bluuebunny/crossref_metadata_2025 huggingface dataset:
The importance of plasma polymorphonuclear (PMN) elastase determination in patients with uveitis
Authors: Akyol Nurettin , Deĝer Orhan , Erdöl Hidayet , Gedik Yusuf , Örem Asim , Imamoglu Halil Ibrahim
Published: May 2009

Purpose: Polymorphonuclear elastase is used as an important marker for inflammatory disease. We wanted to show whether polymorphonuclear elastase could be a marker in uveitis.

Methods: Twenty‐two patients with uveitis and 30 healthy control subjects were included in the study. Polymorphonuclear elastase levels were determined by immunoactivation method before and after periods of corticosteroid and/or ciclosporin treatments.

Results: The levels were high in all of the patients before treatment; the levels reached normal range with treatment. In some cases, however, uveitis could not be suppressed in spite of treatment; these patients had high polymorphonuclear elastase levels.

Conclusion: It was concluded that determination of polymorphonuclear elastase level may be used for monitoring of uveitis.
Relationships of orbital computed tomographic findings and activity scores to the prognosis of corticosteroid therapy in patients with Graves' ophthalmopathy
Authors: Chang Tien‐Chun , Huang Kou‐Mou , Hsiao Yung‐Lien , Tzeng Shiaw‐Shen , Kao Shine C. S.
Published: May 2009

To elucidate the relationships of orbital computed tomographic findings and activity scores to the prognosis of corticosteroid therapy in patients with Graves' ophthalmopathy, 22 cases were treated with corticosteroid. Orbital computed tomographic was performed before treatment and the maximal muscle areas of rectus muscle bellies were calculated from the coronal images. Activity scores were calculated according to the recommendations of an international ad hoc committee. The clinical severity of the eye disease was based on the NOS‐PECS classification. Observation of the effectiveness of treatment at 6 months allowed patients to be classified into good responders or poor responders. Twelve of 22 patients (54.5%) belonged to the good responders. The total muscle areas were less in good responders. Although the total muscle areas were significantly correlated with the activity scores, no difference in the activity scores was noted between these two groups. We concluded that although activity score seems to be a predictor of initial responsiveness to anti‐inflammatory drugs, the maximal muscle area is a prognostic factor of corticosteroid therapy in patients with Graves' ophthalmopathy.
The use of capsaicin in herpes zoster ophthalmicus neuralgia
Authors: Frucht‐Pery Joseph , Feldman Sandy T. , Brown Stuart I.
Published: May 2009

The treatment of neuralgia which occurs during and following herpes zoster ophthalmicus is often unsatisfactory. Capsaicin (trans‐8‐methyl‐N‐vanillyl‐6‐nonenamide) is a drug which depletes substance P and may be effective in inhibiting pain. We utilized topical capsaicin to the affected dermatome five times daily for 4 weeks in 6 patients with acute and post herpetic neuralgia. In four cases pain was markedly relieved and narcotic medications were either discontinued or significantly reduced. In two cases, pain was not reduced. Four patients had side effects including burning sensation at the site of the drug administration (4 cases), dermatitis as a result of overuse of the drug (2 cases) and hyperesthesia (1 case). Our results suggest that capsaicin may be a useful therapy for the alleviation of pain in some individuals with herpes zoster ophthalmicus. However, controlled studies are needed to establish these results.
Choroidal neovascularization complicating epiretinal membrane removal
Authors: Korobelnik Jean‐François , Dureau Pascal , Sarfati Adrien , Chauvaud Dominique , Hoang‐Xuan Thanh
Published: May 2009

Purpose: Surgical removal of epiretinal membranes generally leads to anatomic and functional improvement. Main complications include cataract, retinal breaks and detachment. We describe the onset of a juxtafoveal choroidal neovascularization 2 years after surgery of an epiretinal membrane.

Methods: The neovascular membrane was treated by argon laser photocoagulation.

Results: Complete obliteration of the neovascularization was obtained resulting in functional improvement.

Conclusions: Although rare, choroidal neovascularization as a complication of epiretinal membrane surgery must be suspected in case of poor visual outcome or relapse of symptoms.
Thermal shock and germination in North‐West European Genisteae: implications for heathland management and invasive weed control using fire
Authors: Hanley M.E.
Published: May 2009

Question: Is the stimulation of germination by thermal shock (resulting from the passage of fire) commonly observed for Mediterranean‐climate Fabaceae also apparent for NW European Genisteae (Fabaceae) species?

Location: Southern England and NW France.

Methods: The germination of Cytisus scopiarius, Genista anglica, Ulex europaeus, Ulex gallii and Ulex minor was examined following exposure to a range of temperatures (50°C, 65°C, 80°C, 95°C and 110°C) applied to seeds for 5 min. A sixth Mediterranean‐origin species (Spartium junceum) was also included since it is a common invasive in NW Europe and North America.

Results: All five native NW European species displayed increased germination following thermal shock, even when seeds were heated to 110°C. However, there was some variation depending on provenance: in contrast to seeds collected from southern England, germination of French C. scopiarius seeds was unaffected by temperature. Spartium junceum germinated most at 95°C, but was the only species to show reduced germination when seeds were heated to 110°C.

