bluuebunny/crossref_metadata_2025 huggingface dataset:
High progesterone is related to effective human labor
Authors: LöFgren Mats , BÄCkströM Torbjörn
Published: March 2008

Background. The role of progesterone levels during human labor is unclear.

Objective. To investigate serum concentrations of progesterone and 5α‐pregnane‐3,20‐dione in normal and abnormal deliveries.

Methods. Venous and umbilical cord serum samples were collected from 108 parturient women. In a further 49 deliveries, arterial and venous umbilical cord sera were collected separately. The concentrations of progesterone and 5opregnane‐3,20‐dione were determined by radioimmunoassay. The delivery modes studied were: elective cesarean section; oxytocin‐resistant dystocia; normal but induced delivery, and normal spontaneous delivery.

Results. Progesterone concentrations in maternal and umbilical serum were higher following normal labor than after dystocia (p<0.005) and elective cesarean section (p<0.005). The maternal and umbilical progesterone concentrations in dystocia and elective cesarean section were between 77–43 % of those in normal labor. The concentrations did not vary between gestational weeks 37 and 42, within the different modes of delivery. The 5α‐pregnane‐3,20‐dione serum concentration in the fetal compartment was twice that in the maternal compartment (p<0.001); its concentration in venous umbilical serum was higher than in corresponding arterial samples (p<0.001). No distinct differences in the 5α‐pregnane‐3,20‐dione serum concentration were found with regard to parity or mode of delivery.

Conclusion. High progesterone concentrations during parturition appear to be related to effective labor. The findings support results from in vitro experiments on human term myometrium.
Reduced prevalence of cervical Chlamydia infection among women requesting termination
Authors: JonsdóTtir Kristín , Geirsson Reynir T. , SteingríMsson ólafur , óLafsson Jón H. , StefáNsdóTtir Svava
Published: March 2008

Background. The prevalence and pattern of Chlamydia trachomatis infection among women requesting induced abortion in the three year period 1992–95 was evaluated and compared 10 the results of a previous study in 1982–84. where the prevalence of chlamydial infection had been 13.5%.

Methods. A total of 1995 women requested termination. 1855 (93%) of whom were tested for Chlamydia and were included in the study. Two types of tests for chlamydial infection. ELISA and PCR. were used in two consecutive periods. In addition cultures for gonorrhea were done in each case. Information on age. marital status, parity, gestational age and the results of chlamydia and gonorrhea tests of the women and sexual partners were recorded.

Results. Chlamydia trachomatis positive women were 149 (8.0%). a significant reduction from the previous 1982 84 study (p<0.001). Women with positive tests were significantly younger (80% ≤ 25 years of age: p<0.001) and more frequently single (86.6%; p<0.001). than those with negative tests, as in the previous period. Of the partners, 80.4% were contacted, and 52.1% presented for investigation. Of those tested 42.1% were Chlamydia positive. Four women (0.2%) had Neisseria gonorrhea but none of the partners.

Conclusions. The prevalence of Chlamydia trachomatis is receding among women coming for termination of pregnancy. As treatment before or at operation has repeatedly been shown to be of benefit and since the prevalence is still considerable, continued screening of these women is justified.
Preoperative evaluation of tumor extension in patients with recurrent cervical cancer
Authors: Zeisler Harald , Joura Elmar Armin , Moeschl Peter , Maier Ulrich , Koelbl Heinz
Published: March 2008

Background. Pelvic exenteration is an option in the treatment of locally recurrent cervical cancer. Various preoperative diagnostic procedures in the estimation of tumor invasion of the bladder and rectum or lymphonodal involvement were evaluated.

Design. The sensitivity and specificity of cystoscopy, intravenous pyelography, irrigoscopy, recloscopy, and computed tomography were evaluated by comparing the preoperative findings with the histological result as the “golden standards”.

Results. In the assessment of bladder invasion the sensitivity of cystoscopy, intravenous pyelography and computed tomography was 22.2%. 55.6% and 55.6%, respectively. The overall sensitivity of the three diagnostic procedures was 77.8%. In the assessment of invasion of the rectum irrigoscopy, rectoscopy and CT revealed a sensitivity of 33.3%, respectively. Only 50% of all cases with tumor infiltration of the rectum showed positive results when all three diagnostic procedures were combined. The sensitivity and specificity of computed tomography in the diagnosis of lymphonodal involvement were 75% and 83.3%, respectively.

Conclusion: We think that there is an obvious necessity for all diagnostic procedures for patient selection prior to pelvic exenteration. However, all these investigations are not conclusive but complement each other. Prior to pelvic exenteration, critical interpretation of all preoperative diagnostic procedures is mandatory, otherwise surgery results in an unintended palliative procedure.
Estradiol, gonadotropins, and tumor markers in ovarian cyst fluid
Authors: Reimer Toralf , Gerber Bernd , Kunkel Siegfried , Luettich Karsta
Published: March 2008

Background. The study was designed to improve the discrimination between functional and neoplastic ovarian cysts in order to avoid unnecessary surgery.

