Determination of the Terbium-152 half-life from mass-separated samples from CERN-ISOLDE and assessment of the radionuclide purity.

Terbium-152 is one of four terbium radioisotopes that together form a potential theranostic toolbox for the personalised treatment of tumours. As 152 Tb decay by positron emission it can be utilised for diagnostics by positron emission tomography. For use in radiopharmaceuticals and for activity measurements by an activity calibrator a high radionuclide purity of the material and an accurate and precise knowledge of the half-life is required. Mass-separation and radiochemical purification provide a production route of high purity 152Tb. In the current work, two mass-separated samples from the CERN-ISOLDE facility have been assayed at the National Physical Laboratory to investigate the radionuclide purity. These samples have been used to perform four measurements of the half-life by three independent techniques: high-purity germanium gamma-ray spectrometry, ionisation chamber measurements and liquid scintillation counting. From the four measurement campaigns a half-life of 17.8784(95) h has been determined. The reported half-life shows a significant difference to the currently evaluated half-life (ζ-score = 3.77), with a relative difference of 2.2 % and an order of magnitude improvement in the precision. This work also shows that under controlled conditions the combination of mass-separation and radiochemical separation can provide high-purity 152Tb.

Determination of the 161Tb half-life.

There is significant interest in the use of terbium radioisotopes for applications in cancer therapy and diagnosis. Of these, 161Tb, as a medium energy beta-emitter, is being investigated as a potential alternative to 177Lu. The relatively high proportion of conversion electron and Auger electron emissions per decay make 161Tb an attractive targeted therapeutic. As a product of nuclear fission, 161Tb is also of importance to nuclear forensics. The standard uncertainty of the current evaluated half-life of 6.89(2) d contributes significantly to the standard uncertainty of any decay corrected activity determination made. Furthermore, the accuracy of this evaluated half-life has been called into question by measurements reported in 2020 at the Institute of Radiation Physics (IRA), Switzerland, who reported a half-life of 6.953(2) d. In the current work, the half-life of the 161Tb ground state decay has been measured at three independent laboratories located in the United Kingdom and the United States of America for a total of six determinations using three independent measurement techniques; gamma-ray spectrometry, ionisation chamber measurement and liquid scintillation counting. The half-life determined for 161Tb of 6.9637(29) d confirms the observed 1% relative increase observed by IRA, though the reported half-lives in this work and at IRA are significantly different (ζ-score = 3.1).

Declining Use of Corticosteroids for Crohn's Disease Has Implications for Study Recruitment: Results of a Pilot Randomized Controlled Trial.

BACKGROUND: Corticosteroids (CS) have been used extensively to induce remission in Crohn's disease (CD); however, they are associated with severe side effects. We hypothesized that the administration of an exclusive enteral nutrition (EEN) formula to CS would lead to increased CD remission rates and to decreased CS-related adverse events. We proposed to undertake a pilot study comparing EEN and CS therapy to CS alone to assess decrease symptoms and inflammatory markers over 6 weeks. AIM: The overall aim was to assess study feasibility based on recruitment rates and acceptability of treatment in arms involving EEN. METHODS: The pilot study intended to recruit 100 adult patients with active CD who had been prescribed CS to induce remission as part of their care. The patients were randomized to one of three arms: (i) standard-dose CS; (ii) standard-dose CS plus EEN (Modulen 1.5 kcal); or (iii) short-course CS plus EEN. RESULTS: A total of 2009 CD patients attending gastroenterology clinics were screened from October 2018 to November 2019. Prednisone was prescribed to only 6.8% (27/399) of patients with active CD attending outpatient clinics. Of the remaining 372 patients with active CD, 34.8% (139/399) started or escalated immunosuppressant or biologics, 49.6% (198/399) underwent further investigation and 8.8% (35/399) were offered an alternative treatment (e.g., antibiotics, surgery or investigational agents in clinical trials). Only three patients were enrolled in the study (recruitment rate 11%; 3/27), and the study was terminated for poor recruitment. CONCLUSION: The apparent decline in use of CS for treatment of CD has implications for CS use as an entry criterion for clinical trials.