Conclusions: The NW European Genisteae appear to be pre‐adapted to the high temperatures associated with fire; a response attributable to their evolutionary origins in the fire‐prone ecosystems of the Mediterranean Basin. Consequently, projected increases in fire frequency linked to climate change may stimulate their regeneration in NW European heathlands, potentially altering the species composition of these ecosystems. Additionally, a clearer understanding of the interaction between thermal shock and germination may explain why fire has so frequently been ineffective in controlling invasive Genisteae populations worldwide.
AN UNREASONABLE ARGUMENT AGAINST STUDENT FREE SPEECH
Authors: Blacker David
Published: May 2009

Abstract The U.S. Supreme Court’s recent opinion in Morse v. Frederick (2007), perhaps better known as the “Bong Hits 4 Jesus” case, contains a widely reported concurrence by Justice Clarence Thomas. Challenging well‐established precedent, Thomas argues that students should have no constitutional rights in school. In this essay David Blacker argues that, while philosophically interesting, Thomas’s argument is unreasonable on legal hermeneutic grounds and should therefore be rejected, even by those who may be sympathetic to its conclusions. Toward his own argument, Blacker provides, first, an account of what is reasonable and unreasonable in the juridical context of the students’ rights debate and, second, an explanation of how Thomas’s argument fits into the “unreasonable” category. Still further toward these ends, Blacker analyzes the Morse case in light of the current constitutional framework for student free‐speech rights (with a heuristic). He concludes with speculation about the role nostalgia plays in Thomas’s line of reasoning.
EXPANDING RATIONALITY: THE RELATION BETWEEN EPISTEMIC VIRTUE AND CRITICAL THINKING
Authors: Bevan Ryan
Published: May 2009

Abstract In this essay, Ryan Bevan explores the pedagogical implications of taking virtue epistemology as the philosophical foundation of educational theory rather than following the instrumentalist approach that is currently dominant. According to Bevan, the critical thinking strategies characteristic of instrumentalism generally work to further the vocationalization of educational discourse as well as the cultivation of unreflective moral agents. He contends that critical thinking should be expanded beyond its rationalist criteria to focus on the process of inquiry. Such a virtue epistemology approach, according to Bevan, has the potential to uncover and change fundamental misconceptions that pervade current theoretical assumptions by encouraging learners to engage in a more inclusive inquiry that draws out alternative perspectives. Bevan concludes that citizenship education in particular can benefit greatly from this more expansive theory with concrete pedagogical implications.
TRANSLATION: AN ALTERNATIVE FRAMEWORK FOR CONCEPTUALIZING AND SUPPORTING SCHOOL REFORM EFFORTS
Authors: Cook‐Sather Alison
Published: May 2009

Abstract Alison Cook‐Sather begins this review essay with a discussion of David Tyack and Larry Cuban’s generative phrase “the grammar of schooling” to provide context for her examination of three texts that address the challenges of school reform: John Sylvester Lofty’s Quiet Wisdom: Teachers in the United States and England Talk About Standards, Practice, and Professionalism; Karen Hammerness’s Seeing Through Teachers’ Eyes: Professional Ideals and Classroom Practices; and Mary Kennedy’s Inside Teaching: How Classroom Life Undermines Reform. The “grammar of schooling” metaphor, according to Cook‐Sather, captures what seems most fundamental and intractable about schools. Drawing on the texts under review as well as her own previous work on student voice and translation, Cook‐Sather explores how bringing students into dialogue with teachers and other stakeholders might support us in translating — in the more nuanced senses of the term — the established grammar of schooling into a more flexible, responsive, and variously informed set of structures and practices that would constitute a humane educational system.
Properties of the Kinesin‐3 NcKin3 motor domain and implications for neck function
Authors: Adio Sarah , Woehlke Günther
Published: May 2009

Members of the Kinesin‐3 family are microtubule motors involved in the transport of membranous cargo. NcKin3 from the fungus Neurospora crassa is dimeric but inactivates one of its motor heads to generate nonprocessive motility. To determine how one of the heads is inactivated, we investigated truncated monomeric constructs. None of the constructs generated processive single‐molecule motility, and multimotor velocities depended linearly on the number of residues remaining in the neck. The kinetic analysis suggests futile ATP hydrolysis cycles, because a representative monomer showed a faster ATP turnover than the dimer while supporting slower motility. The K0.5,MT was 70‐fold lower, the microtubule‐bound portion of the kinetic cycle eight‐fold longer and the microtubule detachment rate almost 15‐fold slower than that of the dimer. Moreover, the monomer’s microtubule‐dependent ADP release occurred three‐fold to four‐fold faster than kcat (125 versus 34 s−1), whereas phosphate release was approximately equally fast (29 s−1). A dimeric construct containing a structure‐breaking insert between motor head and neck showed a similar behaviour. These data suggest that the heads of the wild‐type NcKin3 motor are strictly coupled via the neck domain, and that the dimeric structure is required for proper detachment after one ATPase cycle. This is the first direct comparison of a monomeric Kinesin‐3 with its dimeric full‐length counterpart, and the kinetic changes observed here may also apply to other Kinesin‐3 motors.
Cosmic queuing: galaxy satellites, building blocks and the hierarchical clustering paradigm
Authors: Lagos Claudia del P. , Padilla Nelson D. , Cora Sofía A.
Published: May 2009

