bluuebunny/crossref_metadata_2025 huggingface dataset:
Oesophageal epithelial innervation in health and reflux oesophagitis
Authors: Newton M , Kamm M A , Soediono P O , Milner P , Burnham W R , Burnstock G
Published: June 2010

BACKGROUND

The response of the oesophagus to refluxed gastric contents is likely to depend on intact neural mechanisms in the oesophageal mucosa. The epithelial innervation has not been systematically evaluated in health or reflux disease.

AIMS

To study oesophageal epithelial innervation in controls, and also inflamed and non-inflamed mucosa in patients with reflux oesophagitis and healed oesophagitis.

PATIENTS

Ten controls, nine patients with reflux oesophagitis, and five patients with healed oesophagitis.

METHODS

Oesophageal epithelial biopsy specimens were obtained at endoscopy. The distribution of the neuronal marker protein gene product 9.5 (PGP), and the neuropeptides calcitonin gene related peptide (CGRP), neuropeptide Y (NPY), substance P (SP), and vasoactive intestinal peptide (VIP) were investigated by immunohistochemistry. Density of innervation was assessed by the proportion of papillae in each oesophageal epithelial biopsy specimen containing immunoreactive fibres (found in the subepithelium and epithelial papillae, but not penetrating the epithelium).

RESULTS

The proportion of papillae positive for PGP immunoreactive nerve fibres was significantly increased in inflamed tissue when compared with controls, and non-inflamed and healed tissue. There was also a significant increase in VIP immunoreactive fibres within epithelial papillae. Other neuropeptides showed no proportional changes in inflammation.

CONCLUSIONS

Epithelial biopsy specimens can be used to assess innervation in the oesophagus. The innervation of the oesophageal mucosa is not altered in non-inflamed tissue of patients with oesophagitis but alters in response to inflammation, where there is a selective increase (about three- to fourfold) in VIP containing nerves.
Phenotypic and functional characterisation of myofibroblasts, macrophages, and lymphocytes migrating out of the human gastric lamina propria following the loss of epithelial cells
Authors: Wu K C , Jackson L M , Galvin A M , Gray T , Hawkey C J , Mahida Y R
Published: June 2010

BACKGROUND

The basement membrane of human colonic mucosa contains numerous discrete pores. We have recently shown that following loss of the surface epithelium, many cells migrate out of the colonic lamina propria via basement membrane pores.

AIMS

To characterise cells migrating out via basement membrane pores of the human gastric lamina propria, following loss of the surface epithelium.

METHODS

Fresh human gastric mucosal samples were completely denuded of epithelial cells and placed in culture. Tissue samples were studied by electron microscopy (EM) and cells by EM, FACS analysis, immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR).

RESULTS

EM showed numerous discrete pores (0.65–8.29 μm in diameter) in the subepithelial basement membrane. During culture of mucosal samples denuded of epithelial cells, lymphocytes, macrophages, and myofibroblasts migrated out of the lamina propria via the basement membrane pores. The lymphocytes were predominantly CD45RO+ and CD69+ T cells. Macrophages were shown to express cyclooxygenase (COX) 1 and 2 enzymes. Myofibroblasts were established in culture and, despite prolonged culture and passage, retained their phenotype. They expressed mRNA and protein for COX 1 and 2 enzymes and their release of prostaglandin E2 was inhibited by selective COX 1 and 2 inhibitors.

CONCLUSIONS

Lamina propria cells migrating out of cultured denuded gastric mucosal samples have been characterised phenotypically and functionally. Such cells would be suitable for studies of their interactions with epithelial cells and also with Helicobacter pylori and its products.
Indirect evidence for cholinergic inhibition of intestinal bicarbonate absorption in humans
Authors: Mellander A , Sjövall H
Published: June 2010

BACKGROUND

The aim of the study was to test the hypothesis that in the fasting state, proximal intestinal HCO3− absorption, which depends on villus Na+/H+ exchanger activity, is tonically inhibited by a cholinergic atropine sensitive mechanism.

SUBJECTS

The experiments were performed in 34 healthy volunteers and in eight patients with intestinal villus atrophy.

METHODS

HCO3−absorption was measured with a modified triple lumen perfusion technique in the distal duodenum, the most proximal portion of the small intestine. The study was designed to compensate for the inhibitory effects of atropine on intestinal motor activity.

RESULTS

Atropine had three effects on HCO3− transport: it reduced HCO3− concentration at the proximal aspiration site, it displaced the relation between HCO3− concentration and HCO3− absorption to the left, and it induced a significant acidification of the perfusate at the distal aspiration site. The magnitude of the stimulatory effect on HCO3− absorption was similar to the difference between patients with intestinal villus atrophy and healthy controls.

CONCLUSION

The data suggest that, in the fasting state, duodenal HCO3− absorption, which depends on villus Na+/H+ exchanger activity, may be tonically inhibited by an atropine sensitive cholinergic mechanism.
Evidence of improving survival of patients with rectal cancer in France: a population based study
Authors: Finn-Faivre C , Maurel J , Benhamiche A M , Herbert C , Mitry E , Launoy G , Faivre J
Published: June 2010

BACKGROUND

Over the past 20 years there have been many changes in the management of rectal cancer. Their impact on the overall population is not well known.

AIMS

To determine trends in management and prognosis of rectal cancer in two French regions.

SUBJECTS

1978 patients with a rectal carcinoma diagnosed between 1978 and 1993.

