bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodality Approach to Management of the Paralyzed Face
Authors: Hadlock Tessa A. , Greenfield Laura J. , Wernick‐Robinson Mara , Cheney Mack L.
Published: August 2006

Objectives: Despite the ability of facial reanimation techniques to introduce meaningful movement to the paralyzed face, dynamic methods do not address all zones of the face. Our objective was to retrospectively review outcomes after multimodality management of the patient with facial paralysis, to describe several novel surgical methods that introduce subtle improvements in static facial balance, and to present an algorithm for comprehensive management of the paralyzed face.

Methods/Results: Three hundred thirty‐seven patients with facial paralysis were seen and treated in a busy facial nerve center setting over a 3‐year period using a range of standard muscle transfers, physical therapy, chemodenervation with botulinum toxin, and static surgical techniques. Three adjunct techniques emerged as novel and useful procedures that more fully addressed facial balance issues than existing techniques. Of patients proceeding with physical therapy, greater than 80% of patients experienced a benefit, and 97% of those who proceeded with botulinum toxin therapy experienced a benefit.

Conclusions: Facial paralysis is best managed using a multimodality approach that includes surgical interventions, physical therapy, and chemodeneveration. We describe three adjunctive surgical techniques for management of the paralyzed face and present a comprehensive algorithm for management of the paralyzed face. That may provide improved function and cosmesis in all zones of the paralyzed face.
Coordination of Swallowing and Respiration in Normal Sequential Cup Swallows
Authors: Dozier Thomas S. , Brodsky Martin B. , Michel Yvonne , Walters Bobby C. , Martin‐Harris Bonnie
Published: August 2006

Objectives: To establish normative data on laryngeal vestibular closure patterns and respiratory phase patterns during sequential cup swallows in healthy adults.

Study Design: Cross‐sectional study.

Methods: Combined videofluoroscopic and respiratory phase recordings were analyzed in 70 healthy adults during 50 mL sequential liquid cup swallows. The following dependent variables were measured offline from the digitized recordings: 1) number of swallows, 2) number of ingestion cycles (IC) (period of sustained apnea including 1 or more swallows), 3) opening of the laryngeal vestibule after each swallow, and 4) respiratory phase surrounding each IC. Patients were grouped according to the position of the larynx after each swallow.

Results: The mean number of swallows was 4.35, and the mean number of ICs was 3.28. Laryngeal vestibular opening after swallows was categorized into three groups: Always Open = 67.1%, Mixed (Open and Closed) = 31.4%, Always Closed = 1.4%. Statistical differences were not found in laryngeal opening pattern by age or sex, but the Always Open group had fewer swallows (4.02 vs. 5.23, P = .008) and a greater number of ICs (3.62 vs. 2.41, P = .001) than the Mixed Group. Respiratory phase after IC was expiration in 79% and inspiration in 21%.

Conclusions: Normal patterns of laryngeal vestibular closure and respiratory phase coordination during sequential swallowing have been described for the first time. The high occurrence of inspiration and laryngeal vestibular opening that surrounds sequential liquid cup swallows when compared with previous findings in single, discrete swallows may place patients with swallowing disorders at greater risk during this task.
Parathyroid Adenoma Localization: Surgeon‐Performed Ultrasound Versus Sestamibi
Authors: Steward David L. , Danielson Gregory P. , Afman Chad E. , Welge Jeffrey A.
Published: August 2006

Objectives: Compare surgeon‐performed ultrasound versus sestamibi for preoperative parathyroid adenoma localization.

Study Design: Single‐institutional cohort.

Methods: One hundred six consecutive patients undergoing parathyroidectomy at an academic institution between 2004 to 2005 were included. Of those, 103 underwent both surgeon‐performed ultrasound and sestamibi‐Tc99m localization preoperatively. Primary outcome is sensitivity for adenoma localization to correct quadrant (right vs. left, superior vs. inferior).

Results: Hypercalcemia resolved in 97% of patients. Sensitivities for correct quadrant localization for ultrasound versus sestamibi were 87% versus 58% (P < .001). Specificities were 95%. Positive and negative predictive values were 85% versus 78% and 96% versus 87%, respectively. Combined sensitivity was 93%. Sensitivities for correct side localization were 91% and 74% (P = .002).

Conclusions: Ultrasound appears more sensitive than sestamibi for localization to correct quadrant or side when performed in‐office by the author in this cohort.
Use of Er,Cr:YSGG Versus Standard Lasers in Laser Assisted Uvulopalatoplasty for Treatment of Snoring
Authors: Pavelec Vaclav , Polenik Pavel
Published: August 2006

Objectives:The aim of this study was to compare the effectiveness of the Er,Cr:YSGG (Waterlase) laser with KTP and CO2lasers in laser assisted uvulopalatoplasty (LAUP) for treatment of snoring.

Study Design:This is a prospective study of 63 patients who were treated for snoring by LAUP either with Er,Cr:YSGG (n = 21) or with KTP (n = 21) or CO2lasers (n = 21). Histologic analysis was performed, and the effects of KTP and Waterlase on soft tissue were compared.

Methods:Patients were examined by an ENT surgeon and tested with polysomnography. Probands who suffered from obstructive sleep apnea or had an apnea‐hypopnea index of 15 or greater were excluded from the study. The remaining patients were assigned to either Er,Cr:YSGG, KTP, or CO2laser therapy. The three lasers were compared from a postoperative recovery point of view by immunohistochemical examination.

