bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppression of the MicroRNA Pathway by Bacterial Effector Proteins
Authors: Navarro Lionel , Jay Florence , Nomura Kinya , He Sheng Yang , Voinnet Olivier
Published: August 2008

Plants and animals sense pathogen-associated molecular patterns (PAMPs) and in turn differentially regulate a subset of microRNAs (miRNAs). However, the extent to which the miRNA pathway contributes to innate immunity remains unknown. Here, we show that miRNA-deficient mutants of
Arabidopsis
partly restore growth of a type III secretion-defective mutant of
Pseudomonas syringae
. These mutants also sustained growth of nonpathogenic
Pseudomonas fluorescens
and
Escherichia coli
strains, implicating miRNAs as key components of plant basal defense. Accordingly, we have identified
P. syringae
effectors that suppress transcriptional activation of some PAMP-responsive miRNAs or miRNA biogenesis, stability, or activity. These results provide evidence that, like viruses, bacteria have evolved to suppress RNA silencing to cause disease.
Arsenic(III) Fuels Anoxygenic Photosynthesis in Hot Spring Biofilms from Mono Lake, California
Authors: Kulp T. R. , Hoeft S. E. , Asao M. , Madigan M. T. , Hollibaugh J. T. , Fisher J. C. , Stolz J. F. , Culbertson C. W. , Miller L. G. , Oremland R. S.
Published: August 2008

Phylogenetic analysis indicates that microbial arsenic metabolism is ancient and probably extends back to the primordial Earth. In microbial biofilms growing on the rock surfaces of anoxic brine pools fed by hot springs containing arsenite and sulfide at high concentrations, we discovered light-dependent oxidation of arsenite [As(III)] to arsenate [As(V)] occurring under anoxic conditions. The communities were composed primarily of
Ectothiorhodospira
-like purple bacteria or
Oscillatoria
-like cyanobacteria. A pure culture of a photosynthetic bacterium grew as a photoautotroph when As(III) was used as the sole photosynthetic electron donor. The strain contained genes encoding a putative As(V) reductase but no detectable homologs of the As(III) oxidase genes of aerobic chemolithotrophs, suggesting a reverse functionality for the reductase. Production of As(V) by anoxygenic photosynthesis probably opened niches for primordial Earth's first As(V)-respiring prokaryotes.
Bridging the Big Gap
Authors: Ghazanfar Asif A.
Published: August 2008

On Deep History and the Brain
.
By Daniel Lord Smail
. University of California Press, Berkeley, 2008. 286 pp. $21.95, £12.95. ISBN 9780520252899. Paper, $15.95, £9.50. ISBN 9780520258129.

Drawing on neuroscience, cultural evolution, and human biology, the author agues for an approach that abandons "prehistory" and unites our recent and deep pasts.
Low-Dose Priming before Vaccination with the Phase I Chloroform-Methanol Residue Vaccine against Q Fever Enhances Humoral and Cellular Immune Responses toCoxiella burnetii
Authors: Waag David M. , England Marilyn J. , Bolt Christopher R. , Williams Jim C.
Published: August 2008

Although the phase ICoxiella burnetiicellular vaccine is completely efficacious in humans, adverse local and systemic reactions may develop if immune individuals are inadvertently vaccinated. The phase I chloroform-methanol residue (CMRI) vaccine was developed as a potentially safer alternative. Human volunteers with no evidence of previous exposure toC. burnetiireceived a subcutaneous vaccination with the CMRI vaccine in phase I studies under protocol IND 3516 to evaluate the safety and immunogenicity of the vaccine. This clinical trial tested escalating doses of the CMRI vaccine, ranging from 0.3 to 60 μg, followed by a booster dose of 30 μg, in a placebo-controlled study. Although priming doses of the CMRI vaccine did not induce a specific antibody detectable by enzyme-linked immunosorbent assay, booster vaccination stimulated the production of significant levels of anti-C. burnetiiantibody. Peripheral blood cells (PBCs) of vaccinees responded toC. burnetiicellular antigen in vitro in a vaccine dose-dependent manner. After the booster dose, PBCs were activated by recall antigen in vitro, regardless of the priming dose. These findings suggest that vaccination with the CMRI vaccine can effectively prime the immune system to mount significant anamnestic responses after infection.
Disease Severity Associated with Presence in Subgingival Plaque ofPorphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, andTannerella forsythia, Singly or in Combination, as Detected by Nested Multiplex PCR
Authors: Ready D. , D'Aiuto F. , Spratt D. A. , Suvan J. , Tonetti M. S. , Wilson M.
Published: August 2008

This study used a nested multiplex PCR method to detect three periodontal pathogens in subgingival plaque collected before treatment and at 2 and 6 months posttreatment from 107 patients with severe, generalized periodontitis. The proportions of the patients who harbored these bacteria before periodontal treatment were as follows:Tannerella forsythia, 81%;Porphyromonas gingivalis, 78%; andAggregatibacter(formerlyActinobacillus)actinomycetemcomitans, 47%. At 2 months posttreatment there was a significant reduction in the numbers of patients harboringP. gingivalis(46%;P< 0.001) orT. forsythia(63%;P= 0.043) but notA. actinomycetemcomitans(50%) compared to pretreatment data. At 6 months posttreatment, significantly fewer patients harboredP. gingivalis(43%;P< 0.001);A. actinomycetemcomitans, (31%;P= 0.025), orT. forsythia(63%;P= 0.030). Interestingly, at baseline and at 2 months posttherapy, subjects who harbored only a single pathogen had a greater level of periodontal disease than subjects who harbored two, or all three, of these periodontal pathogens. These data suggest that a reduction in the number of species present may be associated with an increase in the severity of periodontal diseases.
Debaryomyces hansenii
(
Candida famata
), a Rare Human Fungal Pathogen Often Misidentified as
Pichia guilliermondii
(
Candida guilliermondii
)
Authors: Desnos-Ollivier Marie , Ragon Marie , Robert Vincent , Raoux Dorothée , Gantier Jean-Charles , Dromer Françoise
Published: August 2008