METHODS

Time trends in treatment, stage at diagnosis, operative mortality, and survival were studied on a four year basis. A non-conditional logistic regression was performed to obtain an odds ratio for each period adjusted for the other variables. To estimate the independent effect of the period a multivariate relative survival analysis was performed.

RESULTS

Over the 16 year period resection rates increased from 66.0% to 80.1%; the increase was particularly noticeable for sphincter saving procedures (+30.6% per four years, p=0.03). The percentage of patients receiving adjuvant radiotherapy increased from 24.0% to 40.0% (p=0.02). The proportion of patients with Dukes’ type A cancer increased from 17.7% to 30.6% with a corresponding decrease in those with more advanced disease. Operative mortality decreased by 31.1% per four years (p=0.03). All these improvements have resulted in a dramatic increase in relative survival (from 35.4% for the 1978–1981 period to 57.0% for the 1985–1989 period).

CONCLUSIONS

Substantial advances in the management of rectal cancer have been achieved, but there is evidence that further improvements can be made in order to increase survival.
Modulation of distal colonic epithelial barrier function by dietary fibre in normal rats
Authors: Mariadason J M , Catto-Smith A , Gibson P R
Published: June 2010

BACKGROUND

Dietary fibre influences the turnover and differentiation of the colonic epithelium, but its effects on barrier function are unknown.

AIMS

To determine whether altering the type and amount of fibre in the diet affects paracellular permeability of intestinal epithelium, and to identify the mechanisms of action.

METHODS

Rats were fed isoenergetic low fibre diets with or without supplements of wheat bran (10%) or methylcellulose (10%), for four weeks. Paracellular permeability was determined by measurement of conductance and 51Cr-EDTA flux across tissue mounted in Ussing chambers. Faecal short chain fatty acid (SCFA) concentrations were assessed by gas chromatography, epithelial kinetics stathmokinetically, and mucosal brush border hydrolase activities spectrophotometrically.

RESULTS

Body weight was similar across the dietary groups. Conductance and 51Cr-EDTA flux were approximately 25% higher in animals fed no fibre, compared with those fed wheat bran or methylcellulose in the distal colon, but not in the caecum or jejunum. Histologically, there was no evidence of epithelial injury or erosion associated with any diet. The fibres exerted different spectra of effects on luminal SCFA concentrations and pH, and on mucosal indexes, but both bulked the faeces, were trophic to the epithelium, and stimulated expression of a marker of epithelial differentiation.

CONCLUSIONS

Both a fermentable and a non-fermentable fibre reduce paracellular permeability specifically in the distal colon, possibly by promoting epithelial cell differentiation. The mechanisms by which the two fibres exert their effects are likely to be different.
Cholinergic blockade inhibits gastro-oesophageal reflux and transient lower oesophageal sphincter relaxation through a central mechanism
Authors: Fang J C , Sarosiek I , Yamamoto Y , Liu J , Mittal R K
Published: June 2010

BACKGROUND

Atropine, an anticholinergic agent with central and peripheral actions, reduces gastro-oesophageal reflux (GOR) in normal subjects and patients with gastro-oesophageal reflux disease (GORD) by inhibiting the frequency of transient lower oesophageal sphincter relaxation (TLOSR).

AIMS

To compare the effect of methscopolamine bromide (MSB), a peripherally acting anticholinergic agent, with atropine on the rate and mechanism of GOR in patients with GORD.

METHODS

Oesophageal motility and pH were recorded for 120 minutes in 10 patients with GORD who were studied on three separate occasions. For the first two recording periods, either atropine (15 μg/kg bolus, 4 μg/kg/h infusion) or saline were infused intravenously. MSB (5 mg orally, four times daily) was given for three days prior to the third recording period.

RESULTS

Atropine significantly reduced basal LOS pressure (12.6 (0.17) mm Hg to 7.9 (0.17) mm Hg), and the number of TLOSR (8.1 (0.56) to 2.8 (0.55)) and reflux episodes (7.0 (0.63) to 2.0 (0.43)) (p<0.005 for all comparisons). MSB reduced basal LOS pressure (12.6 (0.17) to 8.7 (0.15) mm Hg, p<0.005), but had no effect on the frequency of TLOSR (8.1 (0.56) to 7.5 (0.59)) and reflux episodes (7.0 (0.63) to 4.9 (0.60)) (p>0.05).

CONCLUSION

In contrast to atropine, MSB has no effect on the rate of TLOSR or GOR in patients with GORD. Atropine induced inhibition of TLOSR and GOR is most likely mediated through a central cholinergic blockade.
Trefoil peptide TFF2 (spasmolytic polypeptide) potently accelerates healing and reduces inflammation in a rat model of colitis
Authors: Tran C P , Cook G A , Yeomans N D , Thim L , Giraud A S
Published: June 2010

BACKGROUND

The trefoil peptides are major secretory products of mucus cells of the gastrointestinal tract and show increased expression after inflammatory or ulcerative damage. Recombinant human TFF2 (spasmolytic polypeptide) has been shown to be cytoprotective, and enhances repair in models of gastric injury.

AIMS

To test the healing effects of recombinant human (h)TFF2 in a rat model of chronic colitis.

METHODS

Colitis was induced by intracolonic administration of dinitrobenzene sulphonic acid in ethanol. Mucosal repair was quantified macroscopically, microscopically by image analysis of tissue histology, and by measuring myeloperoxidase activity.