We study the properties of building blocks (BBs; i.e. accreted satellites) and surviving satellites of present-day galaxies using the semi-analytic model of galaxy formation SAG (‚semi-analytic galaxies’) in the context of a concordance Λ cold dark matter (ΛCDM) cosmology. We consider large number of dark matter (DM) halo merger trees spanning a wide range of masses (∼1 × 1010–2.14 × 1015 M⊙). We find higher metallicities for BBs with respect to surviving satellites, an effect produced by the same processes behind the build up of the mass–metallicity relation. We prove that these metallicity differences arise from the higher peak height in the density fluctuation field occupied by BBs and central galaxies which have collapsed into a single object earlier than surviving satellites. BBs start to form stars earlier, during the peak of the merger activity in ΛCDM, and build up half of their final stellar mass (measured at the moment of disruption) up to four times faster than surviving satellites. Surviving satellites keep increasing their stellar masses rather quiescently down to z≃ 1. The difference between the metallicities of satellites, BBs and central galaxies depends on the host DM halo mass, in a way that can be used as a further test for the concordance cosmology.
Fluid‐transport evaluation of lateral condensation, ProTaper gutta‐percha and warm vertical condensation obturation techniques
Authors: Mahera Fani , Economides Nikolaos , Gogos Christos , Beltes Panagiotis
Published: May 2009

The purpose of this study was to compare the microleakage of four obturation techniques (lateral condensation, lateral condensation of ProTaper Gutta‐percha, single ProTaper Gutta‐percha and warm vertical condensation) over a 3‐month period. A fluid‐transport model was used to measure microleakage. Sixty human‐extracted teeth, divided into four groups, were prepared with ProTaper rotary instruments before the root canals were filled by one of the four examined techniques. All groups were obturated using Sultan as a root canal sealer. Microleakage was measured 7 days, 1 month and 3 months after the procedures. There were no statistically significant differences between the four groups at any of examination points (P > 0.05). The leakage was increased in all obturation techniques over the 3‐month period.
Reliability of assessing dye penetration along root canal fillings using methylene blue
Authors: Souza Erick Miranda , Pappen Fernanda Geraldes , Shemesh Hagay , Bonanato‐Estrela Cristiane , Bonetti‐Filho Idomeo
Published: May 2009

Methylene blue (MB) remains the most frequently used tracer for dye penetration tests of endodontic fillings, despite its chemical reactions with different materials. This study checked whether dye penetration displayed by MB is comparable to Rhodamine B (RB). One hundred and seventy‐two root canals were filled with gutta‐percha and six sealers. Samples were covered with nail varnish except for the apical area, and immersed in MB or RB solutions under negative pressure. After 24 h, roots were bisected, photographed and the maximal dye penetration recorded. Dye penetrations displayed by MB and RB were compared (Newman–Keuls test). MB and RB displayed comparable results for groups filled with AH Plus, EndoREZ and Polifil (P > 0.05). For Endofill, Sealer 26 and Sealapex, a significant lower dye penetration was observed when MB was used (P < 0.05). Laboratory tests using MB for measuring dye penetration through filled root canals can result in misleading conclusions.
Endodontic treatment of a mandibular first molar with three mesial canals and broken instrument removal
Authors: Faramarzi Farhad , Fakri Hamidreza , Javaheri Homan H
Published: May 2009

To succeed in any dental procedure, the clinician's awareness of the patient's dental anatomy and its variations is crucial. In endodontic therapy, obtaining full information about the root canals' variations can affect the outcome substantially. This case report presents the endodontic treatment of a mandibular first molar exhibiting three mesial root canals with 4 mm of a separated K‐file in the coronal third of the mesiolingual canal on an 18‐year‐old female patient. This case demonstrates the importance of locating additional canals in any roots undergoing endodontic treatment and how the clinician's awareness of aberrant internal anatomy may change the treatment results.
SEM evaluation of the apical external root surface of teeth with chronic periapical lesion
Authors: Felippe Wilson Tadeu , Ruschel Maica Fritzen , Felippe Gabriela Santos , Pozzobon Maria Helena , Felippe Mara Cristina Santos
Published: May 2009

The aim is to verify, under scanning electron microscopy, the occurrence of apical root resorption in anterior and posterior teeth with chronic and radiographically visible periapical lesions. Thirty‐two teeth were extracted, the apical thirds (n = 39) were removed, and prepared to analyse the external apical root surface. All specimens presented irregular areas of root resorption with different depths, located mainly around the apical foramen. Teeth with chronic periapical lesions present areas of external apical root resorption with irregular surface and different depths located mainly around the apical foramen. Root resorptions may show different configurations and destroy the apical root structure more or less extensively.
A systematic review of the nasal index and the significance of the shape and size of the nose in rhinology
Authors: Leong S.C. , Eccles R.
Published: May 2009

Background:  There was great interest in the 19th and early 20th century in classifying human races as Caucasian, Asian African etc. according to nasal shape and size, and the nasal index was the most commonly used measurement to differentiate races.

Objective of review:  To determine if there is any clinical relevance of the shape and size of the nose in relation to physiology, pathology and surgery.

Type of review:  Systematic review.

Search strategy:  A structured search of PubMed was performed from 1966 to 2008 for each section of the review focusing on the ethnic variations in nasal index, the effect of climate of nasal shape, ethic variations of nasal physiology and racial predilection for sinonasal pathology.