Debaryomyces hansenii
is a hemiascomycetous yeast commonly found in natural substrates and in various types of cheese.
Pichia guilliermondii
is widely distributed in nature and is a common constituent of the normal human microflora. Both species have been described in human infections but are extremely difficult to differentiate phenotypically. Thus, frequent errors in identification occur. The 62 clinical and environmental isolates sent between 2000 and 2007 to the French National Reference Center for Mycoses and Antifungals as
D. hansenii
or
P. guilliermondii
were analyzed by using the carbon assimilation pattern, the presence of pseudohyphae, and sequencing of the ITS and D1/D2 regions of the rRNA gene. The objective of this study was to assess using nucleotide sequences whether phenotypic identification was accurate and whether phenotypic characteristics could be used to differentiate the two species when sequencing was not available. We found that 58% of the isolates were misidentified and belong to seven different species:
P. guilliermondii
,
P. caribbica
,
P. jadinii
,
D. hansenii
,
Candida palmioleophila
,
C. haemulonii
type II, and
Clavispora lusitaniae
. In conclusion,
D. hansenii
may not be as common a human pathogen as previously thought. Sequencing of either ITS or D1/D2 regions is a good tool for differentiating the species more frequently confused with
D. hansenii
, keeping in mind that reliable databases should be used.
Inter- and Intra-Assay Reproducibility of Microplate Alamar Blue Assay Results for Isoniazid, Rifampicin, Ethambutol, Streptomycin, Ciprofloxacin, and Capreomycin Drug Susceptibility Testing of
Mycobacterium tuberculosis
Authors: Leonard Brian , Coronel Jorge , Siedner Mark , Grandjean Louis , Caviedes Luz , Navarro Pilar , Gilman Robert H. , Moore David A. J.
Published: August 2008

The intersample and intrasample variability of the results obtained with the microplate Alamar blue assay for the indirect drug susceptibility testing of
Mycobacterium tuberculosis
was investigated. Between 1.2 and 8.5% of paired MICs differed by more than one twofold dilution, resulting in discordant susceptible-resistant designations at frequencies between 0.6% (rifampin) and 18.9% (ethambutol).
Epidemic Keratoconjunctivitis Due to the Novel Hexon-Chimeric-Intermediate 22,37/H8 Human Adenovirus
Authors: Aoki Koki , Ishiko Hiroaki , Konno Tsunetada , Shimada Yasushi , Hayashi Akio , Kaneko Hisatoshi , Ohguchi Takeshi , Tagawa Yoshitsugu , Ohno Shigeaki , Yamazaki Shudo
Published: August 2008

In a 2-month period in 2003, we encountered an outbreak of epidemic keratoconjunctivitis (EKC) in Japan. We detected 67 human adenoviruses (HAdVs) by PCR from eye swabs of patients with EKC at five eye clinics in different parts of Japan. Forty-one of the 67 HAdV DNAs from the swabs were identified as HAdV-37 by phylogenetic analysis using a partial hexon gene sequence. When the restriction patterns of these viral genomes were compared with that of the HAdV-37 prototype strain, one isolate showed a never-before-seen restriction pattern. Within 1 year, we encountered three more EKC cases caused by a genetically identical virus: two nosocomial infections at two different university hospitals and a sporadic infection at an eye clinic. We determined the nucleotide sequences of the full-length hexon and fiber genes of these isolates and compared them to those of the 51 prototype strains. Surprisingly, the sequence of the hexon (ε determinant) loop-1 and -2 regions showed the highest nucleotide identity with HAdV-22, a rare EKC isolate. However, the nucleotide sequence of the fiber gene was identical to that of the HAdV-8 prototype strain. 22 We propose that this virus is a new hexon-chimeric intermediate HAdV-22,37/H8, and may be an etiological agent of EKC.
Efficient Quiescent Infection of Normal Human Diploid Fibroblasts with Wild-Type Herpes Simplex Virus Type 1
Authors: McMahon Robert , Walsh Derek
Published: August 2008

Quiescent infection of cultured cells with herpes simplex virus type 1 (HSV-1) provides an important, amenable means of studying the molecular mechanics of a nonproductive state that mimics key aspects of in vivo latency. To date, establishing high-multiplicity nonproductive infection of human cells with wild-type HSV-1 has proven challenging. Here, we describe simple culture conditions that established a cell state in normal human diploid fibroblasts that supported efficient quiescent infection using wild-type virus and exhibited many important properties of the in vivo latent state. Despite the efficient production of immediate early (IE) proteins ICP4 and ICP22, the latter remained unprocessed, and viral late gene products were only transiently and inefficiently produced. This low level of virus activity in cultures was rapidly suppressed as the nonproductive state was established. Entry into quiescence was associated with inefficient production of the viraltrans-activating protein ICP0, and the accumulation of enlarged nuclear PML structures normally dispersed during productive infection. Lytic replication was rapidly and efficiently restored by exogenous expression of HSV-1 ICP0. These findings are in agreement with previous models in which quiescence was established with HSV mutants disrupted in their expression of IE gene products that included ICP0 and, importantly, provide a means to study cellular mechanisms that repress wild-type viral functions to prevent productive replication. We discuss this model in relation to existing systems and its potential as a simple tool to study the molecular mechanisms of quiescent infection in human cells using wild-type HSV-1.
The Influenza Virus M2 Protein Cytoplasmic Tail Interacts with the M1 Protein and Influences Virus Assembly at the Site of Virus Budding
Authors: Chen Benjamin J. , Leser George P. , Jackson David , Lamb Robert A.
Published: August 2008