RESULTS

Initial validation studies showed that maximal injury and inflammation occurred at the end of the first week after colitis induction (active phase), and that spontaneous healing was complete by eight weeks. Once daily intrarectal application of hTFF2 (2.5 mg/kg; approximately 0.5 mg/rat) for five days after maximal damage had been sustained, reduced both microscopic and macroscopic injury by 80% and inflammatory index by 50% compared with vehicle controls. In addition, endogenous concentrations of rat TFF2 and TFF3 (intestinal trefoil factor) were increased in the active phase of colitis and were reduced to basal levels by hTFF2 treatment.

CONCLUSIONS

This study has shown that hTFF2 enhances the rate of colonic epithelial repair, and reduces local inflammation in a rat model of colitis, and suggests that luminal application of trefoil peptides may have therapeutic potential in the treatment of inflammatory bowel disease.
Expression of the insulin-like growth factors and their receptors in adenocarcinoma of the colon
Authors: Freier S , Weiss O , Eran M , Flyvbjerg A , Dahan R , Nephesh I , Safra T , Shiloni E , Raz I
Published: June 2010

AIMS

To study changes in the expression of insulin-like growth factors (IGFs) and their receptors, as well as production of the IGF-I and IGF-II polypeptides, in adenocarcinoma of the colon.

METHODS

Malignant tissue obtained at operation was used. Total RNA was extracted and specific IGF-I and IGF-II and their receptor mRNAs were measured by a solution hybridisation RNase protection assay. IGF-I and IGF-II polypeptides were measured by specific immunoassays.

RESULTS

All normal tissues expressed IGF-II, IGF-I receptor, and IGF-II/mannose-6-phosphate (Man-6-P) receptor. IGF-I mRNA could not be detected but the polypeptide was present in small but equal amounts in normal and malignant tissue. IGF-II was expressed 40 times more abundantly in colonic tumours than in adjacent normal tissue and the concentration of the corresponding polypeptide was twice as high in the malignant tissue. IGF-I receptor expression was increased by a factor of 2.5 and IGF-II/Man-6-P receptor by a factor of 4.

CONCLUSIONS

This study confirms that in adenocarcinoma of the human colon there is increased expression of IGF-I receptor and IGF-II. Furthermore, IGF-II/Man-6-P receptor message is increased and the increase in IGF-II message is accompanied by a doubling of the IGF-II protein in the tumour tissue compared with the adjacent normal tissue. These findings suggest that the IGF-II/Man-6-P receptor may also be involved in development of adenocarcinoma of the colon. There is rapidly accumulating evidence implicating the IGF system in the development of malignancy of the large bowel.
An ambulant porcine model of acid reflux used to evaluate endoscopic gastroplasty
Authors: Kadirkamanathan S S , Yazaki E , Evans D F , Hepworth C C , Gong F , Swain C P
Published: June 2010

BACKGROUND

There is a lack of suitable models for testing of therapeutic procedures for gastro-oesophageal reflux disease. Endoscopic sewing methods might allow the development of a new less invasive surgical approach to treatment of gastrointestinal disorders.

AIMS

To develop an animal model of gastro-oesophageal reflux for testing the efficacy of a new antireflux procedure, endoscopic gastroplasty, performed at flexible endoscopy without laparotomy or laparoscopy.

METHODS

At endoscopy a pH sensitive radiotelemetry capsule was sewn to the oesophageal wall, 5 cm above the lower oesophageal sphincter, in six large white pigs. Ambulant pH recordings (48–96 hours; total 447 hours) were obtained. The median distal oesophageal pH was 6.8 (range 6.4–7.3); pH was less than 4 for 9.3% of the time. After one week, endoscopic gastroplasty was performed by placing sutures below the gastro-oesophageal junction, forming a neo-oesophagus of 1–2 cm in length. Postoperative manometry and pH recordings (24–96 hours; total 344 hours) were carried out.

RESULTS

Following gastroplasty, the median sphincter pressure increased significantly from 3 to 6 mm Hg and in length from 3 to 3.75 cm. The median time pH was less than 4 decreased significantly from 9.3% to 0.2%.

CONCLUSIONS

These are the first long term measurements of oesophageal pH in ambulant pigs. The finding of spontaneous reflux suggested a model for studying treatments of reflux. Endoscopic gastroplasty increased sphincter pressure and length and decreased acid reflux.
Collagenous gastritis and collagenous colitis: a report with sequential histological and ultrastructural findings
Authors: Pulimood A B , Ramakrishna B S , Mathan M M
Published: June 2010

The case is reported of a young adult man with collagenous gastritis, an extremely rare disorder with only three case reports in the English literature, who subsequently presented with collagenous colitis. Sequential gastric biopsies showed a notable increase in thickness of the subepithelial collagen band. Ultrastructural study of gastric and rectal mucosa showed the characteristic subepithelial band composed of haphazardly arranged collagen fibres, prominent degranulating eosinophils, and activated pericryptal fibroblasts.
Mesalazine (5-aminosalicylic acid) induced chronic hepatitis
Authors: Deltenre P , Berson A , Marcellin P , Degott C , Biour M , Pessayre D
Published: June 2010

BACKGROUND

Treatment of ulcerative colitis or Crohn’s disease with sulphasalazine causes several adverse effects, including hepatitis. Sulphasalazine is cleaved by colonic bacteria into 5-aminosalicylic acid and sulphapyridine. Received wisdom was that 5-aminosalicylic acid was topically active, whereas sulphapyridine was absorbed and caused immunoallergic side effects. Mesalazine, a slow release formulation of 5-aminosalicylic acid, was expected to be a safe alternative. However, several cases of acute hepatitis have been reported.