Results:  Nasal proportions do vary between ethnic groups but the size and shape of the nose does not define Caucasian, Asian and African races respectively. Anthropologists agree that the nasal variations are due to man’s adaptation to the environment. However, this theory remains to be proven. Published data on nasal physiology have not shown significant differences between the ethnic groups despite obvious differences in nasal proportions. There is no evidence of ethnic specific predilection to disease due to anatomical variation, physiological vulnerability or genetic susceptibility. Rhinology research is often confounded by classifying populations according to race, as racial characteristics are not based on any scientific principles and the nasal index may be a more reliable discriminator. The only area in which the size and shape of the nose is of relevance is in aesthetic and reconstruction surgery.

Conclusions:  Nasal proportions are important aesthetically but appear to have little relevance to the rhinologist.
A randomised controlled trial to compare postoperative pain in children undergoing tonsillectomy using cold steel dissection with bipolar haemostasis versus coblation technique
Authors: Parker D. , Howe L. , Unsworth V. , Hilliam R.
Published: May 2009

Objective:  To measure postoperative pain levels in children undergoing tonsillectomy, by two different techniques, cold steel dissection and coblator dissection. The hypothesis – that coblator dissection may be associated with less postoperative pain.

Design:  Prospective, randomised, double blind trial.

Setting:  Single centre, secondary care Children’s Hospital.

Participants:  Children aged between 4 and 16 years, undergoing tonsillectomy, or adeno‐tonsillectomy. Exclusion criteria: children already taking regular analgesia and those who experienced postoperative bleeding. Seventy‐nine children were recruited, nine were excluded.

Main outcome measures:  We compared analgesia requirements during the first 10 days, and also the return to normal eating and drinking. These were assessed, using a validated pain scale. All analgesic administration in hospital and at home was compared. The return to normal eating & drinking patterns, was also compared.

Results:  Whilst in the 24 h postoperatively there was no significant difference in the pain scores between the two groups, the coblator group required less potent analgesia. No statistical difference was identified between the two groups following discharge, except on the sixth postoperative day, when the coblator group had lower pain scores. This may represent chance, rather than a clear difference.

Conclusion:  The findings do not confirm the hypothesis that tonsillectomy undertaken in children, with the coblator device, is associated with lower levels of postoperative pain, but do indicate that less analgesia is required by the coblator patients in the first 12 h postoperatively.
Molecular Basis for Cation Selectivity in Claudin‐2–Based Pores
Authors: Yu Alan S. L.
Published: May 2009

Claudins are transmembrane tight junction proteins that form paracellular pores. Claudins regulate the permeability of small inorganic ions and are selective on the basis of charge. We have developed an inducible expression system to measure the permeability of claudin‐2 and have found that claudin‐2 forms highly cation‐selective paracellular pores. The basis of this charge selectivity is likely to be the presence of a negatively charged binding site within the lumen of the pore. This may be a general mechanism by which claudins achieve selectivity.
Dynamic Regulation of Epithelial Cell Fate and Barrier Function by Intercellular Junctions
Authors: Koch Stefan , Nusrat Asma
Published: May 2009

In the intestine, a single layer of epithelial cells effectively separates potentially harmful luminal content from the underlying tissue. The importance of an intact mucosal layer is highlighted by pathological disorders of the gut such as inflammatory bowel disease, in which disruption of the epithelial barrier leads to severe inflammation of the submucosal tissue compartments. Epithelial barrier function is provided by tightly regulated intercellular junctions, which consist of a plethora of membrane‐associated and transmembrane proteins organized in discreet, spatially restricted complexes. Classically, these complexes are known to be dynamic seals for fluids and small molecules, as well as to provide mechanical strength by anchoring cell‐cell contacts to the cytoskeleton. Rather than just acting as simple gates and adapters, however, junctional complexes themselves can relay extracellular stimuli to the epithelium and initiate cellular responses such as differentiation and apoptosis. In this review, we will highlight recent studies by our group and others which discuss how junctional proteins can promote outside‐to‐inside signaling and modulate epithelial cell fate. Unraveling the complex crosstalk between epithelial cells and their intercellular junctions is essential to understanding how epithelial barrier function is maintained in vivo and might provide new strategies for the treatment of inflammatory disorders of the intestine.
Mechanisms of Epithelial Cell Shedding in the Mammalian Intestine and Maintenance of Barrier Function
Authors: Watson Alastair J.M. , Duckworth Carrie A. , Guan Yanfang , Montrose Marshall H.
Published: May 2009

The intestinal epithelium forms a barrier between the gut lumen and the body. The barrier is potentially challenged by the high turnover of epithelial cells being shed. Our laboratories have shown that the epithelium is punctuated by discontinuities called “gaps” that have the diameter of an epithelial cell and are devoid of cellular contents. At least a proportion of gaps are formed by the shedding of epithelial cells. These gaps are filled with an unknown substance that maintains local barrier function. Gaps have been identified in the mouse by in vivo confocal microscopy and in humans by confocal endomicroscopy. They can be distinguished from goblet cells by the absence of a nucleus and are found in Math1−/− mice where goblet cells are absent. Cell shedding and gap formation is increased by TNF‐α. Barrier function is lost after TNF‐α in approximately 20% of shedding events. These observations suggest that loss of barrier function at sites of cell shedding may be important in intestinal diseases where an increase in epithelial permeability plays a role in pathogenesis.
Pathways of Gliadin Transport in Celiac Disease
Authors: Heyman Martine , Menard Sandrine
Published: May 2009