The cytoplasmic tail of the influenza A virus M2 proton-selective ion channel has been shown to be important for virus replication. Previous analysis of M2 cytoplasmic tail truncation mutants demonstrated a defect in incorporation of viral RNA (vRNA) into virions, suggesting a role for M2 in the recruitment of M1-vRNA complexes. To further characterize the effect of the M2 cytoplasmic tail mutations on virus assembly and budding, we constructed a series of alanine substitution mutants of M2 with mutations in the cytoplasmic tail, from residues 71 to 97. Mutant proteins M2-Mut1 and M2-Mut2, with mutations of residues 71 to 73 and 74 to 76, respectively, appeared to have the greatest effect on virus-like particle and virus budding, showing a defect in M1 incorporation. Mutant viruses containing M2-Mut1 and M2-Mut2 failed to replicate in multistep growth analyses on wild-type (wt) MDCK cells and were able to form plaques only on MDCK cells stably expressing wt M2 protein. Compared to wt M2 protein, M2-Mut1 and M2-Mut2 were unable to efficiently coimmunoprecipitate with M1. Furthermore, statistical analysis of planar sheets of membrane from cells infected by virus containing M2-Mut1 revealed a reduction in M1-hemagglutinin (HA) and M2-HA clustering as well as a severe loss of clustering between M1 and M2. These results suggest an essential, direct interaction between the cytoplasmic tail of M2 and M1 that promotes the recruitment of the internal viral proteins and vRNA to the plasma membrane for efficient virus assembly to occur.
Vaccinia Virus Encodes I5, a Small Hydrophobic Virion Membrane Protein That Enhances Replication and Virulence in Mice
Authors: Sood Cindy L. , Ward Jerrold M. , Moss Bernard
Published: August 2008

The vaccinia virus I5L open reading frame encodes a 79-amino-acid protein, with two predicted transmembrane domains, that is conserved among all sequenced members of the chordopoxvirus subfamily. No nonpoxvirus homologs or functional motifs have been recognized, and the role of the I5 protein remains unknown. We found that synthesis of I5 was dependent on viral DNA replication and occurred exclusively at late times, consistent with a consensus late promoter motif adjacent to the start of the open reading frame. I5 was present in preparations of purified virions and could be extracted with nonionic detergent, suggesting membrane insertion. Transmission electron microscopy of immunogold-labeled thawed cryosections of infected cells revealed the association of an epitope-tagged I5 with the membranes of immature and mature virions. Viable I5L deletion and frameshift mutants were constructed and found to replicate like wild-type virus in a variety of cell lines and primary human epidermal keratinocytes, indicating that the protein was dispensable for in vitro cultivation. However, mouse intranasal challenge experiments indicated that a mutant virus with a frameshift resulting in a stop codon near the N terminus of I5 was attenuated compared to control virus. The attenuation was correlated with clearance of mutant viruses from the respiratory tract and with less progression and earlier resolution of pathological changes. We suggest that I5 is involved in an aspect of host defense that is evolutionarily conserved although a role in cell tropism should also be considered.
Validity of three accelerometers during treadmill walking and motor vehicle travel
Authors: Maddocks Matthew , Petrou Andrea , Skipper Lindsay , Wilcock Andrew
Published: August 2008

Objective

To determine the relative accuracy during treadmill walking and motor vehicle travel of the ActivPAL, PALlite and Digi-Walker accelerometers.

Methods

Forty healthy volunteers wearing all accelerometers undertook either five treadmill walks (n=20) at speeds ranging between 0.6 and 1.4 m/s or a 15 min motor vehicle journey (n=20). Step counts recorded by each accelerometer were compared with the actual step count determined by video analysis (treadmill walking) or with an actual step count of zero (motor vehicle). Mean percentage measurement error was calculated and compared between devices by one-way ANOVA and Student t test.

Results

For treadmill walking, the measurement error was lowest for the ActivPAL, with no significant differences between the ActivPAL and the PALlite monitors. The measurement error was significantly higher for the Digi-Walker at speeds of ≤1 m/s. During vehicle travel erroneous steps were recorded by the PALlite (254 steps) and Digi-Walker (25 steps), but not the ActivPAL monitor (0 steps).

Conclusions

The ActivPAL accelerometer accurately measures step count over a range of walking speeds and, unlike the other accelerometers tested, is not falsely triggered by motor vehicle travel.
MYCOBACTERIAL TUBERCULOUS TENOSYNOVITIS OF THE EXTENSOR TENDON OCCURRING AFTER LIVER TRANSPLANTATION: A CASE REPORT
Authors: Toyokawa Narikazu , Kokubu Takeshi , Fujioka Hiroyuki
Published: August 2008

Mycobacterial tuberculous tenosynovitis of the hand is a rare manifestation of extrapulmonary tuberculosis, while mycobacterial tuberculous tenosynovitis of the extensor tendon sheath is extremely rare. We report a case of tuberculous tenosynovitis of the extensor tendon of the finger, occurring in a man receiving immunosuppression following a liver transplantation. Symptoms improved clinically after conservative treatment with anti-tuberculous drugs.
Divergent Paths: Conflicting Conceptions of Employment Discrimination in Law and the Social Sciences
Authors: Nelson Robert L. , Berrey Ellen C. , Nielsen Laura Beth
Published: August 2008