Methods. Concentrations of tumor markers (CA 125, CEA, CASA. CA 72–4) and hormones (estradiol, FSH. LH) in cyst fluid were detected by enzyme immuno‐ or immunoradiometric assays. Wilcoxon test was used to evaluate the correlation of cyst fluid markers and histology.

Results. One hundred and thirty‐eight ovarian cyst aspirates were investigated. Seventy‐one patients (51.5%) had functional cysts whereas 67 (48.5%) had benign (n = 59) or malignant (n = 8) cystic tumors. Statistically significant correlations of CA 125 (p<0.0005) and CASA (p<0.02) with neoplastic histology were found. No significant correlation could be detected between CA 72–4. CEA. or hormone values and histology. Elevated estradiol concentrations are suspicious for functional cysts in premenopausal age. Low FSH and LH levels seem to be an indicator for functional cysts in peri‐ and postmenopausal age.

Conclusions. The assessed analytes could not reliably distinguish between functional and neoplastic ovarian cysts. Our results indicate that CA 125 is a marker for neoplastic histology in a proportion of ovarian cysts. The use of FSH and LH in the diagnosis of postmenopausal blastemas needs further investigation.
Comparison between the single deepest pocket and amniotic fluid index in predicting fetal distress in small‐for‐gestational age fetuses
Authors: Miyamura Tsunetake , Masuzaki Hideaki , Miyamoto Masashi , Ishimaru Tadayuki
Published: March 2008

Background. The relationship between reduced amniotic fluid volume and increased risk of fetal distress in small‐for‐gestational age fetuses is not yet clear. Furthermore, the criteria used for the diagnosis of ‘oligohydramnios’ are different between the single deepest pocket method and amniotic fluid index. We investigated the relationship between the single deepest pocket and amniotic fluid index and their ability in predicting fetal distress in small‐for‐gestational age fetuses.

Method. We examined 69 pregnant women with singleton pregnancy, intact membranes, birth weight below the 50% percentile − 1.5 s.d., in whom delivery occurred within seven days of the last estimation of amniotic fluid volume. Amniotic fluid volume was measured in each woman simultaneously by single deepest pocket and amniotic fluid index. Fetal distress was determined by intrapartum monitoring of fetal heart rate.

Results. Estimates of amniotic fluid volume measured by the two methods showed a significant correlation at 24 to 41 weeks of gestation. A cut‐off value for single deepest pocket of 3.0 cm was associated with the highest accuracy in predicting fetal distress in small‐for‐gestational age fetuses. The rate of cesarean section among patients with single deepest pocket <3.0 cm was higher than that in amniotic fluid index < 8.0 cm.

Conclusion. Our results demonstrated that a single deepest pocket measurement of < 3 cm is the most useful criterion for ‘oligohydramnios’ in the prediction of fetal distress.
Enhanced separation of X and Y bearing sperm cells by a combined density gradient centrifugation evaluated by fluorescence in situ hybridization of the Y‐chromosome
Authors: Andersen Claus Yding , Byskov Anne Grete
Published: March 2008

Objectives. Fluorescent in situ hybridization of decondensed sperm cells was used to evaluate the effectiveness of separating X‐ and Y chromosome bearing sperm cells using a combination of Percoll and NycoPrep media.

Material and methods. Semen samples from seven healthy men were divided into three equal aliquots. One aliquot served as an untreated control, the other two were either applied to a seven‐step Percoll gradient (100%‐40%), or to a seven‐step Percoll gradient (100%‐40%) underlayered with 100% NycoPrep for sperm purification. After centrifugation Y‐bearing sperm cells in the pellet and in the control sample was determined by fluorescent in situ hybridization.

Results. A significantly reduction of Y‐bearing sperm cells were observed in the pellet of the Percoll + NycoPrep centrifugation (39.3% Y‐bearing sperm cells) compared to the control sample and to Percoll centrifugation without NycoPrep. The Percoll centrifugation without NycoPrep did not show a significant reduction of Y‐bearing sperm cells in the pellet compared to the control sample.

Conclusion. By the addition of a medium with a density higher than 100% Percoll a significantly increased separation of X and Y‐bearing sperm cells can be achieved. This study opens new perspectives for improving separation of X‐ and Y‐bearing spermatozoa by simple centri‐fugations. The described centrifugation technique can be applied in connection with preim‐plantation diagnosis in order to create more pre‐embryos of the desired gender.
Increasing incidence of ectopic pregnancy in one Norwegian county ‐ a population based study, 1970–1993
Authors: Skjeldestad Finn Egil , Kendrick Juliette S. , Atrash Hani K. , Daltveit Anne Kjersti
Published: March 2008

Objective. To estimate time trends related to ectopic pregnancy while considering the contribution of repeat ectopic pregnancy and changing treatment for infertile couples over the past 24 years.