Results:Pain medications were used on average for 4.1, 6.5, and 10.1 days, and the times to return to normal diet were on average 4.5, 6.8, and 8.6 days in the Er,Cr:YSGG, KTP, and CO2groups, respectively. Two cases of bleeding were observed in the CO2group. Foreign body sensation occurred in 14%, 19%, and 19% of subjects in the Er,Cr:YSGG, KTP, and CO2groups, respectively. Velopharyngeal insufficiency was noticed in one KTP treated patient; however, it was transient. Snoring and apnea‐hypopnea index was significantly reduced in all groups. Significantly larger coagulation of soft tissue was found in the KTP group than in the Waterlase group.

Conclusions:Patients treated with Waterlase recovered more quickly in comparison with patients in the KTP and CO2groups, which was confirmed by immunohistochemical findings. The laser techniques did not differ in effectiveness.
Pilot Study of Mucosal Genetic Differences in Early Smokers and Nonsmokers
Authors: Smith Richard V. , Schlecht Nicolas F. , Childs Geoffrey , Prystowsky Michael B. , Belbin Thomas J.
Published: August 2006

Background: Global gene expression analysis is proving to be an important means of assessing human tumors and may identify key components of carcinogenesis or clinical prognosis. This technique has been successfully applied to head and neck squamous cell carcinoma (HNSCC) and thyroid carcinomas; however, little has been done to evaluate premalignant states.

Methods: Human buccal mucosal cells were sampled from smokers and nonsmokers using a noninvasive brush technique. The method was validated by assessing the quantity and quality of RNA obtained. The purified RNA was then assayed using cDNA microarrays containing 27,323 cDNA clones to examine the buccal mucosa in these patients for differences in gene expression patterns. Using unsupervised and supervised hierarchical clustering methods, we developed a gene profile signature for an initial training set of smokers and nonsmokers and then used this to predict smoking status in a subsequent test set of subjects. Selected genes were then cross‐referenced with previously published gene sets found in HNSCC identified by our group.

Results: Nineteen subjects were used in this pilot analysis, 9 smokers and 10 nonsmokers. Smoking among the study group ranged from 1 to 60 pack years. RNA purified from buccal mucosal brushing demonstrated a high degree of similarity in gene expression profiles among independent samples. Through the application of supervised clustering techniques, we were able to identify 113 genes whose expression differed significantly between samples from smokers and nonsmokers (t test, P < .001). This expression signature was able to accurately predict who within the second set of subjects were smokers, with the exception of one person who had a minimal tobacco history and clustered with the nonsmokers. Cross‐referencing data with that found in HNSCC, we were able to identify a tumor suppressor gene involved in the c‐myc pathway (Mxi1) that was similarly under‐expressed in smokers and cancer patients with progressive disease.

Conclusions: Although the sample size was small in this preliminary dataset, our analysis revealed several groups of genes that were either over‐ or under‐expressed in the smokers and which could be used to predict smoking exposure. Many of these represent genes of possible interest as early molecular markers for head and neck carcinogenesis.
Temperature-mediated transitions between isometry and allometry in a colonial, modular invertebrate
Authors: Edmunds Peter J
Published: August 2006

The evolutionary success of animal design is strongly affected by scaling and virtually all metazoans are constrained by allometry. One body plan that appears to relax these constraints is a colonial modular (CM) design, in which modular iteration is hypothesized to support isometry and indeterminate colony size. In this study, growth rates of juvenile scleractinians (less than 40 mm diameter) with a CM design were used to test this assertion using colony diameters recorded annually for a decade and scaling exponents (
b
) for growth calculated from double logarithmic plots of final versus initial diameters. For all juvenile corals,
b
differed significantly among years, with isometry (
b
=1) in 4 years, but positive allometry (
b
>1) in 5 years. The study years were characterized by differences in seawater temperature that were associated significantly with
b
for growth, with isometry in warm years but positive allometry in cool years. These results illustrate variable growth scaling in a CM taxon and suggest that the switch between scaling modes is mediated by temperature. For the corals studied, growth was not constrained by size, but this outcome was achieved through both isometry and positive allometry. Under cooler conditions, positive allometry may be beneficial as it represents a growth advantage that increases with size.
Maternal antibodies postpone hantavirus infection and enhance individual breeding success
Authors: Kallio Eva R , Poikonen Antti , Vaheri Antti , Vapalahti Olli , Henttonen Heikki , Koskela Esa , Mappes Tapio
Published: August 2006

The transfer of maternal antibodies from mother to progeny is a well-known phenomenon in avian and mammalian species. Optimally, they protect the newborn against the pathogens in the environment. The effect of maternal antibodies on microparasite transmission dynamics may have important consequences for both the fitness of the host and the epizootic processes of the pathogens. However, there is a scarcity of studies examining these effects in free-living wild species. We studied the influence of maternal antibodies against the zoonotic Puumala hantavirus (PUUV) on the fitness of bank voles (
Clethrionomys glareolus
) and on PUUV transmission by exposing young maternal antibody-positive (MatAb+) and negative (MatAb−) bank voles (
n
=160) to PUUV in experimental populations. PUUV-specific maternal antibodies delayed the timing of infection. Females were more susceptible to PUUV infection than males. Interestingly, both the females and the males with maternal antibodies matured earlier than the other individuals in the population. Our results highlight the significance of maternal antibodies in the transmission of a pathogen and in the breeding success of the carriers.
Melnikov method approach to control of homoclinic/heteroclinic chaos by weak harmonic excitations
Authors: Chacón Ricardo
Published: August 2006