CASE REPORT

A 65 year old man had increased liver enzymes, anti-nuclear and anti-smooth muscle autoantibodies and IgG levels, and lesions of chronic hepatitis after 21 months of mesalazine treatment. Although liver dysfunction had been identified eight months earlier, simvastatin rather than mesalazine had been withdrawn, without any improvement. In contrast, liver enzyme and IgG levels became normal and autoantibodies disappeared after discontinuation of mesalazine administration.

CONCLUSION

Contrary to initial expectations, mesalazine can cause most of the sulphasalazine induced adverse effects, and hepatic side effects may be almost as frequent. When liver dysfunction occurs, mesalazine administration should be discontinued to avoid the development of chronic hepatitis and liver fibrosis.
Is fascin really a useful marker in distinguishing between classical Hodgkin's lymphoma and various types of Non-Hodgkin's lymphomas in difficult cases?
Authors: Idrees Romana , Ahmad Zubair , Qureshi Asim , Ahsan Aamir , Pervez Shahid
Published: June 2010

Background

Fascin is an actin cross-linking protein, which is part of the cytoskeleton and involved in cell motility in several cell types. The differentiation of epithelial cells is greatly influenced by cell–matrix and cell–cell interactions, which play an important role in the normal organisation and stabilisation of epithelial cells and maintain the cells in a non-migratory state. The malignant conversion of epithelial cells results from a phenotypic switch to a migratory state, which allows tumour invasion beyond the basement membrane, as well as metastasis. Such a switch requires complex rearrangements of the actin cytoskeleton and is governed by multiple actin-binding proteins including fascin. In non-neoplastic lymphoid tissue, fascin expression is highly selective and is predominantly localised in dendritic cells, while lymphocytes, plasma cells, etc are uniformly non-reactive. However, all or nearly all Reed–Sternberg cells and their variants in all types of Hodgkin's lymphoma express fascin and are strongly immunoreactive for fascin.

Conclusion

Lymphomas (Hodgkin's and non-Hodgkin's) are among the commonest malignancies seen in our practice. The Section of Histopathology at the Aga Khan University, Karachi is the largest centre for histopathology in Pakistan, a densely populated country with an estimated population of 170 million. The authors wanted to test the utility of Fascin in distinguishing between Hodgkin's lymphoma and morphologically closely related forms of non-Hodgkin's lymphoma such as diffuse large B cell non-Hodgkin's lymphoma and anaplastic large cell lymphoma in difficult cases. If found useful, this antibody could help us in reaching a correct diagnosis in difficult cases and allow appropriate patient management.
Aberrant upregulation of MUC4 mucin expression in cutaneous condyloma acuminatum and squamous cell carcinoma suggests a potential role in the diagnosis and therapy of skin diseases
Authors: Chakraborty Subhankar , Swanson Benjamin J , Bonthu Neelima , Batra Surinder K
Published: June 2010

Aim

Mucins comprise a family of high-molecular-weight glycoproteins. MUC4, a large transmembrane mucin, has recently emerged as a novel marker for diagnosis, prognosis and therapy in several malignancies. However, its role in skin pathologies remains unknown. The aim of this study was to analyse the expression of MUC4 in cutaneous pathologies by immunohistochemistry for potential diagnostic, prognostic and therapeutic applications.

Methods

A total of 330 tissue spots representing the normal skin, and benign and malignant cutaneous diseases, were analysed after staining with the monoclonal antibody to human MUC4 (clone 8G7).

Results

While the normal epidermis showed a negative to weak-positive expression of MUC4, its expression was significantly upregulated in squamous cell carcinomas (SCCs) where the intensity of staining correlated negatively with tumour grade and positively with age. A moderately strong MUC4 expression was also noted in 2/20 cancer adjacent normal skin and 2/21 chronically inflamed skin tissues, while 10/19 cases of vulval condyloma acuminate, 3/12 of vulval hyperplasia and 2 cases of verruca vulgaris also showed strong MUC4 positivity. Malignant melanoma, basal cell carcinoma and cutaneous cysts were negative.

Conclusion

The results indicate that MUC4 expression is aberrantly upregulated in cutaneous SCCs, vulval condylomas and verruca vulgaris. Further, it appears that MUC4 expression in the skin may be modulated by chronic inflammation and the presence of an adjacent cutaneous malignancy in certain cases. These observations suggest a novel role for MUC4 mucin in the pathogenesis of cutaneous SCC and a possible application as a diagnostic and/or prognostic marker in cutaneous pathologies.
Clone region descriptors
Authors: Duala-Ekoko Ekwa , Robillard Martin P.
Published: June 2010

Source code duplication, commonly known as
code cloning
, is considered an obstacle to software maintenance because changes to a cloned region often require consistent changes to other regions of the source code. Research has provided evidence that the elimination of clones may not always be practical, feasible, or cost-effective. We present a clone management approach that describes clone regions in a robust way that is independent from the exact text of clone regions or their location in a file, and that provides support for tracking clones in evolving software. Our technique relies on the concept of abstract
clone region descriptors
(CRDs), which describe clone regions using a combination of their syntactic, structural, and lexical information. We present our definition of CRDs, and describe a clone tracking system capable of producing CRDs from the output of different clone detection tools, notifying developers of modifications to clone regions, and supporting updates to the documented clone relationships. We evaluated the performance and usefulness of our approach across three clone detection tools and five subject systems, and the results indicate that CRDs are a practical and robust representation for tracking code clones in evolving software.
Underwater cloth simulation with fractional derivatives
Authors: Ozgen Oktar , Kallmann Marcelo , Ramirez Lynnette Es , Coimbra Carlos Fm
Published: June 2010