Development of a reference material for analysing naturally occurring radioactive material from the steel industry.

Accurate measurement of naturally occurring radionuclides in blast furnace slag, a by-product of the steel industry, is required for compliance with building regulations where it is often used as an ingredient in cement. A matrix reference blast furnace slag material has been developed to support traceability in these measurements. Raw material provided by a commercial producer underwent stability and homogeneity testing, as well as characterisation of matrix constituents, to provide a final candidate reference material. The radionuclide content was then determined during a comparison exercise that included 23 laboratories from 14 countries. Participants determined the activity per unit mass for 226Ra, 232Th and 40K using a range of techniques. The consensus values obtained from the power-moderated mean of the reported participant results were used as indicative activity per unit mass values for the three radionuclides: A0(226Ra) = 106.3 (34) Bq·kg-1, A0(232Th) = 130.0 (48) Bq·kg-1 and A0(40K) = 161 (11) Bq·kg-1 (where the number in parentheses is the numerical value of the combined standard uncertainty referred to the corresponding last digits of the quoted result). This exercise helps to address the current shortage of NORM industry reference materials, putting in place infrastructure for production of further reference materials.

Activity measurements and determination of nuclear decay data of 166Ho in the MRTDosimetry project.

Holmium-166 is a high-energy ß--emitter radionuclide (~ 1.8 MeV) with a short half-life (~26.8h) that offers great potential as an alternative to 90Y for the treatment of liver cancer based on radioembolization. The possibility of quantitative Single Photon Emission Computed Tomography (SPECT) imaging of the main γ-ray emission at 80.6 keV, in addition to strong paramagnetic properties suitable for Magnetic Resonance Imaging (MRI), complement this therapeutic potential. The present paper describes the measurements carried out in three European radionuclide metrology laboratories for primary standardization of 166Ho and new determinations of X- and γ-ray photon-emission intensities in the framework of the European EMPIR project MRTDosimetry. New half-life measurements were also performed.

The potential radio-immunotherapeutic α-emitter 227Th - part II: Absolute γ-ray emission intensities from the excited levels of 223Ra.

At the time of publication, radiopharmaceuticals labelled with thorium-227 are in clinical trials in Europe for the treatment of various types of cancer. In part I of this two-part series the primary standardisation of an aqueous solution of 227Th was reported. In part II, the activity derived from the recommended absolute γ-ray emission intensities have been compared to that from the primary standardisation techniques. This comparison showed a negative bias of 4% in the determined activity per unit mass with an 11% spread in the activities determined for the eight most intense γ-ray emissions (Iγ > 1%) from the 227Th α decay. Using the standardised 227Th, measurements of the characteristic γ-ray emissions from the 223Ra excited states were made using a calibrated HPGe γ-ray spectrometer. This has enabled the absolute intensities of 70 γ ray emissions from the 227Th α-decay to be experimentally determined. A significant improvement over the precision of the recommended normalisation scaling factor has been made, with a value of 12.470 (35) % determined. Typically, the precision of the intensities has been improved by an order of magnitude or greater than current recommended values. The correlation matrices for pairs of the most intense γ-ray emission intensities are presented.

The potential radio-immunotherapeutic α-emitter 227Th - part I: Standardisation via primary liquid scintillation techniques and decay progeny ingrowth measurements.