A review on the application of Melnikov's method to control homoclinic and heteroclinic chaos in low-dimensional, non-autonomous and dissipative oscillator systems by weak harmonic excitations is presented, including diverse applications, such as chaotic escape from a potential well, chaotic solitons in Frenkel–Kontorova chains and chaotic-charged particles in the field of an electrostatic wave packet.
Controlling spatio-temporal chaos in the scenario of the one-dimensional complex Ginzburg–Landau equation
Authors: Boccaletti S , Bragard J
Published: August 2006

We discuss some issues related with the process of controlling space–time chaotic states in the one-dimensional complex Ginzburg–Landau equation. We address the problem of gathering control over turbulent regimes with the use of only a limited number of controllers, each one of them implementing, in parallel, a local control technique for restoring an unstable plane-wave solution. We show that the system extension does not influence the density of controllers needed in order to achieve control.
Structural health monitoring based on sensitivity vector fields and attractor morphing
Authors: Yin Shih-Hsun , Epureanu Bogdan I
Published: August 2006

The dynamic responses of a thermo-shielding panel forced by unsteady aerodynamic loads and a classical Duffing oscillator are investigated to detect structural damage. A nonlinear aeroelastic model is obtained for the panel by using third-order piston theory to model the unsteady supersonic flow, which interacts with the panel. To identify damage, we analyse the morphology (deformation and movement) of the attractor of the dynamics of the aeroelastic system and the Duffing oscillator. Damages of various locations, extents and levels are shown to be revealed by the attractor-based analysis. For the panel, the type of damage considered is a local reduction in the bending stiffness. For the Duffing oscillator, variations in the linear and nonlinear stiffnesses and damping are considered as damage. Present studies of such problems are based on linear theories. In contrast, the presented approach using nonlinear dynamics has the potential of enhancing accuracy and sensitivity of detection.
A 5′ RNA element promotes dengue virus RNA synthesis on a circular genome
Authors: Filomatori Claudia V. , Lodeiro Maria F. , Alvarez Diego E. , Samsa Marcelo M. , Pietrasanta Lía , Gamarnik Andrea V.
Published: August 2006

The mechanisms of RNA replication of plus-strand RNA viruses are still unclear. Here, we identified the first promoter element for RNA synthesis described in a flavivirus. Using dengue virus as a model, we found that the viral RdRp discriminates the viral RNA by specific recognition of a 5′ element named SLA. We demonstrated that RNA–RNA interactions between 5′ and 3′ end sequences of the viral genome enhance dengue virus RNA synthesis only in the presence of an intact SLA. We propose a novel mechanism for minus-strand RNA synthesis in which the viral polymerase binds SLA at the 5′ end of the genome and reaches the site of initiation at the 3′ end via long-range RNA–RNA interactions. These findings provide an explanation for the strict requirement of dengue virus genome cyclization during viral replication.
E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells
Authors: Chagraoui Jalila , Niessen Sherry L. , Lessard Julie , Girard Simon , Coulombe Philippe , Sauvageau Martin , Meloche Sylvain , Sauvageau Guy
Published: August 2006

The Polycomb group gene Bmi1 is essential for the proliferation of neural and hematopoietic stem cells. Much remains to be learned about the pathways involved in the severe hematopoietic phenotype observed in Bmi1 homozygous mutant mice except for the fact that loss of p53 or concomitant loss of p16Ink4a and p19Arf functions achieves only a partial rescue. Here we report the identification of E4F1, an inhibitor of cellular proliferation, as a novel BMI1-interacting partner in hematopoietic cells. We provide evidence that Bmi1 and E4f1 genetically interact in the hematopoietic compartment to regulate cellular proliferation. Most importantly, we demonstrate that reduction of E4f1 levels through RNA interference mediated knockdown is sufficient to rescue the clonogenic and repopulating ability of Bmi1−/− hematopoietic cells up to 3 mo post-transplantation. Using cell lines and MEF, we also demonstrate that INK4A/ARF and p53 are not essential for functional interaction between Bmi1 and E4f1. Together, these findings identify E4F1 as a key modulator of BMI1 activity in primitive hematopoietic cells.
Hda-mediated inactivation of the DnaA protein and dnaA gene autoregulation act in concert to ensure homeostatic maintenance of the Escherichia coli chromosome
Authors: Riber Leise , Olsson Jan A. , Jensen Rasmus B. , Skovgaard Ole , Dasgupta Santanu , Marinus Martin G. , Løbner-Olesen Anders
Published: August 2006