We introduce the use of fractional differentiation for simulating cloth deformations underwater. The proposed approach is able to achieve realistic underwater deformations without simulating the Eulerian body of water in which the cloth is immersed. Instead, we propose a particle-based cloth model where half-derivative viscoelastic elements are included for describing both the internal and external dynamics of the cloth. These elements model the cloth responses to fluid stresses and are also able to emulate the memory-laden behavior of particles in a viscous fluid. As a result, we obtain
fractional clothes
, which are able to correctly depict the dynamics of the immersed cloth interacting with the fluid even though the fluid is not simulated. The proposed approach produces realistic underwater cloth deformations and has obvious advantages in simplicity and speed of computation in comparison to volumetric fluid simulation approaches.
Cache-oblivious ray reordering
Authors: Moon Bochang , Byun Yongyoung , Kim Tae-Joon , Claudio Pio , Kim Hye-Sun , Ban Yun-Ji , Nam Seung Woo , Yoon Sung-Eui
Published: June 2010

We present a cache-oblivious ray reordering method for ray tracing. Many global illumination methods such as path tracing and photon mapping use ray tracing and generate lots of rays to simulate various realistic visual effects. However, these rays tend to be very incoherent and show lower cache utilizations during ray tracing of models. In order to address this problem and improve the ray coherence, we propose a novelHit Point Heuristic(HPH) to compute a coherent ordering of rays. The HPH uses the hit points between rays and the scene as a ray reordering measure. We reorder rays by using a space-filling curve based on their hit points. Since a hit point of a ray is available only after performing the ray intersection test with the scene, we compute an approximate hit point for the ray by performing an intersection test between the ray and simplified representations of the original models. Our method is a highly modular approach, since our reordering method is decoupled from other components of common ray tracing systems. We apply our method to photon mapping and path tracing and achieve more than an order of magnitude performance improvement for massive models that cannot fit into main memory, compared to rendering without reordering rays. Also, our method shows a performance improvement even for ray tracing small models that can fit into main memory. This performance improvement for small and massive models is caused by reducing cache misses occurring between different memory levels including the L1/L2 caches, main memory, and disk. This result demonstrates the cache-oblivious nature of our method, which works for various kinds of cache parameters. Because of the cache-obliviousness and the high modularity, our method can be widely applied to many existing ray tracing systems and show performance improvements with various models and machines that have different cache parameters.
Chronic Diarrhea and Pancolitis Caused by Paracoccidioidomycosis: A Case Report
Authors: Bravo Eduar A. , Zegarra Arturo J. , Piscoya Alejandro , Pinto José L. , de los Rios Raúl E. , Prochazka Ricardo A. , Huerta-Mercado Jorge L. , Mayo Nancy L. , Tagle Martin
Published: June 2010

South American blastomycosis is a systemic micosis caused by infection with Paracoccidioides brasiliensis. The most frequently affected sites are the lower lip buccal mucous membrane, palate, tongue, sublingual region, lymph glands, and lungs. However, colonic involvement is not a common expression of Paracoccidioidomycosis. We report a case of chronic diarrhea and pancolitis caused by Paracoccidioidomycosis with fatal outcome.
Valproate in Conversion Disorder: A Case Report
Authors: Messina Antonino , Fogliani Anna Maria
Published: June 2010

Few data are in literature about the pharmacological treatment of conversion disorder and there are not any studies about the use of Valproate extended release (ER) in treating conversion disorder. In this article, we are reporting a case of an Italian woman with a diagnosis of conversion disorder treated effectively and quickly by Valproate ER.
Survey of the Factors Associated with a Woman's Choice to Have an Epidural for Labor Analgesia
Authors: Harkins Jennifer , Carvalho Brendan , Evers Amy , Mehta Sachin , Riley Edward T.
Published: June 2010

Objectives. The purpose of this study was to determine the factors associated with whether a woman received an epidural in labor and to determine the main source used to obtain information about labor epidurals.Methods. Over a one-month period, we surveyed all patients who labored, the day after their delivery. We used multiple logistic regression to identify potential predictive factors after initial univariate analysis.Results. 320 women who met enrollment criteria delivered during the study period and 94% completed the study. Of the 302 patients surveyed, 80% received an epidural for labor. Univariate analysis showed the following variables were associated with whether women received an epidural (P<.01): partner preference, prior epidural, language, education, type of insurance, age, duration, and pitocin use. Using computed multiple logistic regression only partner preference and prior epidural were associated with whether women received an epidural.Conclusion. It was not surprising that a previous epidural was predictive of a patient receiving an epidural. The strong association with partner preference and epidural use suggests this is an important factor when counseling pregnant women with regard to their decision to have a labor epidural.
A Control Source Structure of Single Loudspeaker and Rear Sound Interference for Inexpensive Active Noise Control
Authors: Kobayashi Yasuhide , Fujioka Hisaya , Jinbo Naoki
Published: June 2010