Thorium-227 is a potential therapeutic radionuclide for applications in targeted α-radioimmunotherapy for the treatment of various types of cancer. To provide nuclear medicine departments involved in Phase I clinical trials traceability to the SI unit of radioactivity (Bq), a standardisation of a radiochemically pure 227Th aqueous solution has been performed at the National Physical Laboratory. This was achieved via two primary liquid scintillation (LS) techniques -4π(LS)-γ digital coincidence counting (DCC) and 4π LS counting. These absolute techniques were supported by the indirect determination of the 227Th activity via the measurement of the ingrowth and decay rate of the decay progeny by both ionisations chambers and high purity germanium (HPGe) gamma-ray spectrometry. The results of the primary techniques were found to be consistent, both with each other (zeta score = 1.1) and to the decay progeny ingrowth measurements. An activity per unit mass of 20.726 (51) kBq g-1 was determined for the solution. A procedure has been developed that provided an effective separation of the 227Th from its decay progeny, which was shown by the effective time zero of the 227Th-223Ra nuclear chronometer measured by HPGe gamma-ray spectrometry.

Doped silica fibre thermoluminescence measurements of radiation dose in the use of 223Ra.

Using tailor-made sub-mm dimension doped-silica fibres, thermoluminescent dosimetric studies have been performed for α-emitting sources of 223RaCl2 (the basis of the Bayer Healthcare product Xofigo®). The use of 223RaCl2 in the palliative treatment of bone metastases resulting from late-stage castration-resistant prostate cancer focuses on its favourable uptake in metabolically active bone metastases. Such treatment benefits from the high linear energy transfer (LET) and associated short path length (<100µm) of the α-particles emitted by 223Ra and its decay progeny. In seeking to provide for in vitro dosimetry of the α-particles originating from the 223Ra decay series, investigation has been made of the TL yield of various forms of Ge-doped SiO2 fibres, including photonic crystal fibre (PCF) collapsed, PCF uncollapsed, flat and single-mode fibres. Irradiations of the fibres were performed at the UK National Physical Laboratory (NPL). Notable features are the considerable sensitivity of the dosimeters and an effective atomic number Zeff approaching that of bone, the glass fibres offering the added advantage of being able to be placed directly into liquid. The outcome of present research is expected to inform development of doped fibre dosimeters of versatile utility, including for applications as detailed herein.

Evaluation of the separation and purification of 227Th from its decay progeny by anion exchange and extraction chromatography.

Thorium-227 is currently undergoing evaluation as a potential radionuclide for targeted cancer therapy, and as such a high chemical purity of the material is required. To establish a reliable procedure for radiochemical isolation of 227Th from the parent 227Ac and decay progeny, which includes the radiotherapeutic 223Ra, the performance of three different separation schemes based on ion-exchange and extraction chromatography have been evaluated. The results suggest that both ion exchange and extraction chromatographic techniques can be successfully used for the separation of 227Th from its decay progeny, however extraction chromatographic resins demonstrate favourable performance in terms of Th recovery and purification from radionuclide impurities.

The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication.

BACKGROUND: The probiotic Bifidobacterium longum NCC3001 normalizes anxiety-like behavior and hippocampal brain derived neurotrophic factor (BDNF) in mice with infectious colitis. Using a model of chemical colitis we test whether the anxiolytic effect of B. longum involves vagal integrity, and changes in neural cell function. Methods Mice received dextran sodium sulfate (DSS, 3%) in drinking water during three 1-week cycles. Bifidobacterium longum or placebo were gavaged daily during the last cycle. Some mice underwent subdiaphragmatic vagotomy. Behavior was assessed by step-down test, inflammation by myeloperoxidase (MPO) activity and histology. BDNF mRNA was measured in neuroblastoma SH-SY5Y cells after incubation with sera from B. longum- or placebo-treated mice. The effect of B. longum on myenteric neuron excitability was measured using intracellular microelectrodes. KEY RESULTS: Chronic colitis was associated with anxiety-like behavior, which was absent in previously vagotomized mice. B. longum normalized behavior but had no effect on MPO activity or histological scores. Its anxiolytic effect was absent in mice with established anxiety that were vagotomized before the third DSS cycle. B. longum metabolites did not affect BDNF mRNA expression in SH-SY5Y cells but decreased excitability of enteric neurons. CONCLUSIONS & INFERENCES: In this colitis model, anxiety-like behavior is vagally mediated. The anxiolytic effect of B. longum requires vagal integrity but does not involve gut immuno-modulation or production of BDNF by neuronal cells. As B. longum decreases excitability of enteric neurons, it may signal to the central nervous system by activating vagal pathways at the level of the enteric nervous system.