Legal conceptions of employment discrimination have become increasingly narrow over the past two decades as the law has adopted a “perpetrator” model of discrimination that emphasizes purposeful intent. This tendency runs counter to social scientific research that documents the pervasiveness of unintentional bias and the persistence of organizational processes that generate workplace discrimination. This narrow legal conception, coupled with a system of employment discrimination litigation that emphasizes individual claims and individual remedies, fails to support the organizational approaches that are most promising for redressing workplace discrimination. We review the literature on employment discrimination law, discrimination litigation, continuing patterns of racial and gender inequality, the organizational bases of discrimination, and the impact of equal employment law on organizations. We conclude by discussing the reasons for and implications of this divergence between law and social science.
Stimulation of glucose transport in response to activation of distinct AMPK signaling pathways
Authors: Jing Ming , Cheruvu Vinay K , Ismail-Beigi Faramarz
Published: August 2008

AMP-activated protein kinase (AMPK) plays a critical role in the stimulation of glucose transport in response to hypoxia and inhibition of oxidative phosphorylation. In the present study, we examined the signaling pathway(s) mediating the glucose transport response following activation of AMPK. Using mouse fibroblasts of AMPK wild type and AMPK knockout, we documented that the expression of AMPK is essential for the glucose transport response to both azide and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR). In Clone 9 cells, the stimulation of glucose transport by a combination of azide and AICAR was not additive, whereas there was an additive increase in the abundance of phosphorylated AMPK (p-AMPK). In Clone 9 cells, AMPK wild-type fibroblasts, and H9c2 heart cells, azide or hypoxia selectively increased p-ERK1/2, whereas, in contrast, AICAR selectively stimulated p-p38; phosphorylation of JNK was unaffected. Azide's effect on p-ERK1/2 abundance and glucose transport in Clone 9 cells was partially abolished by the MEK1/2 inhibitor U0126. SB 203580, an inhibitor of p38, prevented the phosphorylation of p38 and the glucose transport response to AICAR and, unexpectedly, to azide. Hypoxia, azide, and AICAR all led to increased phosphorylation of Akt substrate of 160 kDa (AS160) in Clone 9 cells. Employing small interference RNA directed against AS160 did not inhibit the glucose transport response to azide or AICAR, whereas the content of P-AS160 was reduced by ∼80%. Finally, we found no evidence for coimmunoprecipitation of Glut1 and p-AS160. We conclude that although azide, hypoxia, and AICAR all activate AMPK, the downstream signaling pathways are distinct, with azide and hypoxia stimulating ERK1/2 and AICAR stimulating the p38 pathway.
Muscle cells engage Rab8A and myosin Vb in insulin-dependent GLUT4 translocation
Authors: Ishikura Shuhei , Klip Amira
Published: August 2008

Insulin causes translocation of glucose transporter 4 (GLUT4) to the membrane of muscle and fat cells, a process requiring Akt activation. Two Rab-GTPase-activating proteins (Rab-GAP), AS160 and TBC1D1, were identified as Akt substrates. AS160 phosphorylation is required for insulin-stimulated GLUT4 translocation, but the participation of TBC1D1 on muscle cell GLUT4 is unknown. Moreover, there is controversy as to the AS160/TBC1D1 target Rabs in fat and muscle cells, and Rab effectors are unknown. Here we examined the effect of knockdown of AS160, TBC1D1, and Rabs 8A, 8B, 10, and 14 (in vitro substrates of AS160 and TBC1D1 Rab-GAP activities) on insulin-induced GLUT4 translocation in L6 muscle cells. Silencing AS160 or TBC1D1 increased surface GLUT4 in unstimulated cells but did not prevent insulin-induced GLUT4 translocation. Knockdown of Rab8A and Rab14, but not of Rab8B or Rab10, inhibited insulin-induced GLUT4 translocation. Furthermore, silencing Rab8A or Rab14 but not Rab8B or Rab10 restored the basal-state intracellular retention of GLUT4 impaired by AS160 or TBC1D1 knockdown. Lastly, overexpression of a fragment of myosin Vb, a recently identified Rab8A-interacting protein, inhibited insulin-induced GLUT4 translocation and altered the subcellular distribution of GTP-loaded Rab8A. These results support a model whereby AS160, Rab8A, and myosin Vb are required for insulin-induced GLUT4 translocation in muscle cells, potentially as part of a linear signaling cascade.
Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding
Authors: Shapiro Alexandra , Mu Wei , Roncal Carlos , Cheng Kit-Yan , Johnson Richard J. , Scarpace Philip J.
Published: August 2008

It has been suggested that increased fructose intake is associated with obesity. We hypothesized that chronic fructose consumption causes leptin resistance, which subsequently may promote the development of obesity in response to a high-fat diet. Sprague-Dawley rats were fed a fructose-free control or 60% fructose diet for 6 mo and then tested for leptin resistance. Half of the rats in each group were then switched to high-fat diet for 2 wk, while the other half continued on their respective diets. Chronic fructose consumption caused leptin resistance, while serum leptin levels, weight, and adiposity were the same as in control rats that were leptin responsive. Intraperitoneal leptin injections reduced 24-h food intake in the fructose-free group (73.7 ± 6.3 vs. 58.1 ± 8 kcal, P = 0.02) but had no effect in fructose-fed rats (71.2 ± 6.6 vs. 72.4 ± 6.4 kcal, P = 0.9). Absence of anorexic response to intraperitoneal leptin injection was associated with 25.7% decrease in hypothalamic signal transducer and activator of transcription 3 phosphorylation in the high-fructose-fed rats compared with controls ( P = 0.015). Subsequent exposure of the fructose-mediated, leptin-resistant rats to a high-fat diet led to exacerbated weight gain (50.2 ± 2 g) compared with correspondingly fed leptin-responsive animals that were pretreated with the fructose-free diet (30.4 ± 5.8 g, P = 0.012). Our data indicate that chronic fructose consumption induces leptin resistance prior to body weight, adiposity, serum leptin, insulin, or glucose increases, and this fructose-induced leptin resistance accelerates high-fat induced obesity.
Exogenous heat shock protein-70 inhibits cigarette smoke-induced intimal thickening
Authors: Matsumoto Michiaki , Dimayuga Paul C. , Wang Charles , Kirzner Jonathan , Cercek Miha , Yano Juliana , Chyu Kuang-Yuh , Shah Prediman K. , Cercek Bojan
Published: August 2008