Active noise control systems of simple ducts are investigated. In particular, open‐loop characteristics
and closed‐loop performances corresponding to various structures of control sources are compared based on both mathematical models and experimental results. In addition to the standard single loudspeaker and the Swinbanks′ source, we propose and examine a single loudspeaker with a rear sound interference
as a novel structure of control source, where the rear sound radiated from the loudspeaker is interfered with the front sound in order to reduce the net upstream sound directly radiated from the control source. The comparisons of the control structures are performed as follows. First, the open‐loop transfer
function is derived based on the standard wave equation, where a generalized control structure unifying the three structures mentioned above is considered. Secondly, by a comparison of the open‐loop transfer functions from the first principle modeling and frequency response experiments, it is shown that a certain
phase‐lag is imposed by the Swinbanks′ source and the rear sound interference. Thirdly, effects on control performances of control source structures are examined by control experiments with robust controllers.
Leptin Administration Downregulates the Increased Expression Levels of Genes Related to Oxidative Stress and Inflammation in the Skeletal Muscle ofob/obMice
Authors: Sáinz Neira , Rodríguez Amaia , Catalán Victoria , Becerril Sara , Ramírez Beatriz , Gómez-Ambrosi Javier , Frühbeck Gema
Published: June 2010

Obese leptin-deficientob/obmice exhibit a low-grade chronic inflammation together with a low muscle mass. Our aim was to analyze the changes in muscle expression levels of genes related to oxidative stress and inflammatory responses in leptin deficiency and to identify the effect ofin vivoleptin administration.Ob/obmice were divided in three groups as follows: controlob/ob, leptin-treatedob/ob(1 mg/kg/d) and leptin pair-fedob/obmice. Gastrocnemius weight was lower in controlob/obthan in wild type mice (P<.01) exhibiting an increase after leptin treatment compared to control and pair-fed (P<.01)ob/obanimals. Thiobarbituric acid reactive substances, markers of oxidative stress, were higher in serum (P<.01) and gastrocnemius (P=.05) of controlob/obthan in wild type mice and were significantly decreased (P<.01) by leptin treatment. Leptin deficiency altered the expression of 1,546 genes, while leptin treatment modified the regulation of 1,127 genes with 86 of them being involved in oxidative stress, immune defense and inflammatory response. Leptin administration decreased the high expression ofCrybb1, Hspb3, Hspb7, Mt4, Cat, Rbm9, Serpinc1andSerpinb1aobserved in controlob/obmice, indicating that it improves inflammation and muscle loss.
Low Occurrence of Tuberculosis Drug Resistance among Pulmonary Tuberculosis Patients from an Urban Setting, with a Long-Running DOTS Program in Zambia
Authors: Mulenga Chanda , Chonde Allan , Bwalya Innocent C. , Kapata Nathan , Kakungu-Simpungwe Mathilda , Docx Sven , Fissette Krista , Shamputa Isdore Chola , Portaels Françoise , Rigouts Leen
Published: June 2010

We set out to determine the levels ofMycobacterium tuberculosisresistance to first- and second-line TB drugs in an urban population in Zambia. Sputum samples were collected consecutively from all smear-positive, new and previously treated patients, from four diagnostic centres in Ndola between January and July 2006. Drug susceptibility testing was performed using the proportion method against four first- and two second-line TB drugs.Results. Among 156 new cases, any resistance was observed to be 7.7%, monoresistance to isoniazid and rifampicin was 4.5% and 1.3%, respectively. Of 31 retreatment cases, any resistance was observed to be 16.1%, monoresistance to isoniazid and rifampicin was 3.3% for each drug, and one case of resistance to both isoniazid and rifampicin (multidrug resistance) was detected. No resistance to kanamycin or ofloxacin was detected.Conclusion. Although not representative of the country, these results show low levels of drug resistance in a community with a long-standing DOTS experience. Resource constrained countries may reduce TB drug resistance by implementing community-based strategies that enhance treatment completion.
HuR Regulates β-Tubulin Isotype Expression in Ovarian Cancer
Authors: Raspaglio Giuseppina , De Maria Ilaria , Filippetti Flavia , Martinelli Enrica , Zannoni Gian Franco , Prislei Silvia , Ferrandina Gabriella , Shahabi Shohreh , Scambia Giovanni , Ferlini Cristiano
Published: June 2010

The supply of oxygen and nutrients to solid tumors is inefficient because cancer tissues have an inadequate number of microvessels, thus inducing the selective growth of the most aggressive cancer cells. This explains why many of the factors underlying a poor prognosis are induced in hypoxic/hypoglycemic conditions. Among these factors, a prominent role in several solid tumors is played by the class III β-tubulin gene (TUBB3). The study described here reveals that glucose deprivation enhances TUBB3 expression at both the gene and protein levels in A2780 ovarian cancer cells. In silico analysis of TUBB3 mRNA sequence predicted a putative binding site for the RNA-binding protein Hu antigen (HuR) in the 3′ flanking untranslated region. A hypoglycemic-dependent engagement of this site was shown using RNA pull-down and ribonucleoimmunoprecipitation techniques. Thereafter, HuR gene silencing revealed that TUBB3 translation is HuR dependent in hypoglycemia because HuR silencing inhibited the entry of TUBB3 mRNA into cytoskeletal and free polysomes. Finally, the clinical value of this finding was assessed in a clinical cohort of 46 ovarian cancer patients in whom it was found that HuR cytoplasmic staining was associated with high levels of TUBB3 and poor survival. Cancer Res; 70(14); 5891–900. ©2010 AACR.
STAMP1 Is Both a Proliferative and an Antiapoptotic Factor in Prostate Cancer
Authors: Wang Ling , Jin Yang , Arnoldussen Yke Jildouw , Jonson Ida , Qu Su , Mælandsmo Gunhild M. , Kristian Alexandr , Risberg Bjørn , Wæhre Håkon , Danielsen Håvard E. , Saatcioglu Fahri
Published: June 2010