Immunization with adenovirus at the large intestinal mucosa as an effective vaccination strategy against sexually transmitted viral infection.

The large intestinal mucosa contains immunological structures that may potentially serve as a site for induction of mucosal immunity against infections. Adenovirus (Ad), which is effective in gene transfer to epithelia, may be an ideal antigen delivery system for vaccination at the large intestinal mucosa. To investigate this potential, we immunized mice with recombinant replication-deficient Ad through a single intracolorectal (ICR) administration. Effective transfer of encoded genes was found in both the epithelial layer and lamina propria of the colorectal mucosa. Dendritic cells were able to transfer antigen to the draining lymph nodes, where antigen-specific CD8(+) T cells were primed. Functional antigen-specific CD8(+) T cells and IgA-specific antibodies were detected during the effector phase in the large intestine. Compared to other immunization routes (intranasal, subcutaneous), ICR immunization induced stronger colorectal immune responses and more potent protection against rectal challenge with pathogenic viruses. Further, this immunization strategy provided vaginal protection, more potent than that induced by vaccination in the nose or skin. Therefore, large intestine mucosal immunization using Ad represents an effective vaccination strategy against virus infection at both rectal and vaginal mucosal tissue sites.

A comparison of autonomic function in patients with inflammatory bowel disease and in healthy controls.

We evaluated autonomic function, symptoms and psychological parameters in patients with ulcerative colitis (UC), Crohn's disease (CD) and matched controls to assess whether UC patients have greater basal sympathetic autonomic activity. Outpatients with UC (n = 15), CD (n = 13) and healthy controls (n = 28) underwent spectral analysis of heart rate variability to assess cardiac autonomic function, a methacholine challenge to assess cholinergic pulmonary responsiveness, and questionnaires assessing disease severity, anxiety and depression. UC but not CD patients had greater sympathetic activity than controls with increased absolute (6600 vs 5884; P = 0.04) and relative (62.8%vs 54.8%; P = 0.02) low frequency areas. This was not because of increased overall autonomic nervous system (ANS) activation and was independent of disease activity. In UC patients, trait (personality-related) anxiety correlated strongly with disease symptoms (R = 0.84; P < 0.001) and quality of life (R = -0.81; P < 0.001) while situational (state) anxiety did not. In CD patients, ANS measures were similar to controls and disease activity was unrelated to psychological measures. Cholinergic pulmonary responsiveness was normal in both UC and CD patients. UC patients have an increased sympathetic ANS activity which is independent of symptom severity. In these patients symptom severity is strongly associated with measures of personality related (but not current) anxiety.

Continuous administration of low-dose GnRH in mares II. Pituitary and ovarian responses to uninterrupted treatment beginning near the autumnal equinox and continuing throughout the anovulatory season.

We tested the hypothesis that continuous subcutaneous treatment with low-dose GnRH, administered to mares from late September/early October through March, would prevent the development of seasonal anovulation. Quarter Horse mares (n=20) were stratified by age and body condition score and assigned randomly to either a saline control (n=9) or a GnRH (n=11) treatment group. Gonadotropin-releasing hormone was delivered continuously via osmotic minipumps, with sham pumps placed in control mares. Initial pumps were inserted on Day 3 following ovulation or during the follicular phase if the next anticipated ovulation did not occur by 9 October. Delivery rate of GnRH was 2.5 microg/h (60 microg/day) for the first 60 days, followed by 5.0 microg/h (120 microg/day) thereafter. Pumps were replaced every 30 days. Eighty and 100% of all mares had become anovulatory by 1 November and 1 December, respectively, and remained anovulatory through the end of February. Neither serum concentrations of LH throughout the study nor total releasable pools of LH in March differed between groups. Although control mares that exhibited ovulatory cycles after study onset had greater (P<0.05) mean concentrations of LH during the follicular phase and metestrus compared to GnRH-treated mares, neither size of ovulatory follicles nor interovulatory intervals differed between groups. Serum concentrations of FSH were not affected by treatment, but were lowest (P<0.05) from November through January. Continuous infusion of low-dose GnRH, beginning soon after autumnal equinox and continuing until just after vernal equinox, failed to prevent the occurrence of or to hasten transition from seasonal anovulation.