Celiac disease (CD) is an inflammatory enteropathy induced by gluten/gliadins in genetically susceptible individuals. In patients with active CD, an abnormal retro‐transport of IgA/gliadin immune complexes is observed. This retro‐transport is mediated by the expression of CD71 on the apical pole of enterocytes and promotes the entry of harmful gliadin peptides in the intestinal mucosa and the triggering of abnormal immune responses to gliadin peptides. Our results indicate a CD71‐mediated transcytosis of gliadin peptides that may participate in the pathogenesis of CD in genetically predisposed individuals.
Tight Junctions, Intestinal Permeability, and Autoimmunity
Authors: Visser Jeroen , Rozing Jan , Sapone Anna , Lammers Karen , Fasano Alessio
Published: May 2009

Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on celiac disease (CD), an autoimmune enteropathy, and type 1 diabetes (T1D), a hyperglycosaemia caused by a destructive autoimmune process targeting the insulin‐producing pancreatic islet cells. Even if environmental factors and genetic susceptibility are clearly involved in the pathogenesis of autoimmunity, for most autoimmune disorders there is no or little knowledge about the causing agent or genetic makeup underlying the disease. In this respect, CD represents a unique autoimmune disorder because a close genetic association with HLA‐DQ2 or HLA‐DQ8 haplotypes and, more importantly, the environmental trigger (the gliadin fraction of gluten‐containing grains wheat, barley, and rye) are known. Conversely, the trigger for autoimmune destruction of pancreatic ß cells in T1D is unclear. Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity. In this review, each of these components will be briefly reviewed.
Cysteine Mutagenesis to Study the Structure of Claudin‐2 Paracellular Pores
Authors: Angelow Susanne , Yu Alan S.L.
Published: May 2009

The structure and transport mechanism of paracellular pores are only poorly understood. Here we describe for the first time how the substituted cysteine accessibility method (SCAM), previously developed to study transmembrane transport, can be applied to analyze the pathway of paracellular ion permeation. Using stable transfected Madin Darby canine kidney type I cells, induced to express claudin‐2, we show that paracellular cation transport can be blocked by sulfhydryl‐specific methanethiosulfonate (MTS) and that SCAM can be used to identify residues that line paracellular pores.
Mechanisms of Diarrhea in Inflammatory Bowel Diseases
Authors: Binder Henry J.
Published: May 2009

Diarrhea is a frequent symptom/sign in patients with ulcerative colitis and Crohn's disease (inflammatory bowel diseases), and several different mechanisms likely account for this diarrhea. As treatment of diarrhea is dependent on the pathogenetic process(es) responsible for diarrhea, increased understanding of the pathophysiology of diarrhea will help improve therapy. Inflammation is central to the diarrhea in patients with ulcerative colitis, while in Crohn's disease both inflammatory and noninflammatory mechanisms are responsible. This presentation summarizes the pathophysiology of diarrhea in both ulcerative colitis and Crohn's disease.
The Life and Work of Shoichiro Tsukita
Authors: Anderson James Melvin
Published: May 2009

We dedicate the 2008 Berlin conference and this collection of scientific manuscripts to the memory of our colleague Shoichiro Tsukita. His seminal scientific contributions and impact on the field of tight junctions is substantial. Shoichiro was a professor at Kyoto University and one the world's most influential biologists when he passed away on December 11, 2005 at the age of 52 from complications of pancreatic cancer. He was a pioneer in several areas of cell biology; most particularly he will be remembered as the founding father of the molecular study of tight junctions.
No Static at All
Authors: Graham W. Vallen , Marchiando Amanda M. , Shen Le , Turner Jerrold R.
Published: May 2009

Permeability of the intestinal epithelial barrier is regulated in response to physiological and pathophysiological stimuli. Recent work has characterized a critical role of acute tight junction regulation in diarrhea secondary to T cell activation and cytokine release. The intracellular mediators of the ensuing barrier dysfunction include myosin light chain kinase, which phosphorylates myosin II regulatory light chain and triggers structural tight junction reorganization. While the molecular intermediates in this reorganization are not defined, the new discovery that individual tight junction–associated proteins are highly dynamic at steady state may provide insight into the mechanisms of regulation.
Claudin Function in the Thick Ascending Limb of Henle's Loop
Authors: Günzel Dorothee , Haisch Lea , Pfaffenbach Sandra , Krug Susanne M. , Milatz Susanne , Amasheh Salah , Hunziker Walter , Müller Dominik
Published: May 2009

