bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitivity of the Ventilation Process in the North Pacific to Eddy-Induced Tracer Transport*
Authors: Endoh Takahiro , Jia Yanli , Richards Kelvin J.
Published: October 2006

A coarse-resolution isopycnal model coupled with a bulk mixed layer model is used to examine the effect of isopycnal thickness diffusion, which parameterizes the subgrid-scale eddy-induced tracer transport, on ventilation of the North Pacific Ocean. Three numerical experiments with thickness diffusivities of 0 m2 s−1 and around 500 and 2000 m2 s−1 are carried out. The model successfully reproduces a deep winter mixed layer in the subarctic North Pacific, leading to well-formed mode waters and the subtropical countercurrent in the experiment with thickness diffusivity around 500 m2 s−1. The annual-mean subduction rate has peaks at densities of 25.0–25.4 and 26.4 σθ. The former peak spans the densities of North Pacific Subtropical Mode Water and North Pacific Eastern Subtropical Mode Water, whereas the latter peak is centered near the density of North Pacific Central Mode Water. The annual mean obduction rate also has the former peak and a slight enhancement corresponding to the latter peak. The Kuroshio plays a crucial role in obduction of North Pacific Subtropical Mode Water by transferring it northward from the permanent pycnocline to the seasonal pycnocline around the Kuroshio Extension, the importance of which has been overlooked in previous studies. In contrast to the simple expectation that the eddy-induced tracer transport enhances the ventilation process, stronger circulation with lower thickness diffusion increases the annual-mean subduction rate by carrying the subducted water quickly away from the seasonal pycnocline into the permanent pycnocline, as well as the annual-mean obduction rate by transferring much water from the permanent pycnocline to the seasonal pycnocline. As thickness diffusivity increases, the former peaks in the subduction and obduction rates occur at lighter densities, whereas the latter peak in the subduction rate is shifted toward higher densities.
Cold-Water Events and Dissipation in the Mixed Layer of a Lake
Authors: Ozen B. , Thorpe S. A. , Lemmin U. , Osborn T. R.
Published: October 2006

Measurements of temperature, velocity, and microscale velocity shear were made from the research submarine F. A. Forel in the near-surface mixed layer of Lake Geneva under conditions of moderate winds of 6–8 m s−1 and of net heating at the water surface. The submarine carried arrays of thermistors and a turbulence package, including airfoil shear probes. The rate of dissipation of turbulent kinetic energy per unit mass, estimated from the variance of the shear, is found to be lognormally distributed and to vary with depth roughly in accordance with the law of the wall at the measurement depths, 15–20 times the significant wave height. Measurements revealed large-scale structures, coherent over the 2.38-m vertical extent sampled by a vertical array of thermistors, consisting of filaments tilted in the wind direction. They are typically about 1.5 m wide, decreasing in width in the upward direction, and are horizontally separated by about 25 m in the downwind direction. Originating in the upper thermocline, they are characterized in the mixed layer by their relatively low temperature and low rates of dissipation of turbulent kinetic energy and by an upward vertical velocity of a few centimeters per second.
Control of Large-Scale Heat Transport by Small-Scale Mixing
Authors: Cessi Paola , Young W. R. , Polton Jeff A.
Published: October 2006

The equilibrium of an idealized flow driven at the surface by wind stress and rapid relaxation to nonuniform buoyancy is analyzed in terms of entropy production, mechanical energy balance, and heat transport. The flow is rapidly rotating, and dissipation is provided by bottom drag. Diabatic forcing is transmitted from the surface by isotropic diffusion of buoyancy. The domain is periodic so that zonal averaging provides a useful decomposition of the flow into mean and eddy components. The statistical equilibrium is characterized by quantities such as the lateral buoyancy flux and the thermocline depth; here, scaling laws are proposed for these quantities in terms of the external parameters. The scaling theory predicts relations between heat transport, thermocline depth, bottom drag, and diapycnal diffusivity, which are confirmed by numerical simulations. The authors find that the depth of the thermocline is independent of the diapycnal mixing to leading order, but depends on the bottom drag. This dependence arises because the mean stratification is due to a balance between the large-scale wind-driven heat transport and the heat transport due to baroclinic eddies. The eddies equilibrate at an amplitude that depends to leading order on the bottom drag. The net poleward heat transport is a residual between the mean and eddy heat transports. The size of this residual is determined by the details of the diapycnal diffusivity. If the diffusivity is uniform (as in laboratory experiments) then the heat transport is linearly proportional to the diffusivity. If a mixed layer is incorporated by greatly increasing the diffusivity in a thin surface layer then the net heat transport is dominated by the model mixed layer.
Daily to Decadal Sea Surface Temperature Variability Driven by State-Dependent Stochastic Heat Fluxes
Authors: Sura Philip , Newman Matthew , Alexander Michael A.
Published: October 2006