Methods. Population based incidence data on ectopic pregnancy were collected from the only two hospitals in one Norwegian county from 1970 through 1993. Cases were identified through hospital discharge registries and all medical records were reviewed. Only females, aged 15‐44 years. living permanently in the county and having a histologically verified ectopic pregnancy were eligible for the study. Data were analyzed in 5‐year periods and 5‐year age‐groups.

Results. The incidence of ectopic pregnancy (per 1,000 woman‐years) increased fourfold from the first to the last period. When we restricted the analyses to women with no previous ectopic pregnancy and n o previous infertility surgery or treatment, we observed a linear threefold increase in the number of ectopic pregnancies.

Conclusions. Repeat ectopic pregnancy and increased infertility treatment in the late 1970s and early 1980s might explain at most 25% of the increase in the incidence of ectopic pregnancy. After 1985; assisted reproduction might contribute to 445%) of ectopic pregnancies diagnosed. The introduction of laparoscopy might explain some of this increase in the 1970s; however. we doubt that the introduction of more sensitive pregnancy tests or vaginal ultrasound in the 1980s contributed to the observed increase in ectopic pregnancy.
Long‐term effects of climate change on vegetation and carbon dynamics in peat bogs
Authors: Heijmans Monique M.P.D. , Mauquoy Dmitri , van Geel Bas , Berendse Frank
Published: March 2008

Questions:

What are the long‐term effects of climate change on the plant species composition and carbon sequestration in peat bogs?

Methods:

We developed a bog ecosystem model that includes vegetation, carbon, nitrogen and water dynamics. Two groups of vascular plant species and three groups of Sphagnum species compete with each other for light and nitrogen. The model was tested by comparing the outcome with long‐term historic vegetation changes in peat cores from Denmark and England. A climate scenario was used to analyse the future effects of atmospheric CO2, temperature and precipitation.

Results:

The main changes in the species composition since 1766 were simulated by the model. Simulations for a future warmer, and slightly wetter, climate with doubling CO2 concentration suggest that little will change in species composition, due to the contrasting effects of increasing temperatures (favouring vascular plants) and CO2 (favouring Sphagnum). Further analysis of the effects of temperature showed that simulated carbon sequestration is negatively related to vascular plant expansion. Model results show that increasing temperatures may still increase carbon accumulation at cool, low N deposition sites, but decrease carbon accumulation at high N deposition sites.

Conclusions:

Our results show that the effects of temperature, precipitation, N‐deposition and atmospheric CO2 are not straightforward, but interactions between these components of global change exist. These interactions are the result of changes in vegetation composition. When analysing long‐term effects of global change, vegetation changes should be taken into account and predictions should not be based on temperature increase alone.
Salivary gland tissue expression of interleukin‐23 and interleukin‐17 in Sjögren's syndrome: Findings in humans and mice
Authors: Nguyen Cuong Q. , Hu Min H. , Li Yi , Stewart Carol , Peck Ammon B.
Published: March 2008

Objective

Recently, the Th1/Th2 paradigm has been expanded by the discovery of Th17 cells, a subset of CD4+ memory T cells characterized by their unique ability to secrete interleukin‐17 (IL‐17) family cytokines. Importantly, Th17 cells appear to be intimately involved in autoimmunity. We undertook the present study to investigate whether the Th17/IL‐23 system is up‐regulated in Sjögren's syndrome (SS).

Methods

Sera, saliva, and salivary glands from C57BL/6.NOD‐Aec1Aec2 mice (a model for primary SS), as well as sera, saliva, and salivary gland biopsy specimens obtained from patients with primary SS, were evaluated for IL‐17 and IL‐23 expression by immunohistochemistry, real‐time polymerase chain reaction, and the Luminex system.

Results

Immunohistochemical stainings of submandibular glands from C57BL/6.NOD‐Aec1Aec2 mice and of salivary gland biopsy specimens from SS patients revealed strong positive staining for both IL‐17 and IL‐23 within lymphocytic foci and diffuse staining on epithelial tissues. Temporal expression of IL‐17 and IL‐23 in submandibular glands of C57BL/6.NOD‐Aec1Aec2 mice correlated with expression of retinoic acid–related orphan receptor γt, the Th17 cell master control gene. While IL‐17 could not be detected in saliva from 4–20‐week‐old C57BL/6.NOD‐Aec1Aec2 mice, this cytokine was present in the blood of mice up to age 16 weeks. This contrasted with sera and saliva from SS patients, in which IL‐17 and IL‐6 were present at varying levels.

Conclusion

These results suggest that the Th17/IL‐23 system is up‐regulated in C57BL/6.NOD‐Aec1Aec2 mice and SS patients at the time of disease. A correlation between up‐regulated IL‐17/IL‐23 expression and specific clinical manifestations of SS has yet to be identified.
Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: Support for a crucial role of intron 1 polymorphisms
Authors: Kawasaki Aya , Kyogoku Chieko , Ohashi Jun , Miyashita Risa , Hikami Koki , Kusaoi Makio , Tokunaga Katsushi , Takasaki Yoshinari , Hashimoto Hiroshi , Behrens Timothy W. , Tsuchiya Naoyuki
Published: March 2008

Objective

To determine whether the IRF5 gene, which encodes interferon regulatory factor 5, is associated with systemic lupus erythematosus (SLE) in a Japanese population.