During the past decade, claudins have been established as major determinants of paracellular permeablilty in epithelia. In the kidney, each nephron segment expresses a distinct pattern of claudins. Cells of the thick ascending limb of Henle's loop (TAL), which is characterized by high paracellular cation permeability, co‐express an unusually large number of different claudins: claudin‐10, ‐16, and ‐19 and, depending on the species, also claudin‐3, ‐4, ‐8, and/or ‐11. The function of most of these claudins has been investigated in vitro. We present a summary of their function with special emphasis on claudin‐16 and ‐19. Mutations in the corresponding human genes lead to severely impaired renal Ca2+ and Mg2+ handling. To date, 42 different claudin‐16 mutations and three claudin‐19 mutations have been reported. These mutations prevent the claudins from reaching the surface membrane, decrease membrane residence time, or render them functionless. In spite of the clear clinical symptoms such as hypomagnesemia, hypercalciuria, nephrocalcinosis, and renal insufficiency, mechanisms that link claudin‐16 and ‐19 to these symptoms are still unknown. Depending on the cell type used in overexpression studies, claudin‐16 appears to cause a mild increase in paracellular Mg2+‐permeability or a pronounced increase in Na+ permeability. Claudin‐19 selectively decreases Cl− permeability, thus synergistically increasing relative cation permeability, or indiscriminately decreases paracellular permeability. In the light of these results it is hypothesized that the renal Mg2+/Ca2+ waste may not be solely due to reduced resorption in the TAL but at least in part to paracellular back‐leak of Mg2+/Ca2+ into the tubular lumen of the distal convoluted tubule.
Claudin‐2‐dependent Changes in Noncharged Solute Flux Are Mediated by the Extracellular Domains and Require Attachment to the PDZ‐scaffold
Authors: Van Itallie Christina M. , Holmes Jennifer , Bridges Arlene , Anderson James Melvin
Published: May 2009

Paracellular transport through the tight junction shows selectivity for both ionic charge and solute size. It is known that charged residues on the extracellular loops of claudins control charge selectivity. It is also known that inducible expression of claudin‐2, but not claudin‐4, will selectively increase the permeability for polyethylene glycol (PEG) molecules which are <0.4 Å in radius, but it is not known whether permeability is controlled by the same regions of claudins which control charge selectivity. Using inducible expression of chimeras of claudin‐2 and claudin‐4 in monolayers of MDCK II cells we show that the extracellular loops alone are responsible for controlling the permeability for noncharged PEGs as well as for charge selectivity. Further, the cytoplasmic C‐terminal PDZ‐binding motif is required for wild‐type claudin‐2 to control permeability, suggesting a requirement for attachment to the PDZ scaffold in order to form pores. These observations support a model where the loops form pores controlling permeability for both charged and noncharged solutes which are smaller than 0.4 Å. They leave unanswered why both claudin‐2 and ‐4 can influence electrical properties while only ‐2 can selectively increase permeability for small PEGs.
The Tight Junction Protein Cingulin Regulates Gene Expression and RhoA Signaling
Authors: Citi Sandra , Paschoud Serge , Pulimeno Pamela , Timolati Francesco , De Robertis Fabrizio , Jond Lionel , Guillemot Laurent
Published: May 2009

Tight junctions (TJ) regulate the passage of solutes across epithelial sheets, contribute to the establishment and maintenance of epithelial apico‐basal polarity and are involved in the regulation of gene expression and cell proliferation. Cingulin, a Mr 140 kDa protein localized in the cytoplasmic region of TJ, is not directly required for TJ formation and epithelial polarity but regulates RhoA signaling, through its interaction with the RhoA activator GEF‐H1, and gene expression. Here we describe in more detail the effect of cingulin mutation in embryoid bodies (EB) on gene expression, by identifying the genes that show the highest degree of up‐ or downregulation, and the putative canonical pathways that might be affected by cingulin. Furthermore, we show that full‐length canine GEF‐H1, produced in baculovirus‐infected insect cells, interacts with regions both in the cingulin globular head, and in the coiled‐coil rod domain. These results extend our previous studies and provide new perspectives for the mechanistic analysis of cingulin function.
Structure and Function of Extracellular Claudin Domains
Authors: Krause Gerd , Winkler Lars , Piehl Christian , Blasig Ingolf , Piontek Jörg , Müller Sebastian L.
Published: May 2009

Most claudins are tight junction (TJ)–forming proteins. However, their interaction on the molecular level remains unresolved. It is hypothesized that the extracellular loops specify these claudin functions. It is assumed that the first extracellular loop (ECL1) is critical for determining the paracellular tightness and the selective paracellular ion permeability, and that the second extracellular loop may cause narrowing of the paracellular cleft. Using a combination of site‐directed mutagenesis and homology modeling for the second extracellular loop (ECL2) of claudin‐5, we found several amino acids important for claudin folding and/or trans‐interaction to claudins in neighboring cells. These sensitive residues are highly conserved within one group of claudins, whereas the corresponding positions in the remaining claudins show a large sequence variety. Further functional data and analysis of sequence similarity for all claudins has led to their differentiation into two groups, designated as classic claudins (1–10, 14, 15, 17, 19) and nonclassic claudins (11–13, 16, 18, 20–24). This also corresponds to conserved structural features at ECL1 for classic claudins. Based on this, we propose a hypothesis for different pore‐forming claudins. Pore formation or tightness is supported by the spatial encounter of a surplus of repulsing or attracting amino acid types at ECL1. A pore is likely opened by repulsion of equally charged residues, while an encounter of unequally charged residues leads to tight interaction. These considerations may reveal the ECLs of claudins as decisive submolecular determinants that specify the function of a claudin.
The Oligomerization of the Coiled Coil‐domain of Occluddin Is Redox Sensitive
Authors: Walter Juliane K. , Rueckert Christine , Voss Martin , Mueller S.L. , Piontek Jörg , Gast Klaus , Blasig Ingolf E.
Published: May 2009