The classic Frankignoul–Hasselmann hypothesis for sea surface temperature (SST) variability of an oceanic mixed layer assumes that the surface heat flux can be simply parameterized as noise induced by atmospheric variability plus a linear temperature relaxation rate. It is suggested here, however, that rapid fluctuations in this rate, as might be expected, for example, from gustiness of the sea surface winds, are large enough that they cannot be ignored. Such fluctuations cannot be fully modeled by noise that is independent of the state of the SST anomaly itself. Rather, they require the inclusion of a state-dependent (i.e., multiplicative) noise term, which can be expected to affect both persistence and the relative occurrence of high-amplitude anomalies. As a test of this hypothesis, daily observations at several Ocean Weather Stations (OWSs) are examined. Significant skewness and kurtosis of the distributions of SST anomalies is found, which is shown to be consistent with a multiplicative noise model. The observed wintertime SST distribution at OWS P is reproduced using a single-column variable-depth mixed layer model; the resulting non-Gaussianity is found to be largely due to the state dependence of rapidly varying (effectively stochastic) sensible and latent heat flux anomalies. The authors’ model for the non-Gaussianity of anomalous SST variability (counterintuitively) implies that the multiplicative noise increases the persistence, predictability, and variance of midlatitude SST anomalies. The effect is strongest on annual and longer time scales and may, therefore, be important to the understanding and modeling of interannual and interdecadal SST and related climate variability.
Dynamics of the Cold-Water Event off the Southeast Coast of the United States in the Summer of 2003
Authors: Yuan Dongliang
Published: October 2006

The cold-water event along the southeast coast of the United States in the summer of 2003 is studied using satellite data combined with in situ observations. The analysis suggests that the cooling is produced by wind-driven coastal upwelling, which breaks the thermocline barrier in the summer of 2003. The strong and persistent southwesterly winds in the summer of 2003 play an important role of lifting the bottom isotherms up to the surface and away from the coast, generating persistent surface cooling in July–August 2003. Once the thermocline barrier is broken, the stratification in the nearshore region is weakened substantially, allowing further coastal cooling of large magnitudes by episodic southerly wind bursts or passage of coastally trapped waves at periods of a few days. These short-period winds or waves would otherwise have no effects on the surface temperature because of the strong thermocline barrier in summer if not for the low-frequency cooling produced by the persistent southwesterly winds.
Modeling of Bathymetry-Locked Residual Eddies in Well-Mixed Tidal Channels with Arbitrary Depth Variations
Authors: Li Chunyan
Published: October 2006

The concept of the in–out-type exchange flow in estuaries only applies to situations with significant freshwater discharge and/or elongated channels with relatively simple variations in depth and coastline along the channel. In waterways with complex bottom topography, the in–out-type exchange flows may be replaced by residual eddies that are locked to bathymetry. This paper develops an analytic model for such tidally induced residual eddies. The model allows arbitrary depth variations in both along- and across-channel directions. The model produces residual eddies locked to bathymetry features, similar to observations in Wassaw Sound using a ship-mounted ADCP. Analysis indicates that for problems in a “short” channel with standing wave characteristics, the residual circulation is significantly influenced by advection. The frictional effect, however, is dominant and the wave propagation effect cannot be uniformly neglected (i.e., it sometimes can still compete or reinforce the effect of advection). The bathymetry function plays an important role in the generation of residual eddies. The wind during a half-dozen field observations does not appear to have significant effect to alter the structure of the flow field. Nor does the tidal range: the structures of the residual eddies do not change with the spring–neap tidal variation of tidal amplitude and remain robust in location. The persistent nature of these residual eddies makes it useful to map them in a specific area in a way similar to a coastal current. Although variabilities are anticipated in response to wind and coastal low-frequency sea level changes, the residual eddies will have significant implications to the flushing of a tidal channel, material transport, and the ecosystem dynamics.
Disorders of Extreme Stress (DESNOS) Symptoms Are Associated With Type and Severity of Interpersonal Trauma Exposure in a Sample of Healthy Young Women
Authors: Ford Julian D. , Stockton Patricia , Kaltman Stacey , Green Bonnie L.
Published: October 2006

Childhood abuse and other developmentally adverse interpersonal traumas may put young adults at risk not only for posttraumatic stress disorder (PTSD) but also for impairment in affective, cognitive, biological, and relational self-regulation (“disorders of extreme stress not otherwise specified”; DESNOS). Structured clinical interviews with 345 sophomore college women, most of whom (84%) had experienced at least one traumatic event, indicated that the DESNOS syndrome was rare (1% prevalence), but DESNOS symptoms were reported by a majority of respondents. Controlling for PTSD and other anxiety or affective disorders, DESNOS symptom severity was associated with a history of single-incident interpersonal trauma and with more severe interpersonal trauma in a dose-response manner. Noninterpersonal trauma was associated with elevated prevalence of PTSD and dissociation but not with DESNOS severity. Study findings indicate that persistent posttraumatic problems with self-regulation warrant attention, even in relatively healthy young adult populations.
Validation of the Sexual Assault Symptom Scale II (SASS II) Using a Panel Research Design
Authors: Ruch Libby O. , Wang Chang-Hwai
Published: October 2006

To examine the utility of a self-report scale of sexual assault trauma, 223 female victims were interviewed with the 43-item Sexual Assault Symptom Scale II (SASS II) at 1, 3, 7, 11, and 15 months postassault. Factor analyses using principal-components extraction with an oblimin rotation yielded 7 common factors with 31 items. The internal consistency was high for 4 factors and moderate for 2 factors. The multitrait-multimethod matrix, correlating the factor subscale scores of self-reported trauma and clinical assessment ratings, demonstrated both convergent and discriminant validity, indicating that the SASS II has construct validity. Correlations between the SASS II subscales and the intrusion subscale of the Impact of Events Scale also indicated the convergent and discriminant validity of the SASS II. Significant positive correlations between current and prior trauma levels further evidence the validity of the SASS.
Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias
Authors: Weisberg Ellen , Catley Laurie , Wright Renee D. , Moreno Daisy , Banerji Lolita , Ray Arghya , Manley Paul W. , Mestan Juergen , Fabbro Doriano , Jiang Jingrui , Hall-Meyers Elizabeth , Callahan Linda , DellaGatta Jamie L. , Kung Andrew L. , Griffin James D.
Published: October 2006