Cigarette smoke is associated with increased carotid intimal thickening or stroke. Preliminary work showed that exposure to smoke resulted in a 4.5-fold reduction of heat shock protein-70 (HSP70) expression in spleens of mice using gene microarray analysis. In the current study, we investigated the role of extracellular HSP70 in carotid intimal thickening of mice exposed to cigarette smoke. Intimal thickening was induced by placement of a cuff around the right carotid artery of mice. Cuff injury resulted in increased HSP70 mRNA expression in carotid arteries that persisted for 21 days. Cigarette smoke exposure decreased arterial HSP70 expression and significantly increased intimal thickening compared with mice exposed to air. Treatment of mice exposed to cigarette smoke with intravenous recombinant HSP70 attenuated intimal thickening through reduced phosphorylated extracellular signal-regulated kinase (pERK) expression in the arterial wall. In vitro experiments with rat aortic smooth muscle cells confirmed that recombinant HSP70 decreases pERK and proliferating cell nuclear antigen (PCNA) expression in cells exposed to cigarette smoke extract and H2O2. Our study suggests that decreased expression of arterial HSP70 is an important mechanism by which exposure to cigarette smoke augments intimal thickening. The effects of recombinant HSP70 suggest a role for extracellular HSP70.
Intermittent hypoxia has organ-specific effects on oxidative stress
Authors: Jun Jonathan , Savransky Vladimir , Nanayakkara Ashika , Bevans Shannon , Li Jianguo , Smith Philip L. , Polotsky Vsevolod Y.
Published: August 2008

Obstructive sleep apnea is characterized by upper airway collapse, leading to intermittent hypoxia (IH). It has been postulated that IH-induced oxidative stress may contribute to several chronic diseases associated with obstructive sleep apnea. We hypothesize that IH induces systemic oxidative stress by upregulating NADPH oxidase, a superoxide-generating enzyme. NADPH oxidase is regulated by a cytosolic p47phoxsubunit, which becomes phosphorylated during enzyme activation. Male C57BL/6J mice were exposed to IH with an inspired O2fraction nadir of 5% 60 times/h during the 12-h light phase (9 AM–9 PM) for 1 or 4 wk. In the aorta and heart, IH did not affect lipid peroxidation [malondialdehyde (MDA) level], nitrotyrosine level, or p47phoxexpression and phosphorylation. In contrast, in the liver, exposure to IH for 1 wk resulted in a trend to an increase in MDA levels, whereas IH for 4 wk resulted in a 38% increase in MDA levels accompanied by upregulation of p47phoxexpression and phosphorylation. Administration of an NADPH oxidase inhibitor, apocynin, during IH exposure attenuated IH-induced increases in hepatic MDA. In p47phox-deficient mice, MDA levels were higher at baseline and, unexpectedly, decreased during IH. In conclusion, oxidative stress levels and pathways under IH conditions are organ and duration specific.
Intrinsic Functional Relations Between Human Cerebral Cortex and Thalamus
Authors: Zhang Dongyang , Snyder Abraham Z. , Fox Michael D. , Sansbury Mark W. , Shimony Joshua S. , Raichle Marcus E.
Published: August 2008

The brain is active even in the absence of explicit stimuli or overt responses. This activity is highly correlated within specific networks of the cerebral cortex when assessed with resting-state functional magnetic resonance imaging (fMRI) blood oxygen level–dependent (BOLD) imaging. The role of the thalamus in this intrinsic activity is unknown despite its critical role in the function of the cerebral cortex. Here we mapped correlations in resting-state activity between the human thalamus and the cerebral cortex in adult humans using fMRI BOLD imaging. Based on this functional measure of intrinsic brain activity we partitioned the thalamus into nuclear groups that correspond well with postmortem human histology and connectional anatomy inferred from nonhuman primates. This structure/function correspondence in resting-state activity was strongest between each cerebral hemisphere and its ipsilateral thalamus. However, each hemisphere was also strongly correlated with the contralateral thalamus, a pattern that is not attributable to known thalamocortical monosynaptic connections. These results extend our understanding of the intrinsic network organization of the human brain to the thalamus and highlight the potential of resting-state fMRI BOLD imaging to elucidate thalamocortical relationships.
Low-Alcohol Doses Reduce Common 10- to 15-Hz Input to Bilateral Leg Muscles During Quiet Standing
Authors: Boonstra T. W. , Roerdink M. , Daffertshofer A. , van Vugt B. , van Werven G. , Beek P. J.
Published: August 2008