STAMP1 is predicted to encode a six-transmembrane protein whose expression is highly prostate enriched and is deregulated in prostate cancer. However, the biological role of STAMP1 in prostate cancer cells, or its expression profile at the protein level, is unknown. Here, we find that ectopic expression of STAMP1 significantly increased proliferation of DU145 prostate cancer cells as well as COS-7 cells in vitro; conversely, small interfering RNA–mediated knockdown of STAMP1 expression in LNCaP cells inhibited cell growth and, at least partially, induced cell cycle arrest. In parallel, there were alterations in cell cycle–regulatory gene expression. Knockdown of STAMP1 expression in LNCaP cells also induced significant apoptosis under basal conditions as well as in response to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) alone, or TRAIL + AKT inhibitor LY294002, previously established apoptotic agents in LNCaP cells. Consistently, LNCaP cells with short hairpin RNA–mediated knockdown of STAMP1 were dramatically retarded in their ability to grow as xenografts in nude mice. Interestingly, activation of extracellular signal-regulated kinase, which has previously been implicated in prostate cancer progression, was significantly increased on ectopic expression of STAMP1 in DU145 cells and, conversely, was strongly downregulated on STAMP1 knockdown in LNCaP cells. In the normal prostate, STAMP1 protein is localized to the cytosol and the cell membrane of the prostate epithelial cells; furthermore, its expression is increased in prostate cancer compared with normal prostate. Taken together, these data suggest that STAMP1 is required for prostate cancer growth, which may be a useful target in prostate cancer treatment. Cancer Res; 70(14); 5818–28. ©2010 AACR.
MicroRNA Biogenesis Is Required for Myc-Induced B-Cell Lymphoma Development and Survival
Authors: Arrate Maria Pia , Vincent Tiffaney , Odvody Jessica , Kar Rekha , Jones Stephen N. , Eischen Christine M.
Published: June 2010

Many tumor cells express globally reduced levels of microRNAs (miRNA), suggesting that decreased miRNA expression in premalignant cells contributes to their tumorigenic phenotype. In support of this, Dicer, an RNase III–like enzyme that controls the maturation of miRNA, was recently shown to function as a haploinsufficient tumor suppressor in nonhematopoietic cells. Because the Myc oncoprotein, a critical inducer of B-cell lymphomas, was reported to suppress the expression of multiple miRNAs in lymphoma cells, it was presumed that a deficiency of Dicer and subsequent loss of miRNA maturation would accelerate Myc-induced lymphoma development. We report here that, surprisingly, a haploinsufficiency of Dicer in B cells failed to promote B-cell malignancy or accelerate Myc-induced B-cell lymphomagenesis in mice. Moreover, deletion of Dicer in B cells of CD19-cre+/Eμ-myc mice significantly inhibited lymphomagenesis, and all lymphomas that did arise in these mice lacked functional Cre expression and retained at least one functional Dicer allele. Uncharacteristically, the lymphomas that frequently developed in the CD19-cre+/Dicerfl/fl/Eμ-myc mice were of very early precursor B-cell origin, a stage of B-cell development prior to Cre expression. Therefore, loss of Dicer function was not advantageous for lymphomagenesis, but rather, Dicer ablation was strongly selected against during Myc-induced B-cell lymphoma development. Moreover, deletion of Dicer in established B-cell lymphomas resulted in apoptosis, revealing that Dicer is required for B-cell lymphoma survival. Thus, Dicer does not function as a haploinsufficient tumor suppressor in B cells and is required for B-cell lymphoma development and survival. Cancer Res; 70(14); 6083–92. ©2010 AACR.
Membrane Type 1-Matrix Metalloproteinase Cleaves Off the NH2-Terminal Portion of Heparin-Binding Epidermal Growth Factor and Converts It into a Heparin-Independent Growth Factor
Authors: Koshikawa Naohiko , Mizushima Hiroto , Minegishi Tomoko , Iwamoto Ryo , Mekada Eisuke , Seiki Motoharu
Published: June 2010

Epidermal growth factor (EGF) receptors (ErbB) and EGF family members represent promising targets for cancer therapy. Heparin-binding EGF (HB-EGF) is a member of the EGF family and is an important target for therapy in some types of human cancers. Processing of HB-EGF by proprotein convertases, and successively, by ADAM family proteases, generates a soluble growth factor that requires heparin as a cofactor. Although heparin potentiates HB-EGF activity in vitro, it is not clear how the heparin-binding activity of HB-EGF is regulated. Here, we show that membrane type 1-matrix metalloproteinase (MT1-MMP; MMP14), a potent invasion-promoting protease, markedly enhances HB-EGF–dependent tumor formation in mice. MT1-MMP additionally cleaves HB-EGF and removes the NH2-terminal 20 amino acids that are important for binding heparin. Consequently, the processing of HB-EGF by MT1-MMP converts HB-EGF into a heparin-independent growth factor with enhanced mitogenic activity, and thereby, expression of both proteins costimulates tumor cell growth in vitro and in vivo. The ErbB family of receptors expressed in human gastric carcinoma cells play a role in mediating enhanced HB-EGF activity by MT1-MMP during invasive cell growth in collagen. Thus, we shed light on a new mechanism whereby HB-EGF activity is regulated that should be considered when designing HB-EGF–targeted cancer therapy. Cancer Res; 70(14); 6093–103. ©2010 AACR.
Identification of Internalizing Human Single-Chain Antibodies Targeting Brain Tumor Sphere Cells
Authors: Zhu Xiaodong , Bidlingmaier Scott , Hashizume Rintaro , James C. David , Berger Mitchel S. , Liu Bin
Published: June 2010