Methods

A case–control study was performed in 277 SLE patients and 201 healthy controls. Associations between the IRF5 genotype and levels of messenger RNA (mRNA) for interferon (IFN) pathway genes were examined using an mRNA expression database of HapMap samples.

Results

Carriers of the rs2004640T single‐nucleotide polymorphism (SNP) were slightly increased among SLE patients (58.8%) as compared with controls (50.2%). When data from our Japanese population were combined with previously published data from a Korean population, the T allele frequency was found to be significantly increased in SLE patients (P = 8.3 × 10−5). While no association was observed for the rs10954213 SNP or the exon 6 insertion/deletion, significant associations with 3 intron 1 SNPs (−4001, rs6953165, and rs41298401) were found. The allele frequency of rs41298401G was significantly decreased in SLE patients (13.0% versus 18.7% in controls; P = 0.017), and the allele frequency of rs6953165G, which was in absolute linkage disequilibrium with −4001A, was increased in SLE patients (8.8% versus 5.2% in controls; P = 0.034). The Caucasian risk haplotype was not present; instead, a protective haplotype carrying rs2004640G, rs41298401G, the deletion in exon 6, and rs10954213A was identified. SNP rs10954213, but not intron 1 SNPs, was associated with IRF5 at the mRNA level; nevertheless, intron 1 SNPs were also associated with levels of mRNA for several IFN pathway genes, suggesting a functional role.

Conclusion

IRF5 was found to be associated with SLE in Asian populations. Intron 1 SNPs, rather than exon 6 and 3′‐untranslated region polymorphisms, appeared to play a crucial role.
Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: Results from an international inception cohort study
Authors: Hanly J. G. , Urowitz M. B. , Siannis F. , Farewell V. , Gordon C. , Bae S. C. , Isenberg D. , Dooley M. A. , Clarke A. , Bernatsky S. , Gladman D. , Fortin P. R. , Manzi S. , Steinsson K. , Bruce I. N. , Ginzler E. , Aranow C. , Wallace D. J. , Ramsey‐Goldman R. , van Vollenhoven R. , Sturfelt G. , Nived O. , Sanchez‐Guerrero J. , Alarcón G. S. , Petri M. , Khamashta M. , Zoma A. , Font J. , Kalunian K. , Douglas J. , Qi Q. , Thompson K. , Merrill J. T.
Published: March 2008

Objective

To examine, in an inception cohort of systemic lupus erythematosus (SLE) patients, the association between neuropsychiatric (NP) events and anti–ribosomal P (anti‐P), antiphospholipid (lupus anticoagulant [LAC], anticardiolipin), anti–β2‐glycoprotein I, and anti–NR2 glutamate receptor antibodies.

Methods

NP events were identified using the American College of Rheumatology case definitions and clustered into central/peripheral and diffuse/focal events. Attribution of NP events to SLE was determined using decision rules of differing stringency. Autoantibodies were measured without knowledge of NP events or their attribution.

Results

Four hundred twelve patients were studied (87.4% female; mean ± SD age 34.9 ± 13.5 years, mean ± SD disease duration 5.0 ± 4.2 months). There were 214 NP events in 133 patients (32.3%). The proportion of NP events attributed to SLE varied from 15% to 36%. There was no association between autoantibodies and NP events overall. However, the frequency of anti‐P antibodies in patients with central NP events attributed to SLE was 4 of 20 (20%), versus 3 of 107 (2.8%) in patients with other NP events and 24 of 279 (8.6%) in those with no NP events (P = 0.04). Among patients with diffuse NP events, 3 of 11 had anti‐P antibodies (27%), compared with 4 of 111 patients with other NP events (3.6%) and 24 of 279 of those with no NP events (8.6%) (P = 0.02). Specific clinical–serologic associations were found between anti‐P and psychosis attributed to SLE (P = 0.02) and between LAC and cerebrovascular disease attributed to SLE (P = 0.038). There was no significant association between other autoantibodies and NP events.

Conclusion

Clinically distinct NP events attributed to SLE and occurring around the time of diagnosis were found to be associated with anti‐P antibodies and LAC. This suggests that there are different autoimmune pathogenetic mechanisms, although low sensitivity limits the clinical application of testing for these antibodies.
Cilostazol protects rat chondrocytes against nitric oxide–induced apoptosis in vitro and prevents cartilage destruction in a rat model of osteoarthritis
Authors: Lee Sung Won , Song Yeon Suk , Shin Sang Hwa , Kim Kyung Taek , Park Young Chul , Park Bong Soo , Yun Il , Kim Kunhong , Lee Sang Yeob , Chung Won Tae , Lee Hye Jeong , Yoo Young Hyun
Published: March 2008

Objective

To examine whether cilostazol, a selective phosphodiesterase type III inhibitor, protects rat articular chondrocytes against nitric oxide (NO)–induced apoptosis and prevents cartilage destruction in mono‐iodoacetate–induced osteoarthritis (OA) in a rat model in which inducible nitric oxide synthase (iNOS) is expressed.