Critical role of MCP-1 in the pathogenesis of experimental colitis in the context of immune and enterochromaffin cells.

Mucosal changes in inflammatory bowel disease (IBD) are characterized by ulcerative lesions accompanied by a prominent infiltrate of inflammatory cells including lymphocytes, macrophages, and neutrophils and alterations in 5-hydroxytryptamine (5-HT)-producing enterochromaffin (EC) cells. Mechanisms involved in recruiting and activating these cells are thought to involve a complex interplay of inflammatory mediators. Studies in clinical and experimental IBD have shown the upregulation of various chemokines including monocyte chemoattractant protein (MCP)-1 in mucosal tissues. However, precise information on the roles of this chemokine or the mechanisms by which it takes part in the pathogenesis of IBD are not clear. In this study, we investigated the role of MCP-1 in the development of hapten-induced experimental colitis in mice deficient in MCP-1. Our results showed a significant reduction in the severity of colitis both macroscopically and histologically along with a decrease in mortality in MCP-1-deficient mice compared with wild-type control mice. This was correlated with a downregulation of myeloperoxidase activity, IL-1beta, IL-12p40, and IFN-gamma production, and infiltration of CD3+ T cells and macrophages in the colonic mucosa. In addition, we observed significantly lower numbers of 5-HT-expressing EC cells in the colon of MCP-1-deficient mice compared with those in wild-type mice after dinitrobenzenesulfonic acid. These results provide evidence for a critical role of MCP-1 in the development of colonic inflammation in this model in the context of immune and enteric endocrine cells.

Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED; OMIM 240300) is a rare autosomal recessive disorder defined by a variable combination of endocrine failure, chronic mucocutaneous candidiasis (CMC), and dystrophy of the dental enamel and nails. APECED is caused by mutations in the autoimmune regulator gene (AIRE). Alopecia areata (AA) and vitiligo are diseases with autoimmune pathogeneses, and have been recognized as part of the APECED complex. There are rare reports of other cutaneous manifestations. OBJECTIVES: We sought to delineate the dermatological features of APECED in an Irish case series with emphasis on timing of their appearance and association with disease severity. Furthermore, we looked for evidence of genotype: phenotype correlation. Finally, we wanted to determine if the ectodermal changes described represent a primary ectodermal dysplasia or whether the ectodermal manifestations are secondary phenomena. METHODS: Irish patients with APECED were invited to attend a multidisciplinary clinic (Dermatology, Endocrinology, Dentistry and Ophthalmology) held in Our Lady's Hospital for Sick Children, Dublin. Clinical data were compiled from case notes and questionnaires. All patients had a detailed cutaneous examination. Blood samples were obtained for mutational analysis. RESULTS: Eighteen patients (seven males and 11 females) from 15 families were interviewed and examined. The mean age at diagnosis was 6 years (range 8 months-18 years). All patients had evidence of CMC, 13 (72%) had candidal onychomycosis or paronychia, six (33%) had AA and two had vitiligo. In the case of two patients the diagnosis was made on recognition of dermatological manifestations and confirmed by mutational analysis. Both patients developed Addison's disease on follow-up. CMC was an early feature, often predating diagnosis (10 of 18). AA and vitiligo presented later, and may reflect more severe disease in these cases. There was no correlation between the AIRE mutations identified on mutational analysis and the clinical presentation. We found no evidence of an isolated nail dystrophy or features consistent with a primary ectodermal dysplasia. CONCLUSIONS: APECED is a rare but complex and potentially life-threatening autoimmune disease. CMC is a common and early feature; diagnosis at this stage may pre-empt life-threatening endocrinological crises. It is important for dermatologists to be aware of this association as they are likely to be the earliest clinicians who encounter these children. AA and vitiligo in our series occurred in the setting of established disease. The term "ectodermal dystrophy" is misleading as the ectodermal features described in our series and in the literature are most likely to be secondary phenomena.