The effects of low doses of alcohol on neural synchronization in muscular activity were investigated in ten participants during quiet standing with eyes open or closed. We focused on changes in common input to bilateral motor unit pools as evident in surface electromyographic (EMG) recordings of lower leg extensor and flexor muscles. The extensor muscles exhibited bilateral synchronization in two distinct frequency bands (i.e., 0–5 and 10–15 Hz), whereas synchronization between flexor muscles was minimal. As expected, alcohol ingestion affected postural sway, yielding increased sway at higher blood-alcohol levels. Whereas vision affected bilateral synchronization only at 0–5 Hz, alcohol ingestion resulted in a progressive decrease of synchronization at 10–15 Hz between the EMG activities of the extensor muscles. The decrease in common bilateral input is most likely related to reduced reticulospinal activity with alcohol ingestion.
Effect of Static and Dynamic Heat Pain Stimulus Profiles on the Temporal Dynamics and Interdependence of Pain Qualities, Intensity, and Affect
Authors: Hashmi Javeria A. , Davis Karen D.
Published: August 2008

Acute and chronic pains are characterized by a particular constellation of pain qualities, such as burning, aching, stinging, or sharp feelings. However, the temporal pattern of specific pain qualities and their relationship with pain and affect is not well understood. In addition, little is known about how the temperature time course of the stimulus impacts the temporal dynamics of pain qualities and the relationship between pain qualities. Therefore we applied two types of stimuli to the feet of 16 healthy subjects, each calibrated to evoke a similar pain magnitude (50/100): static stimulus held at constant intensity and dynamic stimulus increased in intensity in small steps. Stimulus runs consisted of three 30-s stimuli (either static or dynamic) with an interstimulus interval of 60 s. Continuous on-line ratings of pain, burning, sharp, stinging, cutting, and annoyance were obtained in separate runs, and the evoked responses were characterized by within-stimulus adaptation (early: 0- to 15-s peak vs. late: 25- to 40-s peak) and by their temporal properties (time to onset, peak, and end). The temporal profile of the burning sensation was similar to the pain and annoyance evoked by the static and dynamic stimuli. However, the sharp, stinging and cutting sensations attenuated in response to the static stimuli ( P < 0.01) but intensified along with pain and affect in response to the dynamic stimuli ( P < 0.05), whereas there was no attenuation in the evoked profiles of pain ( P = 0.61), annoyance ( P = 0.27), or burning quality ( P = 0.27). These data demonstrate that specific pain qualities with known differences in underlying mechanisms have distinct temporal dynamics that depend on the stimulus intensity dynamics.
Neuronal Activity of the Human Subthalamic Nucleus in the Parkinsonian and Nonparkinsonian State
Authors: Steigerwald F. , Pötter M. , Herzog J. , Pinsker M. , Kopper F. , Mehdorn H. , Deuschl G. , Volkmann J.
Published: August 2008

We recorded resting-state neuronal activity from the human subthalamic nucleus (STN) during functional stereotactic surgeries. By inserting up to five parallel microelectrodes for single- or multiunit recordings and applying statistical spike-sorting methods, we were able to isolate a total of 351 single units in 65 patients with Parkinson's disease (PD) and 33 single units in 9 patients suffering from essential tremor (ET). Among these were 93 pairs of simultaneously recorded neurons in PD and 17 in ET, which were detected either by the same ( n = 30) or neighboring microelectrodes ( n = 80). Essential tremor is a movement disorder without any known basal ganglia pathology and with normal dopaminergic brain function. By comparing the neuronal activity of the STN in patients suffering from PD and ET we intended to characterize, for the first time, changes of basal ganglia activity in the human disease state that had previously been described in animal models of Parkinson's disease. We found a significant increase in the mean firing rate of STN neurons in PD and a relatively larger fraction of neurons exhibiting burstlike activity compared with ET. The overall proportion of neurons exhibiting intrinsic oscillations or interneuronal synchronization as defined by significant spectral peaks in the auto- or cross-correlations functions did not differ between PD and ET when considering the entire frequency range of 1–100 Hz. The distribution of significant oscillations across the theta (1–8 Hz), alpha (8–12 Hz), beta (12–35 Hz), and gamma band (>35 Hz), however, was uneven in ET and PD, as indicated by a trend in Fisher's exact test ( P = 0.05). Oscillations and pairwise synchronizations within the 12- to 35-Hz band were a unique feature of PD. Our results confirm the predictions of the rate model of Parkinson's disease. In addition, they emphasize abnormalities in the patterning and dynamics of neuronal discharges in the parkinsonian STN, which support current concepts of abnormal motor loop oscillations in Parkinson's disease.
Peroxisome Proliferator‐Activated Receptors (PPARs) as Potential Inducers of Antineoplastic Effects in CNS Tumors
Authors: Tatenhorst Lars , Hahnen Eric , Heneka Michael T.
Published: August 2008

The peroxisome proliferator‐activated receptors (PPARs) are ligand‐inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy.
PPARα Ligands as Antitumorigenic and Antiangiogenic Agents
Authors: Pozzi Ambra , Capdevila Jorge H.
Published: August 2008

Peroxisome proliferator‐activated receptors (PPARs) belong to the nuclear receptor family of ligand‐activated transcription factors. This subfamily is composed of three members—PPARα, PPARδ, and PPARγ—that differ in their cell and tissue distribution as well as in their target genes. PPARα is abundantly expressed in liver, brown adipose tissue, kidney, intestine, heart, and skeletal muscle; and its ligands have been used to treat diseases such as obesity and diabetes. The recent finding that members of the PPAR family, including the PPARα, are expressed by tumor and endothelial cells together with the observation that PPAR ligands regulate cell growth, survival, migration, and invasion, suggested that PPARs also play a role in cancer. In this review, we focus on the contribution of PPARα to tumor and endothelial cell functions and provide compelling evidence that PPARα can be viewed as a new class of ligand activated tumor “suppressor” gene with antiangiogenic and antitumorigenic activities. Given that PPAR ligands are currently used in medicine as hypolipidemic drugs with excellent tolerance and limited toxicity, PPARα activation might offer a novel and potentially low‐toxic approach for the treatment of tumor‐associated angiogenesis and cancer.
Kinetics and Persistence of Cardiovascular and Locomotor Effects of Immobilization Stress and Influence of ACTH Treatment
Authors: Sabban Esther L. , Schilt Nina , Serova Lidia I. , Masineni Shreeharsha N. , Stier, Jr. Charles T.
Published: August 2008