Methods

The NO donor sodium nitroprusside was administered to rat articular chondrocytes that had been pretreated with cilostazol. Induction of apoptosis was evaluated by DNA electrophoresis and pulsed‐field gel electrophoresis. The expression level and the subcellular location of apoptosis‐associated factors were examined by Western blot analysis and confocal microscopy, respectively. Protein kinase CK2 (PKCK2) activity was also assayed. To examine whether orally administered cilostazol prevents cartilage destruction in vivo, cartilage samples obtained from rats with experimentally induced OA were subjected to hematoxylin and eosin, Safranin O, and TUNEL staining and immunohistochemical analysis of iNOS expression.

Results

Cilostazol prevented NO‐induced reduction in viability, in a dose‐dependent manner. It also prevented the up‐regulation of phosphorylated p53 and p38, the down‐regulation of heme oxygenase 1, the subcellular translocation of apoptosis‐inducing factor and cytochrome c, and the activation of caspases 3, 7, and 8 induced by NO treatment, indicating that cilostazol prevented NO‐induced cell death by blocking apoptosis. In addition, cilostazol prevented NO‐induced translocation of cleaved Bid onto mitochondria, and caused phosphorylated Bid to accumulate in the nucleus and cytosol. Cilostazol prevented the down‐regulation of PKCK2 and the reduction in PKCK2 activity induced by NO, indicating that its apoptosis‐preventing activity was mediated via PKCK2. It also prevented chondrocyte apoptosis and cartilage destruction in a rat model of experimentally induced OA.

Conclusion

Our findings indicate that cilostazol prevents NO‐induced apoptosis of chondrocytes via PKCK2 in vitro and prevents cartilage destruction in a rat model of OA.
Crucial role of the interleukin‐6/interleukin‐17 cytokine axis in the induction of arthritis by glucose‐6‐phosphate isomerase
Authors: Iwanami Keiichi , Matsumoto Isao , Tanaka‐Watanabe Yoko , Inoue Asuka , Mihara Masahiko , Ohsugi Yoshiyuki , Mamura Mizuko , Goto Daisuke , Ito Satoshi , Tsutsumi Akito , Kishimoto Tadamitsu , Sumida Takayuki
Published: March 2008

Objective

To clarify the glucose‐6‐phosphate isomerase (GPI)–specific CD4+ T cell lineage involved in GPI‐induced arthritis and to investigate their pathologic and regulatory roles in the induction of the disease.

Methods

DBA/1 mice were immunized with GPI to induce arthritis. CD4+ T cells and antigen‐presenting cells were cocultured with GPI, and cytokines in the supernatant were analyzed by enzyme‐linked immunosorbent assay. Anti–interferon‐γ (anti‐IFNγ) monoclonal antibody (mAb), anti–interleukin‐17 (anti–IL‐17) mAb, or the murine IL‐6 receptor (IL‐6R) mAb MR16‐1 was injected at different time points, and arthritis development was monitored visually. After MR16‐1 was injected, percentages of Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry, and CD4+ T cell proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester.

Results

GPI‐specific CD4+ T cells were found to be differentiated to Th1 and Th17 cells, but not Th2 cells. Administration of anti–IL‐17 mAb on day 7 significantly ameliorated arthritis (P < 0.01), whereas administration of anti‐IFNγ mAb exacerbated arthritis. Neither anti–IL‐17 mAb nor anti‐IFNγ mAb administration on day 14 ameliorated arthritis. Administration of MR16‐1 on day 0 or day 3 protected against arthritis induction, and MR16‐1 administration on day 8 significantly ameliorated existing arthritis (P < 0.05). After administration of MR16‐1, there was marked suppression of Th17 differentiation, without an increase in Th1, Th2, or Treg cells, and CD4+ T cell proliferation was also suppressed.

Conclusion

IL‐6 and Th17 play an essential role in GPI‐induced arthritis. Since it has previously been shown that treatment with a humanized anti–IL‐6R mAb has excellent effects in patients with rheumatoid arthritis (RA), we propose that the IL‐6/IL‐17 axis might also be involved in the generation of RA, especially in the early effector phase.
Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia
Authors: Harris Richard E. , Sundgren Pia C. , Pang Yuxi , Hsu Michael , Petrou Myria , Kim Seong‐Ho , McLean Samuel A. , Gracely Richard H. , Clauw Daniel J.
Published: March 2008

Objective

Fibromyalgia (FM) is a chronic widespread pain condition that is thought to arise from augmentation of central neural activity. Glutamate (Glu) is an excitatory neurotransmitter that functions in pain‐processing pathways. This study was carried out to investigate the relationship between changing levels of Glu within the insula and changes in multiple pain domains in patients with FM.