The transmembrane tight junction protein occludin is sensitive to oxidative stress. Occludin oligomerizes; however, its function in the tight junction is unknown. The cytosolic C‐terminal tail contains a coiled coil‐domain and forms dimers contributing to the oligomerization. The regulation of the oligomerization remains unclear. As the domain area contains sulfhydryl residues, we tested the hypothesis that the dimerization of the coiled coil‐domain depends on these residues. We showed that the dimerization is modulated by the thiol concentration in the low‐millimolar range, which is relevant both for physiological and pathophysiological conditions. Masking the sulfhydryl residues in the fragment by covalent binding of 4‐vinyl pyridine prevented the dimerization but did not affect its helical structure and cylindric shape. The data demonstrate, for the first time, that disulfide bridge formation of murine cystein 408 is involved in the dimerization. This process is redox‐sensitive but the secondary structure of the domain is not. It is concluded that the dimerization of occludin may play a regulatory role in the tight junction assembly under physiological and pathological conditions.
Effect of Probiotics on Intestinal Barrier Function
Authors: Mennigen Rudolf , Bruewer Matthias
Published: May 2009

Impairment of the intestinal barrier is a key event in various gastrointestinal diseases, including inflammatory bowel diseases, celiac disease, gastrointestinal infections, diarrhea, and critical illness. Recent studies demonstrated that probiotic bacteria have beneficial effects in these diseases by effectively improving intestinal barrier function. This article reviews available data on the effect of probiotics on intestinal barrier function in vitro, in animal models, and in clinical studies.
Lymphoepithelial Interactions
Authors: Dahan Stephanie , Roth‐Walter Franziska , Martin Andrea P. , Arnaboldi Paul , Mayer Lloyd
Published: May 2009

Intestinal lymphoepithelial interactions occur in the epithelium and subepithelial space. We asked whether or not lamina propria lymphocytes (LPL) could promote intestinal epithelial cell (IEC) differentiation. In contrast to epithelial cells in UC mucosa, which do not differentiate because of rapid turnover, differentiation of epithelial cells in CD mucosa occurs in the crypts. This dysregulation is driven by alterations in the crosstalk between CD LPL and CD IECs, leading to an acceleration of their differentiation. This alteration seems to involve the transcription factor CDX2 via the activation of the PI3K and MAPK pathways and provides new insights into the dysfunction of the epithelial barrier in CD versus UC. The absence of lymphocytes in Rag1‐deficient mice was associated with a defect in colonic IEC differentiation, restored by co‐transfer of naïve and regulatory T cells. Interestingly, the transfer of naïve T cells alone induced an acceleration of IEC differentiation similar to what was seen in the colonic mucosa of CD patients. Thus, there is a crosstalk between LPL and IECs that is altered in CD, which leads to an absorptive phenotype of IEC differentiation.
The Role of Claudin‐Based Tight Junctions in Morphogenesis
Authors: Furuse Mikio , Moriwaki Kazumasa
Published: May 2009

In morphogenetic events during developmental processes, the hydrostatic pressure caused by fluid accumulation is thought to be an important factor determining the shape of epithelial structures. Recent studies using loss of function of claudins have demonstrated that tight junctions, by their control of fluid accumulation, have crucial roles in morphogenesis. Interestingly, both the barrier and the channel functions of tight junctions appear to contribute to morphogenesis.
Cadherin‐Mediated Regulation of Tight Junctions in Stratifying Epithelia
Authors: Michels Christian , Aghdam Saeed Yadranji , Niessen Carien M.
Published: May 2009

In recent years several seminal breakthroughs have revealed that tight junctions not only regulate barrier properties of simple epithelial cells but also play crucial functions in the regulation of the largest barrier of the organism, the stratifying epidermis of the skin. Here we will address the importance of tight junctions for the skin barrier function and discuss data from our studies and from others that indicate how cadherins, polarity, and other pathways may regulate these junctions in stratifying epithelia.
Q Fever during Pregnancy
Authors: Carcopino Xavier , Raoult Didier , Bretelle Florence , Boubli Léon , Stein Andreas
Published: May 2009

Q fever is a worldwide zoonosis caused by Coxiella burnetii. Q fever may be present as an acute or a chronic infection and can be reactivated during subsequent pregnancies. Although its exact prevalence remains unknown, it is likely that the number of cases of Q fever in pregnant women is underestimated. During pregnancy, the illness is likely to be asymptomatic, and diagnosis is based on serology. Acute infection results in appearance of IgM and IgG antibodies mainly directed against the avirulent form of C. burnetii (phase II). Chronic Q fever results in particularly high level of IgG and IgA antibodies directed against both virulent (phase I) and avirulent (phase II) forms of the bacterium. Q fever may result in adverse pregnancy outcome, including spontaneous abortion, intrauterine growth retardation, oligoamnios, intrauterine fetal death (IUFD), and premature delivery. Obstetric complications occur significantly more often as C. burnetii infects the patient at an early stage of her pregnancy. Occurrence of IUFD is correlated with the presence of placental infection by C. burnetii and might be the consequence of direct infection of the fetus. The mother is exposed to the risk of chronic Q fever and endocarditis with potential fatal evolution. Long‐term cotrimoxazole therapy prevents from placental infection, IUFD, and maternal chronic Q fever. Such treatment should be used to treat pregnant women with Q fever. Women with previous history of Q fever should have a regular serological follow up. Obstetricians’ knowledge about Q fever must be improved.
Ixodes ovatus Ehrlichia Exhibits Unique Ultrastructural Characteristics in Mammalian Endothelial and Tick‐derived Cells
Authors: Munderloh Ulrike G. , Silverman David J. , MacNamara Katherine C. , Ahlstrand Gilbert G. , Chatterjee Madhumouli , Winslow Gary M.
Published: May 2009