Stress triggers crucial responses, including elevated blood pressure and heart rate (HR), to handle the emergency and restore homeostasis. However, continuation of these effects following cessation of the stress is implicated with many stress-related disorders. Here, we examine the kinetics and persistence of cardiovascular and locomotor responses to single and repeated immobilization stress (IMO), with and without prior treatment with adrenocorticotropic hormone (ACTH). Radiotelemetry probes were implanted into male Sprague-Dawley rats to continually monitor mean arterial pressure (MAP), HR and locomotor activity. Rats were subjected to IMO for 2 h daily (10 a.m. to noon, 6 consecutive days). The first IMO induced the greatest change in MAP (about 30 mm Hg) and HR (about 200 bpm). Following each IMO, MAP and HR were elevated during the remaining light phase and in the subsequent dark phase, HR was lower than prior to IMO. We further examined whether elevation of ACTH to a level similar to IMO will elicit similar effects, and if it will alter subsequent responses to IMO. Injection of ACTH (13 IU/kg, s.c.) triggered a short-lived rise in MAP, and decreased HR. After six daily injections of ACTH and recovery time (8 days), rats were immobilized as above. The cardiovascular responses were similar during the IMO, but the ACTH-pretreated group displayed differences following cessation of the IMO. In addition, IMO led to a large reduction of locomotor activity during the dark (normally active) phase to levels similar to the light phase. Following the IMOs, locomotor activity recovered more slowly in the ACTH-pretreated group. The study revealed that IMO-triggered cardiovascular and locomotor responses are evident after termination of the stress. In addition, prior exposure to ACTH delayed recovery in cardiovascular and locomotor functions following cessation of stress.
Effects of Vitamins C and E on the Outcome after Acute Myocardial Infarction in Diabetics: A Retrospective, Hypothesis-Generating Analysis from the MIVIT Study
Authors: Jaxa-Chamiec Tomasz , Bednarz Bronislaw , Herbaczynska-Cedro Krystyna , Maciejewski Pawel , Ceremuzynski Leszek
Published: August 2008

Background: There is significant evidence that reactive oxygen species play an important role in endothelial dysfunction, ischemia/reperfusion injury as well as in the pathogenesis of diabetes mellitus (DM). It is also known that vitamins C and E have substantial antioxidant properties. However, clinical evidence concerning this topic is insufficient so far. The aim of the present study was to determine if the administration of vitamins C and E influences the outcome in diabetic patients with acute myocardial infarction (AMI). Methods: Among 800 patients with AMI included in the MIVIT (Myocardial Infarction and Vitamins) study, 122 patients (15%) had confirmed DM. A retrospective analysis of the influence of vitamins C and E on 30-day cardiac mortality in patients with or without DM was performed. Results: There was a significant reduction in 30-day cardiac mortality in diabetic patients treated with antioxidant vitamins C and E [5 (8%) vs. 14 (22%); OR 0.32, 95% CI 0.11–0.93; p = 0.036]. Such an effect has not been observed in patients without DM [19 (6%) vs. 19 (6%); OR 0.97, 95% CI 0.51–1.85; p = 0.94]. Conclusion: The results suggest that early administration of antioxidant vitamins C and E in patients with AMI and concomitant DM reduces cardiac mortality.
Speech Outcome regarding Overall Intelligibility, Articulation, Resonance and Voice in Flemish Children a Year after Pharyngeal Flap Surgery
Authors: van Lierde Kristiane M. , Bonte Katrien , Baudonck Nele , van Cauwenberge P. , De Leenheer Els M.R.
Published: August 2008

Objective: The main purpose of this study is to determine the treatment effectiveness of pharyngeal flap surgery by measuring speech outcome 1 year after surgery. The authors hypothesized that flap surgery is an effective technique for velopharyngeal inadequacy resulting in improved intelligibility, decreased hypernasality and nasalance scores and normal voice characteristics. Patients and Methods: Objective (Nasometer, Dysphonia Severity Index) as well as subjective (perceptual evaluations) assessment techniques were performed in 7 subjects. Speech evaluations were performed 1 year after flap surgery and comparison was made between the speech results of the preoperative condition (1 week before surgery) and the first postoperative condition (6 weeks after surgery). Results: After pharyngeal flap surgery there was improved though still slightly impaired intelligibility, with normal nasality, normal nasalance values for standard Flemish speech and normal voice characteristics. The normal nasality and nasalance values were not present in the preoperative condition. Persistence of the incorrect production of the thrill sound /r/ and the fricatives /s/ and /sch/ were observed. Conclusion: It is likely that the slightly impaired speech intelligibility is determined by the presence of persistent articulation disorders.
The Principle of Homologous Groups in Regulatory Affairs of Allergen Products – A Proposal
Authors: Lorenz A.R. , Lüttkopf D. , May S. , Scheurer S. , Vieths S.
Published: August 2008