Methods

Ten patients with FM underwent 2 sessions of proton magnetic resonance spectroscopy (H‐MRS) and 2 sessions of functional magnetic resonance imaging (FMRI), each conducted before and after a nonpharmacologic intervention to reduce pain. During H‐MRS, the anterior and posterior insular regions were examined separately using single‐voxel spectroscopy. The levels of Glu and other metabolites were estimated relative to levels of creatine (Cr) (e.g., the Glu/Cr ratio). During FMRI, painful pressures were applied to the thumbnail to elicit neuronal activation. Experimental pressure‐evoked pain thresholds and clinical pain ratings (on the Short Form of the McGill Pain Questionnaire [SF‐MPQ]) were also assessed prior to each imaging session

Results

Both experimental pain (P = 0.047 versus pretreatment) and SF‐MPQ–rated clinical pain (P = 0.043 versus pretreatment) were reduced following treatment. Changes from pre‐ to posttreatment in Glu/Cr were negatively correlated with changes in experimental pain thresholds (r = −0.95, P < 0.001) and positively correlated with changes in clinical pain (r = 0.85, P = 0.002). Changes in the FMRI‐determined blood oxygenation level–dependent effect (a measure of neural activation) were positively correlated with changes in Glu/Cr within the contralateral insula (r = 0.81, P = 0.002).

Conclusion

Changes in Glu levels within the insula are associated with changes in multiple pain domains in patients with FM. Thus, H‐MRS data may serve as a useful biomarker and surrogate end point for clinical trials of FM.
Mediation of the proinflammatory cytokine response in rheumatoid arthritis and spondylarthritis by interactions between fibroblast‐like synoviocytes and natural killer cells
Authors: Chan Antoni , Filer Andrew , Parsonage Greg , Kollnberger Simon , Gundle Roger , Buckley Christopher D. , Bowness Paul
Published: March 2008

Objective

Fibroblast‐like synoviocytes (FLS) are potentially directly involved in the propagation of inflammation. We have previously shown evidence of an expanded activated population of natural killer (NK) cells in spondylarthritis (SpA) patients. In the present study, we sought to determine whether the interaction between NK cells and FLS from SpA patients results in a proinflammatory response.

Methods

Autologous NK cells and FLS were obtained from 6 patients with SpA, 4 patients with rheumatoid arthritis (RA), and 8 patients with osteoarthritis (OA). Physical interactions between NK cells and FLS were studied by time‐lapse phase‐contrast microscopy. Fluorescence‐activated cell sorting was used to study the activation, proliferation, and survival of NK cells in contact with FLS. Cytokine and stromal factor production were measured by a multiple cytokine bead assay.

Results

NK cells both adhered to and migrated beneath the FLS monolayer (pseudoemperipolesis). FLS from SpA and RA patients supported increased pseudoemperipolesis, activation, cytokine production, and survival of NK cells. The production of proinflammatory cytokines, including interleukin‐6 (IL‐6), IL‐8, IL‐1β, and IL‐15, was increased in cocultures of NK cells and FLS, particularly in those from RA and SpA patients. Production of interferon‐γ, RANTES, and matrix metalloproteinase 3 (MMP‐3) by NK cell and FLS coculture was greatest in SpA patients. Surface expression of IL‐15 on FLS was significantly increased in SpA and RA patients, but not OA patients. Blockade with an IL‐15 monoclonal antibody resulted in increased apoptosis of NK cells.

Conclusion

FLS promote the migration, activation, and survival of NK cells. The interaction of NK cells with FLS results in increased IL‐15 expression by FLS and the production of proinflammatory chemokines, cytokines, and MMPs, which may contribute to joint inflammation. This response was much more marked in SpA and RA patients as compared with OA patients.
Health economic consequences related to the diagnosis of fibromyalgia syndrome
Authors: Annemans L. , Wessely S. , Spaepen E. , Caekelbergh K. , Caubère J. P. , Lay K. Le , Taïeb C.
Published: March 2008

Objective

To evaluate the use and costs of medical resources before and after a diagnosis of fibromyalgia syndrome (FMS) in a large primary care population in the UK.

Methods

We applied an existing data set for medical resource use among patients with a coded diagnosis of FMS. The observed quantities of 157 types of medical resource use before and after the diagnosis of FMS were multiplied by unit costs in order to calculate the cost of care (general practitioner [GP] visits, drugs, referrals, and diagnostics) within the National Health Service, excluding hospital costs. Costs before diagnosis were used in a trend analysis to predict later costs, assuming the diagnosis had never been made, and these predicted costs were compared with the observed costs after diagnosis.

Results

Following a diagnosis of FMS, a decrease in costs as compared with the predicted trend was observed. In the 4 years after diagnosis, the average difference between the predicted and observed cost was £66.21 per 6 months per patient. This suggests that making the diagnosis leads to savings and a decrease in resource use. The main effect was observed for tests and imaging (£24.02 per 6 months), followed by pharmaceuticals (£22.27), referrals (£15.56), and GP visits (£4.36).

