failure. None of 99 patients with initial urinary heme dipstick results of <2+ developed acute renal failure, compared with 9 of 44 patients with urinary heme dipstick results of ≥2+. Higher initial creatinine kinase levels and higher fluid administration rates were associated with higher maximal creatinine levels.

CONCLUSIONS. The cause of acute pediatric rhabdomyolysis is different from that of adult rhabdomyolysis. The risk of acute renal failure in children is much less than the risk reported for adults.