Drug resistance resulting from emergence of imatinib-resistant BCR-ABL point mutations is a significant problem in advanced-stage chronic myelogenous leukemia (CML). The BCR-ABL inhibitor, nilotinib (AMN107), is significantly more potent against BCR-ABL than imatinib, and is active against many imatinib-resistant BCR-ABL mutants. Phase 1/2 clinical trials show that nilotinib can induce remissions in patients who have previously failed imatinib, indicating that sequential therapy with these 2 agents has clinical value. However, simultaneous, rather than sequential, administration of 2 BCR-ABL kinase inhibitors is attractive for many reasons, including the theoretical possibility that this could reduce emergence of drug-resistant clones. Here, we show that exposure of a variety of BCR-ABL+ cell lines to imatinib and nilotinib results in additive or synergistic cytotoxicity, including testing of a large panel of cells expressing BCR-ABL point mutations causing resistance to imatinib in patients. Further, using a highly quantifiable bioluminescent in vivo model, drug combinations were at least additive in antileukemic activity, compared with each drug alone. These results suggest that despite binding to the same site in the same target kinase, the combination of imatinib and nilotinib is highly efficacious in these models, indicating that clinical testing of combinations of BCR-ABL kinase inhibitors is warranted.
Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia
Authors: Malinge Sebastien , Ben-Abdelali Raouf , Settegrana Catherine , Radford-Weiss Isabelle , Debre Marianne , Beldjord Kheira , Macintyre Elizabeth A. , Villeval Jean-Luc , Vainchenker William , Berger Roland , Bernard Olivier A. , Delabesse Eric , Penard-Lacronique Virginie
Published: October 2006

Activation of tyrosine kinase genes is a frequent event in human hematologic malignancies. Because gene activation could be associated with gene dysregulation, we attempted to screen for activating gene mutation based on high-level gene expression. We focused our study on the Janus kinase 2 (JAK2) gene in 90 cases of acute leukemia. This strategy led to the identification of a novel JAK2-acquired mutation in a patient with Down syndrome (DS) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This mutation involves a 5–amino acid deletion within the JH2 pseudokinase domain (JAK2ΔIREED). Expression of JAK2ΔIREED in Ba/F3 cells induced constitutive activation of the JAK-STAT pathway and growth factor–independent cell proliferation. These results highlight the JAK2 pseudokinase domain as an oncogenic hot spot and indicate that activation of the JAK-STAT pathway may contribute to lymphoid malignancies and hematologic disorders observed in children with DS.
Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo
Authors: Yaccoby Shmuel , Ling Wen , Zhan Fenghuang , Walker Ronald , Barlogie Bart , Shaughnessy John D.
Published: October 2006

Dickkopf-1 (DKK1), a soluble inhibitor of Wnt signaling secreted by multiple myeloma (MM) cells contributes to osteolytic bone disease by inhibiting the differentiation of osteoblasts. In this study, we tested the effect of anti-DKK1 therapy on bone metabolism and tumor growth in a SCID-rab system. SCID-rab mice were engrafted with primary MM cells expressing varying levels of DKK1 from 11 patients and treated with control and DKK1-neutralizing antibodies for 4 to 6 weeks. Whereas bone mineral density (BMD) of the implanted myelomatous bone in control mice was reduced during the experimental period, the BMD in mice treated with anti-DKK1 increased from pretreatment levels (P < .001). Histologic examination revealed that myelomatous bones of anti-DKK1–treated mice had increased numbers of osteocalcin-expressing osteoblasts and reduced number of multinucleated TRAP-expressing osteoclasts. The bone anabolic effect of anti-DKK1 was associated with reduced MM burden (P < .04). Anti-DKK1 also significantly increased BMD of the implanted bone and murine femur in nonmyelomatous SCID-rab mice, suggesting that DKK1 is physiologically an important regulator of bone remodeling in adults. We conclude that DKK1 is a key player in MM bone disease and that blocking DKK1 activity in myelomatous bones reduces osteolytic bone resorption, increases bone formation, and helps control MM growth.
Characterization of HIV-1 subtype C envelope glycoproteins from perinatally infected children with different courses of disease
Authors: Zhang Hong , Hoffmann Federico , He Jun , He Xiang , Kankasa Chipepo , West John T , Mitchell Charles D , Ruprecht Ruth M , Orti Guillermo , Wood Charles
Published: October 2006

Background

The causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The applicability of such findings to other subtypes, such as subtype C, remains to be substantiated. In this study, we longitudinally characterized the evolution of the Env V1–V5 region from seven subtype C HIV-1 perinatally infected children with different clinical outcomes. We investigated the possible influence of viral genotype and humoral immune response on disease progression in infants.