Conclusion

Failure to diagnose a true case of FMS has its own costs, largely in excess GP visits, investigations, and prescriptions.
Spondylarthritis in the absence of B lymphocytes
Authors: Baeten Dominique , Kruithof Elli , Breban Maxime , Tak Paul P.
Published: March 2008

The highly effective treatment of rheumatoid arthritis by B cell depletion and the presence of B cells in the peripheral and axial lesions of patients with spondylarthritis (SpA) raise the question as to whether B lymphocytes could also be an appropriate therapeutic target in the latter disease. We describe 2 male HLA–B27–positive patients who had active SpA despite absence of B cells. One patient developed SpA with sacroiliitis and asymmetric oligoarthritis after having been diagnosed as having severe Bruton agammaglobulinemia. Since extensive investigations excluded an infectious origin of the SpA, this case illustrates that functional B cells and/or gamma globulins are not strictly required for SpA pathogenesis. The second patient had severe axial and peripheral SpA that was treated successfully with etanercept. After discontinuation of etanercept treatment because of non‐Hodgkin's B cell lymphoma, both axial and peripheral SpA symptoms relapsed rapidly, and this exacerbation of articular disease activity was not modulated by successful B cell depletion therapy for the lymphoma. Although case reports have obvious limitations, our clinical observations provide evidence that active SpA can occur in the absence of functional mature B cells and thus emphasize the need for systematic studies of the exact role and function of B lymphocytes in this disease.
Autoimmune disease in individuals and close family members and susceptibility to non‐Hodgkin's lymphoma
Authors: Mellemkjaer Lene , Pfeiffer Ruth M. , Engels Eric A. , Gridley Gloria , Wheeler William , Hemminki Kari , Olsen Jørgen H. , Dreyer Lene , Linet Martha S. , Goldin Lynn R. , Landgren Ola
Published: March 2008

Objective

Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome have been consistently associated with an increased risk of non‐Hodgkin's lymphoma (NHL). This study was initiated to evaluate the risks of NHL associated with a personal or family history of a wide range of autoimmune diseases.

Methods

A population‐based case–control study was conducted that included 24,728 NHL patients in Denmark (years 1977–1997) and Sweden (years 1964–1998) and 55,632 controls. Using univariate logistic and hierarchical regression models, we determined odds ratios (ORs) of NHL associated with a personal history of hospital‐diagnosed autoimmune conditions. Risks of NHL associated with a family history of the same autoimmune conditions were assessed by similar regression analyses that included 25,941 NHL patients and 58,551 controls.

Results

A personal history of systemic autoimmune diseases (RA, SLE, Sjögren's syndrome, systemic sclerosis) was clearly linked with NHL risk, both for individual conditions (hierarchical odds ratios [ORh] ranged from 1.6 to 5.4) and as a group (ORh 2.64 [95% confidence interval (95% CI) 1.72–4.07]). In contrast, a family history of systemic autoimmune diseases was modestly and nonsignificantly associated with NHL (ORh 1.31 [95% CI 0.85–2.03]). An increased risk of NHL was found for a personal history of 5 nonsystemic autoimmune conditions (autoimmune hemolytic anemia, Hashimoto thyroiditis, Crohn's disease, psoriasis, and sarcoidosis) (ORh ranged from 1.5 to 2.6) of 27 conditions examined.

Conclusion

Overall, our results demonstrate a strong relationship of personal history of systemic autoimmune diseases with NHL risk and suggest that shared susceptibility may explain a very small fraction of this increase, at best. Positive associations were found for a personal history of some, though far from all, nonsystemic autoimmune conditions.
Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic‐onset juvenile idiopathic arthritis
Authors: Donn Rachelle , Ellison Stuart , Lamb Rebecca , Day Thomas , Baildam Eileen , Ramanan Athimalaipet V.
Published: March 2008

Objective

To investigate whether single‐nucleotide polymorphisms (SNPs) within the genes PRF1, GZMB, UNC13D, and Rab27a, which are involved in natural killer cell dysfunction and known to contribute to the risk of hemophagocytic lymphohistiocytosis (HLH), confer an increased risk of susceptibility to systemic‐onset juvenile idiopathic arthritis (JIA).

Methods

Four SNPs across the PRF1 gene locus, 5 for GZMB, 7 for UNC13D, and 11 for Rab27a were investigated using MassArray genotyping in 133 UK Caucasian patients with systemic‐onset JIA and 384 ethnically matched unrelated control subjects. Additional control genotypes were accessed from the data generated by the Wellcome Trust Case Control Consortium.

Results

No significant association was found between any SNP within the 4 selected loci and systemic‐onset JIA, by either single‐point or haplotype analysis.