Among other legal regulations, the Note for Guidance on Allergen Products CPMP/BWP/243/96 released by the European Medicines Agency provides regulatory instructions regarding the quality of allergen extracts for diagnostic or therapeutic purposes. The current revision of this guideline intends to transform the so-called ‘principle of taxonomic families’ to the ‘principle of homologous groups’. According to this concept, the data of one allergen extract demonstrating stability, efficacy and safety can, to a limited extent, be extrapolated to other allergen extracts belonging to the same homologous groups. The present work proposes the formation of homologous groups for pollen species and animal-derived materials on the basis of similar biochemical composition and homology/cross-reactivity of allergens or allergen sources. Some tree pollen species could be assigned to three different homologous groups, some weed pollen species to one homologous group and numerous grass pollen species to one homologous group on condition that data rely on single defined representative species. A homologous group for mites is limited to the Dermatophagoides species and the grouping of vertebrate-derived materials such as dander could be possible under restrictions. The criteria for the formation of the proposed homologous groups are illustrated in detail to provide an opportunity for extending existing homologous groups by further species in case of new insights in allergens and cross-reactivity of allergen sources. In this way, the concept of homologous groups could serve as a dynamic tool in the regulation of allergen products.
Enhancement of the Antibiotic Activity against a Multiresistant Escherichia coli by Mentha arvensis L. and Chlorpromazine
Authors: Coutinho Henrique D.M. , Costa José G.M. , Lima Edeltrudes O. , Falcão-Silva Vivyanne S. , Siqueira-Júnior José P.
Published: August 2008

Background: This is the first report testing the antibiotic resistance-modifying activity of Mentha arvensis. Methods: In this study an ethanol extract of M. arvensis L. and chlorpromazine were tested for their antimicrobial activity alone or in combination with conventional antibiotics against strains of Escherichia coli. Results: The growth of two E. coli strains tested was not inhibited by the extract. The minimum inhibitory concentration and minimal bactericide concentration values were ≧1 mg/ml for both strains of E. coli used. A potentiating effect of this extract on gentamicin was demonstrated. Similarly, there was a potentiating effect of chlorpromazine on kanamycin, amikacin and tobramycin, indicating the involvement of an efflux system in the resistance to these aminoglycosides. Conclusions: It is therefore suggested that extracts from M. arvensis could be used as a source of plant-derived natural products with resistance-modifying activity, such as in the case of gentamicin, constituting a new weapon against bacterial resistance to antibiotics, as with chlorpromazine.
Very-Low-Density Lipoprotein-Induced Triglyceride Accumulation in Human Mesangial Cells Is Mainly Mediated by Lipoprotein Lipase
Authors: Li Jing , Li Hang , Wen Yu-bing , Li Xue-wang
Published: August 2008

Background: Very-low-density lipoprotein (VLDL) in vitro can induce foam cell formation in human mesangial cells. Lipoprotein lipase (LPL) expressed in the arterial wall plays a key role in atherogenesis by actions of enzymolysis and ‘molecular bridge’, and, thereby, leads to the formation of lipid-loaded foam cells. It is known that LPL is expressed by glomerular mesangial cells. This study was designed to investigate if LPL plays a role in VLDL-induced lipid accumulation in human mesangial cells and its underlying mechanism. Methods: Human wild-type LPL (hLPLwt), catalytically inactive LPL (hLPL194) or control alkaline phosphatase (hAP) were expressed in human mesangial cell line (HMCLs) via adenoviral vectors. Orlistat (tetrahydrolipstatin), a specific inhibitor of the lipoidolytic activity of endogenous LPL, and heparinase, which degrades cell-surface heparan sulfate proteoglycans, were also used to estimate the role of either the enzymolysis or ‘molecular bridge’ actions of LPL in the uptake of VLDL. Anti-low-density lipoprotein receptor (LDLr) antibody and anti-LDL receptor-related protein antibody were used to evaluate the effect of lipoprotein receptors on VLDL-induced lipid accumulation in HMCLs. Cellular lipid deposition was visualized by Oil Red O staining and analyzed quantitatively by standard enzymatic procedures. LPL protein expression and activity were measured by Western blot and a chemical analysis, respectively. Results: VLDL induced triglyceride accumulation in HMCLs in a time- and dose-dependent manner. Compared with Ad-hAP transfected HMCLs, cellular triglyceride content increased 4.55-fold (p < 0.05) in Ad-hLPLwt-transfected HMCLs and 1.52-fold (p < 0.05) in Ad-hLPL194-transfected HMCLs. Triglyceride accumulation in response to VLDL was mostly blocked by orlistat. Pretreatment of the cells with heparinase slightly reduced cellular triglyceride accumulation in the present of high concentrations of VLDL. The blockade of some lipoprotein receptors, such as LDLr, did not significantly reduce cellular triglyceride accumulation. LPL expression was upregulated by VLDL. Conclusions: VLDL-induced triglyceride accumulation in human mesangial cells is mainly mediated by LPL, and the enzymolysis action of LPL could be a major factor in this process. These results suggest that LPL may be an important factor participating in the initiation and progression of VLDL-mediated lipid renal injury.
Progressive Disseminated Essential Telangiectasia and Erythrosis Interfollicularis Colli as Examples for Successful Treatment with a High-Intensity Flashlamp
Authors: Wenzel Sabrina M. , Hohenleutner Ulrich , Landthaler Michael
Published: August 2008

Background: Treatment of progressive disseminated essential telangiectasia and erythrosis interfollicularis colli by flashlamp pulsed dye laser frequently results in a mottled appearance and often leads to hypo- or hyperpigmentation after treatment. Furthermore, treatment is time-consuming due to the small spot size. Objective: To report the successful removal of thin vessels in patients with the above-mentioned indications by an intense pulsed light (IPL) source. Methods: Four patients with progressive disseminated telangiectasia on the extremities and 5 patients with erythrosis interfollicularis colli were treated with IPL. Results: A clearance of up to 90% of the telangiectasias was achieved. Conclusion: The superficial, thin vessels of progressive disseminated essential telangiectasia and erythrosis interfollicularis colli can be successfully treated by IPL.