Results

Genetic analyses revealed that rapid progressors (infants that died in the first year of life) received and maintained a genetically homogeneous viral population throughout the disease course. In contrast, slow progressors (infants that remained clinically asymptomatic for up to four years) also exhibited low levels variation initially, but attained higher levels of diversity over time. Genetic assessment of variation, as indicated by dN/dS, showed that particular regions of Env undergo selective changes. Nevertheless, the magnitude and distribution of these changes did not segregate slow and rapid progressors. Longitudinal trends in Env V1–V5 length and the number of potential N-glycosylation sites varied among patients but also failed to discriminate between fast and slow progressors. Viral isolates from rapid progressors and slow progressors displayed no significant growth properties differencesin vitro. The neutralizing activity in maternal and infant baseline plasma also varied in its effectiveness against the initial virus from the infants but did not differentiate rapid from slow progressors. Quantification of the neutralization susceptibility of the initial infant viral isolates to maternal baseline plasma indicated that both sensitive and resistant viruses were transmitted, irrespective of disease course. We showed that humoral immunity, whether passively acquired or developedde novoin the infected children, varied but was not predictive of disease progression.

Conclusion

Our data suggest that neither genetic variation inenv, or initial maternal neutralizing activity, or the level of passively acquired neutralizing antibody, or the level of thede novoneutralization response appear to be linked to differences in disease progression in subtype C HIV-1 infected children.
Novel Signal Transduction Pathways
Authors: ATREYA R. , ATREYA I. , NEURATH M.F.
Published: October 2006

Abstract:  Although the precise etiology of inflammatory bowel disease still remains unclear, considerable progress has been made in the identification of novel signal transduction pathways that elucidate the immunopathogenesis involved in the perpetuation of the inflammatory process. Augmented T cell resistance against apoptosis is regarded as a pivotal factor in the pathogenesis, as it impairs mucosal homeostasis and leads to unrestrained accumulation of activated T cells, which subsequently lead to the amplification of the inflammatory response. Therefore novel therapeutic strategies aim at restoring mucosal T cell susceptibility to apoptosis through targeting of signal transduction pathways that are elemental for augmented resistance of T lymphocytes against apoptosis. For example, a newly developed humanized anti‐IL‐6R monoclonal antibody that induces intestinal T cell apoptosis showed clinical efficacy in patients with active Crohn`s disease. Moreover, recent data that relate the immunosuppressive effects of azathioprine in inflammatory bowel disease to its apoptosis‐inducing potential, have important implications for the design of a more specific therapeutic approach.The examination of these novel signal transduction pathways has elucidated the pathogenetic mechanisms involved in inflammatory bowel disease and gives hope for the development of new strategies that may result in a more effective and less toxic therapeutic procedure.
Probiotics
Authors: BÖHM S.K. , KRUIS W.
Published: October 2006

Abstract:  There is currently a growing appreciation for the role of the enteric flora in health and disease. In the past years overwhelming evidence has accumulated for the role of commensal gut bacteria in the inflammatory bowel diseases Crohn's disease and ulcerative colitis. Both entities are mainly located in areas with high bacterial concentrations. Reduction of the enteric bacterial concentration by antibiotics, lavage, or surgical bypass results in a mitigation of symptoms, while experimental colitis models depend on the presence of the bacterial flora and the NOD2/CARD15‐mutation results in inefficient clearance of invasive bacteria. Those findings helped to bring the concept of probiotic therapy to the forefront, a therapy that had been known for millennia, but had been disregarded by the scientific world. Probiotics are meanwhile established in the maintenance therapy of ulcerative colitis and chronic recurrent or refractory pouchitis. Promising data exist for the primary prevention of pouchitis. Probiotic research at the intersection of gastroenterology, immunology and microbiology is highly dynamic in both the basic and the clinical field. Further understanding of the complex molecular mechanisms leading to the effectiveness of probiotics will also spur the development of more successful probiotic formulations.
Animal Models of Inflammatory Bowel Disease
Authors: ECKMANN LARS
Published: October 2006

Abstract:  Mouse models of intestinal inflammation have played a key role in understanding the mechanisms that govern the inflammatory response in the intestine, and in designing new therapeutic strategies in the treatment of patients with inflammatory bowel disease (IBD). Most of these models use chemical challenges, whereas relatively few robust models of intestinal inflammation caused by microbial infection are known. Two common models of infectious murine colitis and typhlitis are infection with the murine epithelial‐adherent pathogen, Citrobacter rodentium, and infection of streptomycin‐pretreated mice with Salmonella typhimurium. Studies in these models have helped to define the interactions between bacterial pathogens and host immune defenses, thus broadening the understanding of host–microbial interactions in the intestinal tract. Furthermore, such models help to determine the physiologic consequences of neutralizing specific mediators and signaling pathways implicated in inflammation on antimicrobial host defense.
Synergistic Costimulation by Both B7 Molecules Regulates Colitis Pathogenesis
Authors: KIM GISEN , SCHOENBERGER STEPHEN P. , SHARPE ARLENE , KRONENBERG MITCHELL
Published: October 2006