Initiation of DNA replication in Eschericia coli requires the ATP-bound form of the DnaA protein. The conversion of DnaA–ATP to DnaA–ADP is facilitated by a complex of DnaA, Hda (homologous to DnaA), and DNA-loaded β-clamp proteins in a process termed RIDA (regulatory inactivation of DnaA). Hda-deficient cells initiate replication at each origin mainly once per cell cycle, and the rare reinitiation events never coincide with the end of the origin sequestration period. Therefore, RIDA is not the predominant mechanism to prevent immediate reinitiation from oriC. The cellular level of Hda correlated directly with dnaA gene expression such that Hda deficiency led to reduced dnaA gene expression, and overproduction of Hda led to DnaA overproduction. Hda-deficient cells were very sensitive to variations in the cellular level of DnaA, and DnaA overproduction led to uncontrolled initiation of replication from oriC, causing severe growth retardation or cell death. Based on these observations, we propose that both RIDA and dnaA gene autoregulation are required as homeostatic mechanisms to ensure that initiation of replication occurs at the same time relative to cell mass in each cell cycle.
The transcriptional activity of RNA polymerase I is a key determinant for the level of all ribosome components
Authors: Laferté Arnaud , Favry Emmanuel , Sentenac André , Riva Michel , Carles Christophe , Chédin Stéphane
Published: August 2006

Regulation of ribosome biogenesis is a key element of cell biology, not only because ribosomes are directly required for growth, but also because ribosome production monopolizes nearly 80% of the global transcriptional activity in rapidly growing yeast cells. These observations underscore the need for a tight regulation of ribosome synthesis in response to environmental conditions. In eukaryotic cells, ribosome synthesis involves the activities of the three nuclear RNA polymerases (Pol). Although postulated, there is no clear evidence indicating whether the maintenance of an equimolar supply of ribosomal components reflects communication between the nuclear transcriptional machineries. Here, by constructing a yeast strain expressing a Pol I that remains constitutively competent for the initiation of transcription under stress conditions, we demonstrate that derepression of Pol I transcription leads to a derepression of Pol II transcription that is restricted to the genes encoding ribosomal proteins. Furthermore, we show that the level of 5S rRNA, synthesized by Pol III, is deregulated concomitantly with Pol I transcription. Altogether, these results indicate that a partial derepression of Pol I activity drives an abnormal accumulation of all ribosomal components, highlighting the critical role of the regulation of Pol I activity within the control of ribosome biogenesis.
Disconnection analysis of CA3 and DG in mediating encoding but not retrieval in a spatial maze learning task
Authors: Jerman Taylor , Kesner Raymond P. , Hunsaker Michael R.
Published: August 2006

The dentate gyrus (DG) subregion of the hippocampus has been shown to be involved in encoding but not retrieval in a spatial maze task (modified Hebb-Williams maze). The first experiment in this study examined whether a lesion to the CA3 would contribute to a similar encoding deficit. A DG group was included in order to replicate previous results. Relative to controls, animals receiving CA3 lesions were impaired in encoding, not retrieval, on the modified Hebb-Williams maze—similar to a group that received DG lesions. This suggests the possibility that CA3 and DG are working together to mediate encoding processes. The second experiment in this study was designed to test the interaction between CA3 and DG using a disconnection paradigm. Animals with contralateral lesions (CA3 lesioned in one hemisphere, DG lesioned in the other hemisphere) showed a significant disruption effect on encoding, but not retrieval, when compared with animals with ipsilateral lesions (CA3 and DG lesioned in the same hemisphere, leaving the other hemisphere intact). This suggests an interaction between CA3 and DG in supporting encoding but not retrieval processes in a spatial maze learning task.
Retrieval induces hippocampal-dependent reconsolidation of spatial memory
Authors: Rossato Janine I. , Bevilaqua Lia R.M. , Medina Jorge H. , Izquierdo Iván , Cammarota Martín
Published: August 2006

Nonreinforced retrieval can cause extinction and/or reconsolidation, two processes that affect subsequent retrieval in opposite ways. Using the Morris water maze task we show that, in the rat, repeated nonreinforced expression of spatial memory causes extinction, which is unaffected by inhibition of protein synthesis within the CA1 region of the dorsal hippocampus. However, if the number of nonreinforced retrieval trials is insufficient to induce long-lasting extinction, then a hippocampal protein synthesis-dependent reconsolidation process recovers the original memory. Inhibition of hippocampal protein synthesis after reversal learning sessions impairs retention of the reversed preference and blocks persistence of the original one, suggesting that reversal learning involves reconsolidation rather than extinction of the original memory. Our results suggest the existence of a hippocampal protein synthesis-dependent reconsolidation process that operates to recover or update retrieval-weakened memories from incomplete extinction.
The refolding of different α‐fetoprotein variants
Authors: Leong Susanna S.J. , Middelberg Anton P.J.
Published: August 2006

The effect of glycosylation on AFP foldability was investigated by parallel quantitative and qualitative analyses of the refolding of glycosylated and nonglycosylated AFP variants. Both variants were successfully refolded by dialysis from the denatured‐reduced state, attaining comparable “refolded peak” profiles and refolding yields as determined by reversed‐phase HPLC analysis. Both refolded variants also showed comparable spectroscopic fingerprints to each other and to their native counterparts, as determined by circular dichroism spectroscopy. Inclusion body‐derived AFP was also readily refolded via dilution under the same redox conditions as dialysis refolding, showing comparable circular dichroism fingerprints as native nonglycosylated AFP. Quantitative analyses of inclusion body‐derived AFP showed sensitivity of AFP aggregation to proteinaceous and nonproteinaceous inclusion body contaminants, where refolding yields increased with increasing AFP purity. All of the refolded AFP variants showed positive responses in ELISA that corresponded with the attainment of a bioactive conformation. Contrary to previous reports that the denaturation of cord serum AFP is an irreversible process, these results clearly show the reversibility of AFP denaturation when refolded under a redox‐controlled environment, which promotes correct oxidative disulfide shuffling. The successful refolding of inclusion body‐derived AFP suggests that fatty acid binding may not be required for the attainment of a rigid AFP tertiary structure, contrary to earlier studies. The overall results from this work demonstrate that foldability of the AFP molecule from its denatured‐reduced state is independent of its starting source, the presence or absence of glycosylation and fatty acids, and the refolding method used (dialysis or dilution).
Genetic factors involved in the development of Helicobacter pylori‐related gastric cancer
Authors: Hamajima Nobuyuki , Naito Mariko , Kondo Takaaki , Goto Yasuyuki
Published: August 2006