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain tumor for which there is no curative treatment to date. Resistance to conventional therapies and tumor recurrence pose major challenges to treatment and management of this disease, and therefore new therapeutic strategies need to be developed. Previous studies by other investigators have shown that a subpopulation of GBM cells can grow as neurosphere-like cells when cultured in restrictive medium and exhibits enhanced tumor-initiating ability and resistance to therapy. We report here the identification of internalizing human single-chain antibodies (scFv) targeting GBM tumor sphere cells. We selected a large naive phage antibody display library on the glycosylation-dependent CD133 epitope–positive subpopulation of GBM cells grown as tumor spheres and identified internalizing scFvs that target tumor sphere cells broadly, as well as scFvs that target the CD133-positive subpopulation. These scFvs were found to be efficiently internalized by GBM tumor sphere cells. One scFv GC4 inhibited self-renewal of GBM tumor sphere cells in vitro. We have further developed a full-length human IgG1 based on this scFv, and found that it potently inhibits proliferation of GBM tumor sphere cells and GBM cells grown in regular nonselective medium. Taken together, these results show that internalizing human scFvs targeting brain tumor sphere cells can be readily identified from a phage antibody display library, which could be useful for further development of novel therapies that target subpopulations of GBM cells to combat recurrence and resistance to treatment. Mol Cancer Ther; 9(7); 2131–41. ©2010 AACR.
p53-Independent Induction of G1 Arrest and p21WAF1/CIP1 Expression by Ascofuranone, an Isoprenoid Antibiotic, through Downregulation of c-Myc
Authors: Jeong Ji-Hak , Kang Shin-Sung , Park Kwan-Kyu , Chang Hyeun-Wook , Magae Junji , Chang Young-Chae
Published: June 2010

Ascofuranone has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we study the effects of ascofuranone on cell cycle progression in human cancer cells and find that ascofuranone induces G1 arrest without cytoxicity with upregulation of p53 and p21WAF1/CIP1 while downregulating c-Myc and G1 cyclins. Chromatin immunoprecipitation assay and RNA interference studies with cells deficient in p53 and p21 show that ascofuranone induces p21WAF1/CIP1 expression and subsequent G1 arrest through the release of p21WAF1/CIP1 promoter from c-Myc–mediated transcriptional repression, independent of p53. Ascofuranone-induced p21WAF1/CIP1 associates with CDK2 and prevents CDK2-cyclin E complex formation, leading to the inactivation of E2F transcriptional activity. These results suggest that ascofuranone upregulates p21WAF1/CIP1 through p53-independent suppression of c-Myc expression, leading to cytostatic G1 arrest. Thus, ascofuranone represents a unique natural antitumor compound that targets c-Myc independent of p53. Mol Cancer Ther; 9(7); 2102–13. ©2010 AACR.
Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805
Authors: Baffert Fabienne , Régnier Catherine H. , De Pover Alain , Pissot-Soldermann Carole , Tavares Gisele A. , Blasco Francesca , Brueggen Josef , Chène Patrick , Drueckes Peter , Erdmann Dirk , Furet Pascal , Gerspacher Marc , Lang Marc , Ledieu David , Nolan Lynda , Ruetz Stephan , Trappe Joerg , Vangrevelinghe Eric , Wartmann Markus , Wyder Lorenza , Hofmann Francesco , Radimerski Thomas
Published: June 2010

The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2V617F mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2V617F and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2V617F-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2V617F cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats. Mol Cancer Ther; 9(7); 1945–55. ©2010 AACR.
The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma
Authors: Voss Valerie , Senft Christian , Lang Verena , Ronellenfitsch Michael W. , Steinbach Joachim P. , Seifert Volker , Kögel Donat
Published: June 2010

Antiapoptotic Bcl-2 family members suppress both apoptosis and autophagy and are of major importance for therapy resistance of malignant gliomas. To target these molecules, we used BH3 mimetics and analyzed the molecular mechanisms of cell death induced thereby. Glioma cells displayed only limited sensitivity to single-agent treatment with the BH3 mimetics HA14-1, BH3I-2′, and ABT-737, whereas the pan-Bcl-2 inhibitor (−)-gossypol efficiently induced cell death. Furthermore, (−)-gossypol potentiated cell death induced by temozolomide (TMZ) in MGMT (O6-methylguanine-DNA methyltransferase)-negative U343 cells and, to a lesser extent, in MGMT-expressing U87 cells. (−)-Gossypol triggered translocation of light chain 3 to autophagosomes and lysosomes and cytochrome c release, but cell death occurred in the absence of lysosomal damage and effector caspase activation. Lentiviral knockdown of Beclin1 and Atg5 in U87, U343, and MZ-54 cells strongly diminished the extent of cell death induced by (−)-gossypol and combined treatment with TMZ, indicating that autophagy contributed to this type of cell death. In contrast, stable knockdown of the endogenous autophagy inhibitor mammalian target of rapamycin increased autophagic cell death. Our data suggest that pan-Bcl-2 inhibitors are promising drugs that induce caspase-independent, autophagic cell death in apoptosis-resistant malignant glioma cells and augment the action of TMZ. Furthermore, they indicate that efficient killing of glioma cells requires neutralization of Mcl-1. Mol Cancer Res; 8(7); 1002–16. ©2010 AACR.