Abstract:  It has been reported that B7‐1 and B7‐2 play different roles in the pathogenesis of autoimmunity, but this issue is controversial. Here we analyzed colitis induced by transfer of CD45RBhigh CD4+ T cells to immune‐deficient recipients that lack expression of either B7‐1 or B7‐2. Surprisingly, disease was greatly accelerated in Rag−/− recipients deficient for either B7 molecule. Antigen presenting cells (APCs) lacking B7‐1 or B7‐2 stimulated T cell proliferation in vitro, but caused suboptimal IL‐2 production, leading to decreased induction of CTLA‐4. The data suggest that regulatory T cells function relatively normally in B7 single‐deficient recipients, but they cannot restrain the increased pathogenesis by naïve cells primed in B7 single‐deficient mice. Therefore, the inhibitory effect of CTLA‐4 on pathogenic T cells likely slows colitis, even in the absence of regulatory T cells. While a full block of costimulation may prevent autoimmunity, our data indicate, surprisingly, that a partial block may in some cases augment disease.
Role of the Melanocortin System in Inflammation
Authors: MAASER CHRISTIAN , KANNENGIESSER KLAUS , KUCHARZIK TORSTEN
Published: October 2006

Abstract:  In recent years, scientific interest in melanocortins (MC) has progressively increased due to their wide range of effects and expression on various tissues.Primarily discovered as mediators of skin pigmentation, recent research has shown their important roles in various body functions, such as energy homeostasis, sexual function, and inflammation. The anti‐inflammatory and immunomodulatory properties discovered so far have led to the hypothesis that alpha‐melanocyte‐stimulating hormone (MSH) and its cognate receptors might present potential anti‐inflammatory treatment options.
Inflammatory Bowel Disease and the Apical Junctional Complex
Authors: BRUEWER MATTHIAS , SAMARIN STANISLAV , NUSRAT ASMA
Published: October 2006

Abstract: A critical function of the intestinal mucosa is to form a barrier that separates luminal contents from the underlying interstitium. This intestinal barrier is primarily regulated by the apical junctional complex (AJC) consisting of tight junctions (TJs) and adherens junctions (AJs) and is compromised in a number of intestinal diseases, including inflammatory bowel disease (IBD).In vitrostudies have demonstrated that proinflammatory cytokines, such as interferon‐gamma (IFN‐γ) and tumor necrosis factor‐alpha (TNF‐α), that are increased in the intestinal mucosa of patients with IBD can induce a leaky mucosal barrier. There is a growing evidence that the increased permeability and altered AJC structure observed in IBD are mediated by internalization of junctional proteins. This review summarizes barrier defects observed in IBD and addresses mechanisms by which proinflammatory cytokines, such as IFN‐γ and TNF‐α, modulate AJC structure and epithelial barrier function.
Innate Immune Sensing of Microbes by Nod Proteins
Authors: KUFER THOMAS A. , BANKS DIANA J. , PHILPOTT DANA J.
Published: October 2006

Abstract:  Nod1 and Nod2 are proteins involved in innate immune defense. These intracellular surveillance proteins detect bacterial peptidoglycan, although requiring distinct motifs to achieve sensing. Detection through Nod1 and Nod2 initiates proinflammatory signaling via NF‐κB activation, which is necessary for clearance of infecting pathogens from the host. The peptidoglycan product sensed by Nod1 is a motif characteristic of Gram‐negative bacteria plus some Gram‐positive bacteria, such as Bacillus and Listeria spp. The specificity of Nod1 to detect this subset of bacteria might represent a selective advantage for the host in certain cases when Gram‐negative bacteria represent the main threat, such as in the epithelial cells lining the intestinal mucosa. In contrast, Nod2 has been implicated as a general sensor for both Gram‐positive and Gram‐negative bacteria since muramyl dipeptide (MDP), which is the minimal motif in all peptidoglycans, is the structure recognized by Nod2. Mutations in Nod2 have been associated with autoinflammatory disease in humans, including Crohn's disease. Interestingly, the most common mutation in Nod2 associated with Crohn's disease results in protein product that no longer detects MDP. Although the implications of these findings are still not fully understood, it appears that lack of bacterial sensing through a loss of interaction between mutant Nod2 and MDP contributes to the pathology of disease. A loss of surveillance activity by Nod2 may result in the inability of local responses in the intestinal mucosa to control bacterial infection, thereby initiating systemic responses and leading to aberrant inflammation.
Inflammatory Bowel Disease
Authors: SCHÖLMERICH JÜRGEN
Published: October 2006

Abstract:  Current treatment of inflammatory bowel disease is rather effective through it is only working in symptomatic fashion. Most recombinant “biologicals” have not been an overwhelming success. Infliximab has shown clinically relevant efficacy and is used in patients not responding to the standards. Alternatives such as modulating the bacterial‐epithelial interaction, tightening of the mucosal barrier and maybe even immunostimulation should be studied since most recent finding on etiology and pathophysiology point to a disturbed barrier with consequent abnormal bacterial epithelial interaction as the main problem in the IBD syndrome. We still need to learn much but we should not focus only on immunosuppressive systems.
Therapeutic Drug Delivery by Genetically Modified Lactococcus lactis
Authors: STEIDLER LOTHAR , ROTTIERS PIETER
Published: October 2006