Developmental process to gastric cancer by Helicobacter pylori infection consists of three steps: (1) H. pylori infection; (2) gastric atrophy development; and (3) carcinogenesis. In each step, genetic traits may influence the process, interacting with lifestyle. In the step of H. pylori infection, two lines of genetic polymorphisms were assumed: one influencing gastric acid inhibition interacting with smoking, and the other concerning innate immune response attenuation. The former includes functional polymorphisms of IL‐1B (C‐31T or tightly linked T‐511C), and TNF‐A (T‐1031C and C‐857T), and the latter possibly includes NQO1 C609T. In the step to gastric atrophy, polymorphisms pertaining to the signal transduction from cytotoxin‐associated gene A (PTPN11 A/G at intron 3) and to T‐cell responses (IL‐2 T‐330G and IL‐13 C‐1111T) were hypothesized. There are a limited number of epidemiological genotype studies on the final step of literal carcinogenesis, potentially interacting with smoking, a low vegetable and fruit intake, and salty foods, the well‐documented risk factors. In past case‐control studies on the associations between genotype and gastric cancer risk, the cases consisted of H. pylori‐related and unrelated gastric cancer patients and the controls consisted of individuals including the uninfected (H. pylori unexposed and exposed) and the infected with and without gastric atrophy. Accordingly, it was not clear whether the observed risk was for H. pylori‐related or ‐unrelated gastric cancer, nor which step was involved in the observed associations even when nearly all cases were H. pylori‐related. In order to elucidate the genetic traits of H. pylori‐related gastric cancer, stepwise evaluation will be required. (Cancer Sci 2006; 97: 1129–1138)
Recent insights into R gene evolution
Authors: MCDOWELL JOHN M. , SIMON STACEY A.
Published: August 2006

Plants are under strong evolutionary pressure to maintain surveillance against pathogens. Resistance (R) gene‐dependent recognition of pathogen avirulence (Avr) determinants plays a major role in plant defence. Here we highlight recent insights into the molecular mechanisms and selective forces that drive the evolution of NB‐LRR (nucleotide binding‐leucine‐rich repeat) resistance genes. New implications for models of R gene evolution have been raised by demonstrations that R proteins can detect cognate Avr proteins indirectly by ‘guarding’ virulence targets, and by evidence that R protein signalling is regulated by intramolecular interactions between different R functional domains. Comparative genomic surveys of NB‐LRR diversity in different species have revealed ancient NB‐LRR lineages that are unequally represented among plant taxa, consistent with a Birth and Death Model of evolution. The physical distribution of NB‐LRRs in plant genomes indicates that tandem and segmental duplication are important factors in R gene proliferation. The majority of R genes reside in clusters, and the frequency of recombination between clustered genes can vary strikingly, even within a single cluster. Biotic and abiotic factors have been shown to increase the frequency of recombination in reporter transgene‐based assays, suggesting that external stressors can affect genome stability. Fitness penalties have been associated with some R genes, and population studies have provided evidence for maintenance of ancient R allelic diversity by balancing selection. The available data suggest that different R genes can follow strikingly distinct evolutionary trajectories, indicating that it will be difficult to formulate universally applicable models of R gene evolution.
Absolute lymphocyte count predicts overall survival in follicular lymphomas
Authors: Siddiqui Mustaqeem , Ristow Kay , Markovic Svetomir N. , Witzig Thomas E. , Habermann Thomas M. , Colgan Joseph P. , Inwards David J. , White William L. , Ansell Stephen M. , Micallef Ivana N. , Johnston Patrick B. , Call Timothy G. , Porrata Luis F.
Published: August 2006

The peripheral blood absolute lymphocyte count (ALC) recovery after autologous stem cell transplantation has been shown to be an independent prognostic factor for survival for different haematologic malignancies. The role of ALC at diagnosis for follicular (grades 1 and 2) lymphomas (FL) on survival is not well described. The primary objective of this study was to assess the role of ALC on overall survival (OS) in FL patients. Of 1104 FL patients, 228 patients were originally diagnosed, followed, and had all treatment at the Mayo Clinic from 1984 and 1999, were evaluated. The median follow‐up was 89 months (range: 8·35–248). ALC as a continuous variable was identified as a predictor for OS [Hazard ratio (HR) = 0·74, P < 0·04]. ALC ≥ 1·0 × 109/l (n = 164) predicted a longer OS versus ALC < 1·0 × 109/l (n = 64; 175 vs. 73 months respectively, P < 0·0001). When compared with the Follicular Lymphoma International Prognostic Index (FLIPI), ALC was an independent prognostic factor for OS by multivariate analysis (HR = 0·677, P < 0·0001). These data suggest a critical role of FL patients’ immune status at diagnosis on survival.
Significant increase of CKS1B amplification from monoclonal gammopathy of undetermined significance to multiple myeloma and plasma cell leukaemia as demonstrated by interphase fluorescence in situ hybridisation
Authors: Chang Hong , Yeung Joanna , Xu Wei , Ning Yi , Patterson Bruce
Published: August 2006