Induction of a fibrogenic response in mouse colon by overexpression of monocyte chemoattractant protein 1.

BACKGROUND AND AIMS: Monocyte chemoattractant protein 1 (MCP-1) is increased transmurally in inflammatory bowel disease (IBD). Although MCP-1 is considered to play an important role in fibrotic disease in other organs, the role of MCP-1 in gut fibrosis is unknown. We investigated the fibrotic potential of MCP-1 in the gut by overexpressing this chemokine in the mouse colorectal wall. METHODS: Intramural gene transfer by direct injection of adenovector into the mouse rectal wall was established. C57BL/6 and Rag2(-/-) (B and T cell deficient) mice received 2.5 x 10(9) plaque forming units of an adenovector encoding murine MCP-1 (AdMCP-1) or control virus (AdDL70) via intramural injection. Mice were killed at various time points and tissues were obtained for histopathological and biochemical analysis. RESULTS: AdMCP-1 significantly increased collagen production in the colorectum and this was associated with significant elevation of transforming growth factor beta (TGF-beta) and tissue inhibitor of metalloproteinase (TIMP-1) protein. Transmural collagen deposition was observed after AdMCP-1 administration, and was accompanied by CD3+ T cells, F4/80+ macrophages, and vimentin+ cell infiltrates. Collagen was differentially distributed, with type I deposited in the muscularis mucosa and muscularis propria and type III in the submucosa and myenteric plexus. AdMCP-1 failed to induce collagen overproduction in immunodeficient Rag2(-/-) mice. CONCLUSION: These findings suggest that MCP-1 can induce fibrosis in the gut and that this process involves interaction between T cells and vimentin positive fibroblasts/myofibroblasts, as well as the subsequent upregulation of TGF-beta and TIMP-1 production. This model provides a basis for considering MCP-1 in the pathogenesis of strictures in IBD.

Ultraviolet exposure patterns of Irish and Danish gardeners during work and leisure.

BACKGROUND: Skin cancer, caused by solar ultraviolet (UV) radiation, is a growing problem in Europe. Reliable data on occupational exposure of outdoor workers are needed to develop protective strategies. OBJECTIVES: To compare UV radiation exposure patterns between outdoor workers in two European populations. METHODS: Fifty-three gardeners, 31 Irish and 22 Danish (age range 24-69 years) wore personal UV dosimeters, measuring time-stamped UV doses continuously during a 4-month summer period. The current and historical sun exposure pattern was recorded by means of a diary and questionnaire. Assessment of pigmentation, naevi, freckles and solar lentigines was performed. The relationship between UV dose and sun exposure pattern was analysed. RESULTS: Regarding work days, the Irish had a significantly lower percentage of ambient UV exposure than the Danes, 4.5% vs. 8.1%; a lower UV dose per day, 0.97 standard erythema dose (SED) vs. 1.6 SED; a lower UV dose between 12.00 and 15.00 h, 0.43 SED vs. 0.75 SED; and fewer hours with positive dosimeter measurements, 3.2 h vs. 4.8 h (all values are medians, P < 0.01). Regarding days off work, the same patterns emerged for both UV doses and exposure hours. The Irish had significantly fewer days off than the Danes, median 21 days vs. 49 days, and fewer days with risk behaviour (sunbathing/exposing upper body), median 0 days vs. 8 days (P < 0.01). CONCLUSIONS: The lower UV exposure received by the Irish gardeners may have been due to indoor breaks during peak ambient UV. Other contributing factors may include differences in natural shade between the parks. Our data suggest that consideration of such factors in scheduling of outdoor work can significantly reduce the occupational UV exposure.