Abstract:  Food‐grade bacteria have been consumed throughout history without associated pathologies and are, therefore, absolutely safe to ingest. Unexpectedly, Lactococcus lactis (L. lactis), known from cheese production, can be genetically engineered to constantly secrete satisfactory amounts of bioactive cytokines. Both of these features enabled the development of a new kind of topical delivery system: topical and active delivery of therapeutic proteins by genetically modified micro‐organisms. The host organism's record inspired the development of applications that target intestinal diseases. In a variety of mouse models, chronic colon inflammation can be successfully treated with (interleukin) IL‐10–secreting L. lactis. Trefoil factor (TFF) producer strains have also been shown to be very effective in the treatment of acute colitis. Such novel therapeutic strains are textbook examples of genetically modified (GM) organisms. There are legitimate concerns with regard to the deliberate release of GM micro‐organisms. On development of these applications, therefore, we have engineered these bacteria in such a way that biological containment is guaranteed. The essential gene thyA, encoding thymidylate synthase, has been exchanged for IL‐10. This makes the GM strain critically dependent on thymidine. Lack of thymidine, for example, resulting from thymidine consumption by thyA‐deficient strains–will irreversibly lead to induced “thymidine‐less death.” This accomplishment has created the possibility of using this strategy for application in human medicine.
Current Limitations of IBD Treatment
Authors: TARGAN STEPHAN R.
Published: October 2006

Abstract:  Great progress has been made over the last decade in the development of targeted specific therapies for inflammatory bowel disease. Nevertheless, accumulating experience with these modalities and results from ongoing investigations of agents currently on the market and those in development have demonstrated that efficacy may be limited to certain patient phenotypes. Recently, great interest has been applied to studies of the interplay between the adaptive and innate immune responses to achieve a better understanding of the immunopathogeneses of inflammatory bowel diseases as well as to identify targets for even more potent intervention.
Helminths and Mucosal Immune Modulation
Authors: WEINSTOCK JOEL V.
Published: October 2006

Abstract:  Geographic and ethnic variations in ulcerative colitis and Crohn's disease frequency suggest that environmental factors affect disease risk. Prevention of parasitic worms (helminths) through improved hygiene may be one factor leading to the increased disease prevalence. Helminths alter host mucosal and systemic immunity. Animals exposed to helminths are protected from experimental colitis and other immunological diseases, and helminthic colonization can be used to treat ongoing murine and human disease. Helminths induce mucosal T cells to make Th2 and regulatory cytokines. Helminth‐induced mucosal IL4, TGFβ, and IL10 likely are part of the protective process. Helminths affect pathways of innate immunity like TLR4 expression and function. Worms also induce various regulatory‐type T‐cell subsets in the gut that limit effector T‐cell growth and function. These effects of once ever‐present helminths may have protected people from immune‐mediated illnesses like inflammatory bowel disease.
CCR6 and CCL20
Authors: WILLIAMS IFOR R.
Published: October 2006

Abstract:  The CCR6 chemokine receptor is expressed by most B cells and subsets of T cells and dendritic cells (DCs) found in the gut mucosal immune system. CCL20, the single chemokine ligand for CCR6, is selectively made by the follicle‐associated epithelium (FAE) overlying Peyer's patches (PPs) and isolated lymphoid follicles (ILFs). CCL20 contributes to the recruitment of CCR6‐expressing B cells to these structures. CCL20 expression by the intestinal epithelium is also highly inducible in response to inflammatory stimuli. Thus, CCL20 functions as both an inflammatory and homeostatic chemokine. Interactions between CCR6 and CCL20 play a role at several stages in the development of intestinal lymphoid structures. A subset of the c‐kit+ lymphoid precursors found in cryptopatches (CPs) expresses CCR6. Recruitment of B cells to CPs and the subsequent expansion and organization of these B cells allows differentiation of some of these structures into ILFs. In CCR6 knockout mice, PPs are smaller with fewer follicles and the development of ILFs is compromised. These defects in the development of mucosal inductive sites in CCR6‐deficient mice are responsible for decreased IgA production to oral antigens. CCR6 can be included with CXCR5 and CCR7 in a list of chemokine receptors that participate in shaping the organized lymphoid structures that are part of the intestinal immune system.
Immunomodulatory Roles of the Carcinoembryonic Antigen Family of Glycoproteins
Authors: SHAO LING , ALLEZ MATTHIEU , PARK MEE‐SOOK , MAYER LLOYD
Published: October 2006

Abstract:  One of the most remarkable aspects of the immune system is its ability to fashion an immune response most appropriate to the activating stimulus. Although the immune system possesses a number of adaptations to accomplish this, an important theme is local immune regulation by site‐specific expression of receptors and ligands. One family of molecules that is gaining attention as modulators of the immune system is the carcinoembryonic antigen cell‐adhesion molecule family (CEACAM). Functionally, the carcinoembryonic antigen family can mediate cell–cell contact, host–pathogen interactions, and immune regulation. For example, biliary glycoprotein (CEACAM1) can have direct activity on T cells, leading to the inhibition of helper or cytotoxic T cell function. The expression of carcinoembryonic antigen (CEACAM5) on intestinal epithelial cells is involved in the activation of populations of regulatory CD8+ T cells, while a distinct subset of regulatory CD8+ T cells is activated by nonspecific cross‐reacting antigen (CEACAM6) on placental trophoblasts. Interestingly, the function and phenotype of these cells depend upon the specific member of the carcinoembryonic antigen family expressed, as well as the antigen‐presenting molecule with which it associates. Thus, these glycoproteins comprise a family of molecules whose functions can depend on their nature and context.
Immunology of Crohn's Disease
Authors: BRAAT HENRI , PEPPELENBOSCH MAIKEL P. , HOMMES DAAN W.
Published: October 2006