The genetic events that lead to tumour progression in plasma cell dyscrasia are not well understood. Interphase cytoplasmic fluorescence in situ hybridisation was used to investigate the CKS1B amplification status (at 1q21) in clonal plasma cells from 123 patients: 23 monoclonal gammopathy of undetermined significance (MGUS), 75 multiple myeloma (MM) and 26 plasma cell leukaemia (PCL). While CKS1B amplification was absent in MGUS patients, such amplification (3–8 copies) was detected in 36% of newly diagnosed MM, 52% relapsed MM and 62% PCL (P < 0·001). Our results suggest that CKS1B amplification is associated with transformation from MGUS to MM and progression to PCL.
Synthetic double‐stranded RNA induces multiple genes related to inflammation through Toll‐like receptor 3 depending on NF‐κB and/or IRF‐3 in airway epithelial cells
Authors: Matsukura S. , Kokubu F. , Kurokawa M. , Kawaguchi M. , Ieki K. , Kuga H. , Odaka M. , Suzuki S. , Watanabe S. , Takeuchi H. , Kasama T. , Adachi M.
Published: August 2006

Background
We hypothesized that synthetic double‐stranded (ds)RNA may mimic viral infection and induce expression of genes related to inflammation in airway epithelial cells.

Objective
We analysed what gene was up‐regulated by synthetic dsRNA poly I : C and then focused this study on the role of Toll‐like receptor 3 (TLR3), a receptor of dsRNA and its transcriptional pathway.

Methods
Airway epithelial cell BEAS‐2B and normal human bronchial epithelial cells were cultured in vitro. Expression of targets RNA and protein were analysed by PCR and ELISA. Localization of TLR3 expression in the cells was analysed with flow cytometry. To analyse the role of TLR3 and transcription factors, knockdown of these genes was performed with short interfering RNA (siRNA).

Results
Real‐time PCR revealed that poly I : C significantly increased the expression of mRNAs for chemokines IP‐10, RANTES, LARC, MIP‐1α, IL‐8, GRO‐α and ENA‐78 and cytokines IL‐1β, GM‐CSF, IL‐6 and the cell adhesion molecule ICAM‐1 in both cell types. Increases in protein levels were also observed. Expression of these genes was significantly inhibited in BEAS‐2B cells in which TLR3 expression was knocked down. However, pre‐treatment with anti‐TLR3 mAb, which interferes with the function of TLR3 expressed on the cell surface, did not inhibit the genes expression and these data were concordant with the results that TLR3 was expressed inside airway epithelial cells. The study of siRNA for NF‐κB and IRF3 showed that they transduce the signal of poly I : C, but their roles were different in each target gene.

Conclusion
TLR3 is expressed inside airway epithelial cells and transduces synthetic dsRNA signals. These signals may increase expression of inflammatory cytokines, chemokines and ICAM‐1 through activation of transcription factors NF‐κB and/or IRF3 in airway epithelial cells.
Investigation of the skin characteristics in patients with severe GH deficiency and the effects of 6 months of GH replacement therapy: a randomized placebo controlled study
Authors: Tanriverdi Fatih , Borlu Murat , Atmaca Hulusi , Koc Cagdas Atasavun , Unluhizarci Kursad , Utas Serap , Kelestimur Fahrettin
Published: August 2006

Objective  The presence of GH receptor in human skin and its appendages suggests a direct effect of GH on skin characteristics. The skin is usually thin and dry in patients with GH deficiency (GHD). Sheehan's syndrome classically refers to postpartum hypopituitarism and GH is one of the earliest pituitary hormones lost. While severe GHD is a well‐established feature of Sheehan's Syndrome, skin characteristics and the effects of GH replacement therapy (GHRT) have been investigated neither in Sheehan's syndrome nor in other disorders of GHD. The aim of this study was to investigate the skin characteristics, including the sebum content, hydration (skin capacitance), transepidermal water loss (TEWL), pH and skin temperature, and particularly the effects of 6 months of GHRT on these parameters in GH deficient patients with Sheehan's syndrome.

Patients and design  Sixteen severely GH deficient women with Sheehan's syndrome (48·1 ± 10·9 years), and 20 age and menopausal status similar women as control subjects were included. Ten patients received recombinant GH for 6 months (treatment group) and 6 patients received placebo (placebo group) during this period. Skin properties were measured at baseline and after 6 months of GHRT using noninvasive and well‐established measuring methods.

Results  At baseline the skin capacitance was significantly decreased on the forehead and forearm, and sebum content was significantly decreased on forehead in patients with Sheehan's syndrome compared to control subjects (P < 0·05). In the treatment group there was a significant increase in sebum content on forehead after 6 months of GHRT compared to the baseline value (P < 0·05). However there were no significant changes in other parameters including sebum content on the forearm, TEWL, Ph, skin capacitance and temperature of both the forearm and forehead. In the placebo group there were no changes in any of the evaluated parameters after 6 months of treatment compared to baseline values.