Tick‐borne pathogens in the genus Ehrlichia cause emerging zoonoses. Although laboratory mice are susceptible to Ehrlichia infections, many isolates do not cause clinical illness. In contrast, the Ixodes ovatus Ehrlichia‐like agent (IOE) causes disease and immune responses in mice comparable to the human illness caused by Ehrlichia chaffeensis. No culture system had been developed for IOE, however, which limited studies of this pathogen. We reasoned that endothelial and tick cell lines could potentially serve as host cells, since the IOE is found in ticks and in endothelial cells in mice. Infected spleen cells from RAG‐deficient mice were overlaid onto ISE6 and RF/6A cultures, and colonies typical of Ehrlichia were noted in RF/6A cells within 2 weeks. Infection of ISE6 cells was established after transfer of IOE from RF/6A cells. Electron microscopy revealed densely packed inclusions in infected RF/6A and ISE6 cells; these inclusions contained copious amounts of filamentous structures, apparently originating from Ehrlichial cells. In particular, within RF/6A cells the structures assumed an ordered morphology of finely combed hair. IOE from RF/6A cells, when inoculated into C57BL/6 and RAG‐deficient mice, induced fatal disease. These data reveal unique structural features of IOE that may contribute to the pathogen's high virulence.
Characterization of Rickettsial Diseases in a Hospital‐Based Population in Central Tunisia
Authors: Kaabia Naoufel , Letaief Amel
Published: May 2009

In Tunisia, 2 rickettsial groups, spotted fever group and typhus group, have been described since the beginning of the 20th century. Mediterranean spotted fever (MSF), also known as Boutonneuse fever, caused by Rickettsia conorii and transmitted by the dog tick Rhipicephalus sanguineus, is the most frequent rickettsial infection observed. Its seroprevalence in our region is 9% among blood donors and 23% in hospitalized febrile patients. Typhus group rickettsioses, caused by R. typhi and R. prowazekii, are less frequently reported than in the 1970s. Only sporadic cases of typhus were reported in the last decade. However, R. typhi antibodies were present in 3.6% among healthy people and 40% in patients with acute fever of undetermined origin. In the unit of Infectious Diseases at Farhat Hached University Hospital in Sousse, during 2007, 5% of hospitalized patients had eruptive fever, and half of the cases met clinical criteria of MSF and/or were confirmed by rickettsial serology. The majority of cases (90%) were noted in hot seasons, and contact with domestic animals was found in 76%. The most common symptoms were fever (present in all cases), skin rash (in 85% to 98% of cases), and headache (in 69.5% of cases). The clinical triad (fever + rash +“tache noire”) was noted in 32 to 61%. Normal blood cells or leukopenia, cytolysis, and thrombopenia were the most frequent biological abnormalities. Complications and malignant forms of rickettsial infections were reported in 3.5 to 6% among hospitalized adult patients. When specific serology was performed, MSF was confirmed in 15%, and we noted an emergence of murine typhus (MT) mistaken for R. conorii or viral infection. Rickettsia felis was identified in 1 patient, whereas 17% of cases remained undetermined. Rickettsia conorii Malish was identified by PCR in skin biopsies. Doxycycline was the antibiotic of choice for rickettsial infections; it was prescribed in the majority of patients, associated with fever defervescence, in a mean of 72 hours. The mean length of stay among hospitalized patients with rickettsial infections was 5.9 days. In conclusion, in our region, MSF and murine typhus are endemic. Doxycycline should be prescribed in patients with acute fever and skin rash, especially in hot seasons. These rickettsioses were characterized by benign prognosis. More skin biopsies are needed to identify other SFG rickettsies.
Status of the “East Side Hypothesis” (Transovarial Interference) 25 Years Later
Authors: Telford Sam R.
Published: May 2009

Rocky Mountain spotted fever (RMSF) cases in the notorious Bitterroot Valley outbreak of the early 20th century were peculiarly distributed, with virtually all reported from the west side of the valley. Such a distribution remained unexplained until Burgdorfer and colleagues (1981) reported that endosymbiotic rickettsiae were prevalent in wood ticks on the east side of the Bitterroot River valley but not on the west side. The “East Side agent” was said to prevent the transovarial transmission of Rickettsia rickettsii, thereby severely limiting the prevalence of the latter. This hypothesis has been considered one of the most innovative explanations for an epidemiological conundrum and, indeed, has generally been accepted as a fact in the medical entomology literature. I review the evidence for the interference hypothesis, and suggest that the distribution of the Bitterroot Valley RMSF outbreak might actually have its basis in habitat or microclimate‐related factors, as opposed to reflecting interspecific competition by closely related rickettsiae.