The gene transfer of soluble VEGF type I receptor (Flt-1) attenuates peritoneal fibrosis formation in mice but not soluble TGF-beta type II receptor gene transfer.

Peritoneal fibrosis formation is a consequence of inflammation/injury and a significant medical problem to be solved. The effects of soluble VEGF receptor type I (sFlt-1) gene transfer on experimental peritoneal fibrosis were examined and compared with soluble transforming growth factor-beta (TGF-beta) receptor type II (sTGF beta RII) gene transfer. Male C57BL/6 mice were injected with 1.5 x 10(8) plaque-forming unit of adenovirus encoding active TGF-beta (AdTGF beta) intraperitoneally. Some mice had been treated with sTGF betaRII or sFlt-1 plasmid injection into skeletal muscle with electroporation 4 days before virus administration. Mice were euthanized at day 14 after virus administration. AdTGF beta induced significant elevation of serum active TGF-beta, caused significant inflammatory response [weight loss, elevation of serum amyloid-P (SAP) and IL-12, increased expression of monocyte chemoattractant protein-1 (MCP-1) mRNA], and induced marked thickening of the peritoneum and collagen deposition. Gene transfer of sFlt-1 reduced the collagen deposition approximately 81% in mesenteric tissue. Treatment with sFlt-1 decreased ICAM-1 and MCP-1 mRNA expression significantly. Significant negative correlation between serum sFlt-1 and placental growth factor level was observed, whereas there was no significant negative correlation between sFlt-1 and VEGF. On the other hand, sTGF beta RII treatment enhanced the AdTGF beta-induced inflammation (significant elevation of SAP, TNF-alpha, and IL-12 levels and upregulation of ICAM-1 and MCP-1 mRNA expressions) and failed to prevent collagen deposition. These observations indicate that sFlt-1 gene transfer might be of therapeutic benefit in peritoneal fibrosis.

Disruption of CD40-CD40 ligand pathway inhibits the development of intestinal muscle hypercontractility and protective immunity in nematode infection.

In our previous studies, we demonstrated that during Trichinella spiralis infection, T helper (Th) 2 cells contribute to the development of intestinal muscle hypercontractility and worm expulsion from the gut via STAT6. In addition, we have linked the altered muscle contractility to the eviction of the parasite and thereby to the host defense. However, the initial events linking infection to the development of muscle hypercontractility are poorly understood. In this study, we examined the contribution of CD40-CD40 ligand (CD40L) interaction in the development of intestinal muscle hypercontractility, in monocyte chemoattractant protein-1 (MCP-1) production, and in the Th2 response in CD40 ligand-deficient (CD40L -/-) mice infected with T. spiralis. Expulsion of intestinal worms was substantially delayed in CD40L -/- mice compared with the wild-type mice after T. spiralis infection. Consistent with delayed worm expulsion, there was a significant attenuation of intestinal muscle contractility in CD40L -/- mice. Infected CD40L -/- mice also exhibited marked impairment in the production of MCP-1, IL-4, IL-13, IgG1, IgE, and mouse mucosal MCP 1 (MMCP-1), and in goblet cell response. These results demonstrate that CD40-CD40 ligand interaction plays an important role in MCP-1 production, Th2 response, intestinal muscle hypercontractility, and worm expulsion in nematode infection. The present data suggest that the early events leading to the generation of Th2 response include CD40-CD40 ligand interaction, which subsequently influences the production of Th2 cytokines, most likely via upregulation of MCP-1.