Conclusions  The present study clearly shows that the sebum content on the forehead and skin hydration of the forehead and forearm are significantly decreased in GH deficient patients with Sheehan's syndrome. However 6 months of GHRT significantly increased only the sebum content on the forehead. These data suggest that GH and/or IGF‐I may have a modulatory role on several skin characteristics.
Current treatment options in children with pulmonary arterial hypertension and experiences with oral bosentan
Authors: Beghetti M.
Published: August 2006

Pulmonary arterial hypertension (PAH) is a life‐threatening disease characterized by vasoconstriction and progressive remodelling of the pulmonary arterial wall leading to right ventricular failure and death. Idiopathic PAH (IPAH) and PAH associated with congenital heart defects account for the majority of paediatric patients with PAH. During the last few decades, several pharmacological approaches have been introduced, including calcium channel‐blockers (CCBs), prostacyclin analogues, endothelin receptor antagonists and, most recently, phosphodiesterase inhibitors.

This paper reviews the treatment options available to children with a special focus on the initial experience with bosentan. Although CCBs have been shown to increase survival in IPAH, the beneficial effect appears to be limited to a small number of patients, defined as ‘responders’ to the vasoreactivity testing. With the availability of prostacyclin (intravenous epoprostenol) and then prostacyclin analogues, the treatment options have increased markedly and particularly in patients who have not responded to conventional therapy. Although epoprostenol has been shown to be efficacious in PAH, the drug is not ideal owing to serious complications arising from the invasive mode of application, particularly in children. Phosphodiesterase‐5 inhibitors have also shown beneficial effects. Targeting the endothelin (ET) system with the oral, dual ETA/ETB receptor antagonist, bosentan has been demonstrated to improve the cardiopulmonary haemodynamics, exercise capacity, quality‐of‐life and survival in adult patients with PAH. Specific ETA antagonists may also present the same beneficial profile. Recent experience with bosentan in paediatric patients with PAH indicates that the results obtained in adult patients may be extrapolated to children, thus offering a safe and effective therapy that is easy to administer.
Bosentan therapy of pulmonary arterial hypertension in connective tissue diseases
Authors: Cozzi F. , Montisci R. , Marotta H. , Bobbo F. , Durigon N. , Ruscazio M. , Sfriso P. , Iliceto S. , Todesco S.
Published: August 2006

Background  Pulmonary arterial hypertension (PAH) is a life‐threatening and debilitating complication of several connective tissue diseases. We aimed to evaluate the effects of long‐term treatment with bosentan, an oral dual endothelin ETA/ETB receptor antagonist, in a cohort of patients with PAH related to connective tissue diseases.

Material and methods  In the present prospective, noncontrolled study, 13 patients (nine with systemic sclerosis, two with systemic lupus erythematosus, one with mixed connective tissue disease and one with overlap syndrome including scleroderma and myositis), mostly nonresponders to prostanoids therapy, were treated for 1 year with bosentan. Cardiac haemodynamics and the diagnosis of PAH were performed by Doppler ultrasound examination. Exercise capacity was assessed by 6‐min walking test at baseline and at 3, 6 and 12 months of therapy.

Results  During bosentan treatment, progressive improvement of exercise capacity was observed. Walk distance increased in seven patients, remained unchanged in three and slightly decreased in three patients. A progressive significant decrease of right ventricular systolic pressure was also observed, whereas pulmonary artery mean pressure remained unchanged. Adverse effects related to bosentan (elevation of hepatic aminotransferases) were noted in two patients.

Conclusion  Long‐term treatment with bosentan was effective in improving exercise capacity and pulmonary haemodynamics in patients with PAH related to connective tissue diseases.
Bosentan for the treatment of pulmonary arterial hypertension associated with congenital heart defects
Authors: Sitbon O. , Beghetti M. , Petit J. , Iserin L. , Humbert M. , Gressin V. , Simonneau G.
Published: August 2006

Background  Bosentan is an effective first‐line therapy in New York Heart Association (NYHA) III patients with idiopathic pulmonary arterial hypertension (PAH). Pre‐clinical data support the rationale for the potential benefit of bosentan in PAH associated with congenital heart disease (CHD).

Materials and Methods  We performed a retrospective analysis of patients with PAH‐associated CHD who were treated with bosentan on top of conventional therapy. Bosentan was started at 62·5 mg bid for 4 weeks, then titrated to 125 mg bid. New York Heart Association (NYHA) functional class, 6‐min walking distance (6MWD), Borg dyspnoea index, arterial oxygen saturation and cardiopulmonary haemodynamic data (cardiac output, pulmonary blood flow and systemic and pulmonary vascular resistances) were collected at baseline and at follow up.

Results  Twenty‐seven patients (23 females, mean 35 ± 15 years) with NYHA class III–IV PAH‐associated CHD (not repaired in 23 cases) were treated with bosentan for a mean 18·3 ± 9·9 months. Bosentan improved 6MWD from 298 ± 92 m at baseline to 355 ± 82 m at 3 months (P = 0·0002) and to 364 ± 92 m (P = 0·0001) at the last follow up (mean 15·2 ± 9·7 months). At the last follow up, 13 patients had improved (= 1 NYHA class) and 14 remained stable. A favourable effect was observed in pulmonary blood flow and pulmonary vascular resistance for the 11 available patients. No change in pulse oximetry or liver enzyme elevation was reported.