Abstract:  The immense microbiological load of the gastrointestinal tract poses a daunting challenge for the mucosal immune system: whereas it should tolerate the vast number of commensal bacteria, it should adequately attack pathogenic organisms. Millions of years of co‐evolution have produced an intricate system in which interactions between the endogenous flora and mucosal immune system manage to perform this difficult balancing act. When components of this interaction are defective, for instance by mutation, inflammatory bowel disease may result. In the present review, we comprehensively discuss the mucosal immune system in the context of Crohn's disease (CD) and its genetic risk factors, describe the clinical management of the disease, and discuss how knowledge of the mucosal immune system may yield novel therapeutical avenues for dealing with this debilitating disease.
Experience with immediate and delayed mandibular reconstruction
Authors: Lawson William , Loscalzo Louis J. , Baek Se‐Min , Biller Hugh F. , Krespi Yosef P.
Published: October 2006

The functional disability and cosmetic deformity after jaw and neck dissection can be very severe due to soft tissue and mandibular loss. Reconstruction of the mandible alone without soft tissue coverage can be complicated with prosthetic exposure, infection and, finally, rejection. We attempted to reconstruct the mandible at the time of tumor resection in a group of patients, using titanium mesh with marrow, rib, scapular spine, and clavicle. We used myocutaneous flaps in order to obtain intraoral coverage of the mandibular grafts. In a second group of patients, delayed reconstruction of the jaw was performed 6 months to 2 years after tumor resection. Titanium mesh prostheses were used for reconstruction of the mandible in conjunction with myocutaneous flaps for soft tissue augmentation. Osteomyocutaneous flaps were also used. The results and complications in 54 patients are presented.
A new assay to assess steroid‐hormone responsiveness in head and neck cancer
Authors: Berg Nicholas J. , Neel H. Bryan , Weiland Louis H. , Spelsberg Thomas C.
Published: October 2006

A new assay has been developed to predict the effectiveness of steroid‐hormone therapy in various tumors. The Biopsy Nuclear Binding assay measures the amount of biologically active receptor that binds both steroid hormone and acceptor sites in the nucleus. This assay does not measure the entire receptor population, only those that are biologically active; therefore, it should more accurately predict the response to steroid‐hormone therapy. We applied this assay effectively in breast and endometrial carcinoma. Preliminary studies have shown that 40% of patients with head and neck squamous‐cell carcinomas have biologically active (nuclear bound) progesterone receptors. If nuclear binding predicts a remission with hormonal therapy, then the quality of life of appropriately selected patients could greatly improve.
Limited septoplasty as treatment for recurrent epistaxis in a child with glanzmann's thrombasthenia
Authors: Guarisco J. Lindhe , Cheney Mack L. , Lejeune Francis E. , Ohene‐Frempong Kwaku , Blair Paul A.
Published: October 2006

Recurrent epistaxis can be a serious problem in children with coagulation disorders. We present a case of severe, recurrent nosebleeds in a 3‐year‐10‐month‐old boy with Glanzmann's thrombasthenia.

The nature of Glanzmann's disease and medical treatment of epistaxis in children is reviewed. A method of controlling recurrent epistaxis with a very simple and limited septoplasty is described. This technique should be applicable to patients with recurrent nosebleeds and other more common coagulation disorders.
Acute bilateral deafness with nephritis: A human temporal bone study
Authors: Yanagita Noriyuki , Yokoi Hisashi , Koide Junichi , Toriyama Minoru , Ishii Tetsuo
Published: October 2006

Temporal bone pathology is described in a 37‐year‐old man who had acute, bilateral, profound sensorineural hearing loss without improvement 4 months before death. The patient had suffered from low complement nephritis, for which he had received prednisolone therapy. Autopsy revealed malignant lymphoma with non‐Hodgkin's type, membranous proliferative glomerulonephritis and necrotizing vasculitis of middle and small arteries. In the temporal bone study, pathological changes were limited to the cochlear region. The vestibular structure showed no detectable pathological changes. The changes included total absence of the organ of Corti, atrophy and/or disappearance of the stria vascularis in the upper turns, collapse of Reissner's membrane in the middle turn, and new bone formation in the apical turn.
Congenital absence of the oval window
Authors: Lambert Paul R.
Published: October 2006

From 1983 to 1987, seven patients with conductive hearing loss were found to have congenital absence of the oval window. Six of these patients underwent vestibulotomies and reconstruction with House wires or total ossicular reconstruction prostheses. Surgical findings included absent or rudimentary stapes in all cases, abnormal facial nerves in four cases, and abnormal long processes of the incus in four cases. All patients had normal external ear canals and tympanic membranes. Hearing initially improved 20 to 45 dB in four of the six patients reconstructed. Over time, however, much of this initial hearing gain was lost. A marked difference in hearing results was evident between this series of absent oval window cases and a recent series of major atresia cases.
Surgery for sinusitis and aspirin triad
Authors: Mcfadden Edith A. , Kany Robert J. , Fink Jordan N. , Toohill Robert J.
Published: October 2006

An 11‐year retrospective study was conducted to evaluate the surgical treatment of sinusitis in aspirin‐triad patients. Twenty‐five patients were selected for surgery when their sinus disease and asthma progressed despite intense medical treatment. Sixteen patients had radiographic evidence of severe ethmoid disease, and their initial surgical procedures were limited (i.e., bilateral intranasal ethmoidec‐tomies). Of these 16 patients, 6 required subsequent surgery for recurrent sinusitis. Nine of the 25 patients had radio‐graphic evidence of severe antral, as well as ethmoid, disease. Their initial surgical procedures were radical, i.e., bilateral Caldwell‐Luc operations with intranasal and transantral sphenoethmoidectomies. None of these 9 patients required further surgical treatment for control.