Conclusions  Bosentan improves exercise capacity, functional class and haemodynamics in most patients with PAH‐associated CHD, without serious side‐effects, suggesting bosentan may be an important treatment option for these patients.
Bosentan treatment of portopulmonary hypertension related to liver cirrhosis owing to hepatitis C
Authors: Grander W. , Eller P. , Fuschelberger R. , Tilg H.
Published: August 2006

Pulmonary arterial hypertension (PAH) with coexisting portal hypertension has been defined as portopulmonary hypertension (PPHTN). It is often related to liver cirrhosis of various aetiologies and is associated with a high mortality rate. Endothelin‐1 (ET) is supposed to play an important role in the pathogenesis of PAH as well as portal hypertension. Therefore, therapy with an ETA/ETB receptor antagonist might be of use in the treatment of PPHTN. We report the case of a 76‐year‐old male with liver cirrhosis owing to chronic hepatitis C virus infection and PPHTN who was treated with the dual ETA/ETB receptor antagonist bosentan. The patient showed remarkable improvement of 6‐min walking distance from 300 to 480 m after 2 weeks and to 540 m after 14 weeks, respectively. In addition, a significant decline of N‐terminal pro B‐type natriuretic peptide fraction (NT‐proBNP) from 4928 ng mL−1 to 640 ng mL−1 was observed. Bosentan might be a promising new therapeutical option for patients suffering from PPHTN.
Endothelin and endothelin receptor antagonism in portopulmonary hypertension
Authors: Neuhofer W. , Gülberg V. , Gerbes A. L.
Published: August 2006

Portopulmonary hypertension (PPHT) is a rare but devastating complication in patients with portal hypertension, characterized by pulmonary arterial obliterative disease with a concomitant rise in pulmonary vascular resistance. A broad body of evidence has accumulated, indicating that endothelin (ET) peptides and their cognate receptors are causally involved in the pathophysiology of pulmonary arterial hypertension (PAH) owing to different aetiologies, including PPHT. In addition, the ET system may be involved in hepatic fibrotic remodelling and portal hypertension. Several experimental models have provided evidence that ET receptor antagonism may have therapeutic potential in PPHT. Initial experience has accumulated during the last 2 years, suggesting that targeting the ET system may have beneficial effects in the clinical setting. In these studies, the orally active, dual ET receptor antagonist bosentan improved pulmonary haemodynamics and functional capacity. These effects were sustained and occurred in the absence of adverse events. If these observations can be corroborated by controlled clinical trials, bosentan would offer several advantages over available therapies, which have major drawbacks owing to their invasive and demanding mode of application.
Soil carbon storage potential of direct seeding mulch‐based cropping systems in the Cerrados of Brazil
Authors: CORBEELS MARC , SCOPEL ERIC , CARDOSO ALEXANDRE , BERNOUX MARTIAL , DOUZET JEAN‐MARIE , NETO MARCOS SIQUEIRA
Published: August 2006

No‐tillage cropping systems with direct seeding into a mulch of plant residues from cover crops – the so‐called direct seeding mulch‐based cropping (DMC) systems – have been adopted widely over the last 10–15 years in the Cerrado region of Brazil. They are replacing the traditional soybean monoculture with bare fallow using conventional tillage (CT) practices. The objective of this study was to examine how DMC practices affect soil organic carbon (SOC) dynamics and to assess their potential for enhanced soil carbon (C) storage. The approach was to determine soil C stocks along a chronosequence of fields under DMC, and then to apply the generic decomposition and yield (G'DAY) plant–soil model to analyse the soil C storage potential for a number of cropping systems. Forty‐five fields were selected on a plateau of Ferralsols in the central Cerrado region to represent a chronosequence of 0–12 years under continuous DMC. Before DMC the fields had been under CT soybean monoculture following the clearing of the native savannah. An average increase in SOC stocks of 0.83 Mg C ha−1 yr−1 in the 0–20 cm topsoil was measured. The corresponding increase in total soil nitrogen was 79 kg N ha−1 yr−1. The G'DAY model predicted a net accumulation of 0.70–1.15 Mg C ha−1 yr−1 in the 0–40 cm topsoil for the first 12 years, depending on the type of soil and DMC system. Model predictions showed that less soil C was accumulated under DMC systems that commenced immediately after clearing the native savannah. Gains in soil C under DMC were primarily due to the introduction of a second crop that caused higher net primary productivity, leading to higher plant C inputs to soil. A rough estimation shows that the conversion of 6 million ha of CT soybean monoculture to DMC in the Cerrados would enhance soil C storage by 4.9 Tg C yr−1 during at least the first 12 years following the conversion to DMC.
Transcriptional response of Choristoneura fumiferana to sublethal exposure of Cry1Ab protoxin from Bacillus thuringiensis
Authors: Meunier L. , Préfontaine G. , Van Munster M. , Brousseau R. , Masson L.
Published: August 2006

Bacillus thuringiensis is a microbial control agent active against Choristoneura fumiferana, a lepidopteran defoliator of North American forests. Although the B. thuringiensis insecticidal crystal protoxins have a relatively narrow host range, there is concern about their impact on non‐target species where intoxication effects may not be overt. Larval toxicity effects can be assessed at the molecular level by determining altered transcriptional profiles in response to sublethal protoxin exposure in sensitive insects. Subtraction hybridization libraries were created using two larval populations, control and protoxin‐fed and were characterized by sequencing 1091 clones. Differential mRNA expression of selected clones, as measured by quantitative polymerase chain reaction, identified a number of metabolic and stress‐related genes that were either transcriptionally enhanced or repressed after protoxin exposure.