This review indicates that if antral and sphenoid disease are detected in association with ethmoid involvement, a radical surgical approach is the operation of choice.
Chronic cough in infants and children: An update
Authors: Holinger Lauren D. , Sanders Anthony D.
Published: October 2006

Cough is a symptom frequently encountered by the otolaryngologist—head and neck surgeon. Although most coughs are self limited, chronic cough often proves to be a frustrating problem. Seventy‐two infants and children under age 16 with a normal chest radiogram have now been evaluated for chronic cough persisting for longer than 4 weeks. Cough‐variant asthma was the most common cause of cough, followed by sinusitis, gastroesophageal reflux, aberrant innominate artery, psychogenic cough, and sub‐glottic stenosis.

Chronic cough is best managed by first following an individualized diagnostic protocol designed to determine the etiology of the cough. This is followed by specific therapy to treat the underlying disorder. Children with persistent cough and normal chest radiograph are best served when referred promptly for evaluation by an otolaryngologist when the primary physician's initial efforts at diagnosis and treatment are not effective. Endoscopy is underutilized in practice and its importance understated in the literature. It is particularly helpful in establishing a precise diagnosis in infants under 18 months of age.
Plasminogen activators in tissue extract of aural cholesteatoma
Authors: Nakamura Mariko , Yamashiro Yutaka , Nakahodo Kazuhiro , Sunagawa Masanori , Huang Guang‐Wu , Kosugi Tadayoshi , Morimitsu Tamotsu
Published: October 2006

Using a biochemical technique, the authors characterized and identified the plasminogen activator (PA) derived from tissue extracts of six aural cholesteatomas. The results of fibrin zymography indicated that the tissue extracts of two cholesteatomas demonstrated two lytic zones on fibrin‐agarose plates. One of the lytic zones was at about 72 kd, while the other zone was at about 64 kd. Using various goat immunoglobulin G (IgG)‐containing antibodies (anti‐human uterine tissue type PA (t‐PA), anti‐human low‐molecular‐weight (LMW) urokinase, and nonspecific goat IgG) and plasminogen‐free fibrin‐agarose plates, we confirmed that the cholesteatoma tissue extracts contained 72 kd t‐PA and 64 kd urokinase type PA (u‐PA).

Furthermore, we measured the t‐PA and u‐PA activities in the tissue extracts selectively by parabolic rate assay. In order to estimate the PA activity, we developed optimal conditions for this assay. The specific t‐PA activity ranged from 0.03 to 0.43 mIU/μg‐protein and the specific u‐PA activity ranged from 0 to 0.35 mIU/μg‐protein. The highest percentage of u‐PA with respect to the total PA activity was 44.9%. However, in four of the six cases, we failed to detect u‐PA activity.

In the present study, we thus clarified the presence of PAs in tissue extracts of aural cholesteatomas. Furthermore, we confirmed that measurable u‐PA occurred in some tissue extracts. We anticipate that the u‐PA in inflammatory tissues plays an important role in the degradation of the extracellular matrix via the formation of plasmin and collagenases.
Care of the terminal head and neck cancer patient in the hospice setting
Authors: Talmi Yoav P. , Roth Yehudah , Waller Alexander , Chesnin Vladimir , Adunski Abraham , Lander Martin I. , Kronenberg Jona
Published: October 2006

The ratio of incidence to mortality is somewhat less than 3:1 for head and neck cancer, and the 5‐year relative survival rate is 50%. Despite the high mortality rate, few reports have focused on patients with terminal head and neck cancer. A growing number of these patients end their lives in a hospice facility. A retrospective analysis was undertaken of 67 patients with terminal head and neck cancer who were admitted to the Tel Hashomer Hospice between 1988 and 1992. Patient data were reviewed and analyzed, and the particular characteristics of this population were defined. This study found that terminal head and neck cancer patients seem to receive better support in a hospice than in a general hospital or some family settings.
The Valley task: Understanding intention from goal‐directed motion in typical development and autism
Authors: Castelli Fulvia
Published: October 2006

A novel paradigm investigates the ability to understand an agent's intended goal in children with autism (N = 25), typically developing children (N = 46), and adults (N = 16+12) by watching a non‐human agent's kinematic properties alone. Computer animations depict a circle at the bottom of a U‐shaped valley rolling up and down its slopes and getting closer to a target resting at the top of either side of the valley. The circle's persistent motion and improving attempts evoke the attribution of the intention to reach the target, regardless of whether the circle fails or attains its goal. Children with autism are as able as controls to infer an agent's intended‐goal, disregarding its failure to reach the target. In addition, the study showed that the perception of persistent motion is a sufficient but not a necessary cue for very young children and children with autisn to attribute intention to an agent, whereas adults consider the persistent motion cue as a sufficient and necessary cue to attribute intention to an agent.