Conclusion

The results of this study demonstrate that genes involved in HLH do not confer a significant risk of association with systemic‐onset JIA.
Reduced fragmentation of apoptotic chromatin is associated with nephritis in lupus‐prone (NZB × NZW)F1 mice
Authors: Zykova Svetlana N. , Seredkina Natalya , Benjaminsen Jørgen , Rekvig Ole Petter
Published: March 2008

Objective

Antinucleosome autoantibodies are pathogenic factors in lupus nephritis. Defects in apoptotic pathways may result in increased levels of apoptotic nucleosomes. The objectives of this study were 1) to determine whether low molecular weight oligonucleosomes are present in the kidneys of autoimmune (NZB × NZW)F1 mice, 2) to analyze whether the presence of glomerular membrane–associated TUNEL‐positive electron‐dense structures reflect the existence of low molecular weight oligonucleosomes, and 3) to determine an eventual temporal relationship between glomerular electron‐dense structures, oligonucleosomes, and proteinuria in these mice.

Methods

DNA was isolated from mouse 111s34 hybridoma cells and from the kidneys of normal BALB/c mice in which apoptosis was induced by camptothecin and from the kidneys of (NZB × NZW)F1 mice at ages 4 weeks, 8 weeks, 20 weeks, and ≥26 weeks (nephritic mice). The DNA fragmentation pattern was determined with an Agilent bioanalyzer. An electron microscopy–based TUNEL assay was performed to detect apoptotic chromatin in glomerular membranes, and immunoelectron microscopy was used to determine antibody binding. Transcription levels for nucleases associated with apoptosis and necrosis were determined by real‐time polymerase chain reaction.

Results

DNA from camptothecin‐treated cell lines and BALB/c mouse kidneys, but not that from untreated (NZB × NZW)F1 mouse kidneys, demonstrated DNA cleavage consistent with apoptotic fragmentation. DNA from (NZB × NZW)F1 mice was devoid of apoptotic fragmentation, irrespective of the age of the mice, whereas TUNEL‐positive chromatin particles were detected in glomerular membranes in nephritic mice. Renal DNase I transcription was reduced in nephritic mice. Nucleosomal DNA fragmentation in response to camptothecin exposure was highly reduced in (NZB × NZW)F1 mouse kidneys compared with that in their normal counterparts.

Conclusion

The results of this study demonstrate that TUNEL‐positive chromatin particles are deposited in the glomeruli of nephritic (NZB × NZW)F1 mice, due to reduced fragmentation and clearance of chromatin.
Tumor‐induced osteomalacia: Lessons learned
Authors: Lewiecki E. Michael , Urig Edward J. , Williams Ralph C.
Published: March 2008

Tumor‐induced osteomalacia is a rare acquired metabolic disorder characterized by hypophosphatemia and inappropriately low serum levels of 1,25‐dihydroxyvitamin D. Symptoms include chronic muscle and bone pain, weakness, and fatigue in association with a high risk of fragility fractures due to osteomalacia. The diagnosis is commonly delayed for years due to the nonspecific nature of the presenting symptoms, failure to include determination of serum phosphorus levels in blood chemistry testing, and difficulty in identifying the responsible tumor. The pathogenesis of tumor‐induced osteomalacia involves tumor expression of fibroblast growth factor 23, a hormone that inhibits proximal renal tubular reabsorption of phosphate and down‐regulates renal conversion of 25‐hydroxyvitamin D to its active form, 1,25‐dihydroxyvitamin D. The metabolic abnormalities may be partially or completely corrected with phosphate supplementation and calcitriol. A definitive diagnosis and treatment require excision of the responsible tumor.
Gene polymorphisms in the NALP3 inflammasome are associated with interleukin‐1 production and severe inflammation: Relation to common inflammatory diseases?
Authors: Verma Deepti , Lerm Maria , Blomgran Julinder Robert , Eriksson Per , Söderkvist Peter , Särndahl Eva
Published: March 2008

Objective

NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1–mediated interleukin‐1β (IL‐1β) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic‐resistant fever carried mutations in the genes encoding the NALP3 inflammasome.

Methods

Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD‐8) was performed on genomic DNA from the patient and from a population‐based collection of DNA (806 subjects). For in vitro studies of IL‐1β production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL‐1 receptor antagonist, as well as from 5 healthy age‐ and sex‐matched control subjects.

Results

Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD‐8 (C10X) genes. The allele frequencies of these single‐nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL‐1β measured in samples from the patient returned to normal levels after treatment with anakinra.

Conclusion

Our results indicate that the patient's symptoms were due to elevated levels of IL‐1β, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL‐1β levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.
The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation
Authors: Vandooren Bernard , Cantaert Tineke , Noordenbos Troy , Tak Paul P. , Baeten Dominique
Published: March 2008

Objective

Spondylarthritis (SpA) and rheumatoid arthritis (RA) have different patterns of bone damage, with more pronounced bone erosions in RA. The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in bone resorption by promoting the maturation and activation of osteoclasts. To assess the potential role of this system in the distinct bone phenotype, we studied the synovial expression of these mediators in SpA and RA peripheral synovitis.

Methods

Synovial biopsy specimens were obtained from the actively inflamed peripheral joints of 35 patients with SpA and 19 patients with RA. Paired synovial biopsy samples were obtained from 24 patients with SpA after tumor necrosis factor α (TNFα) blockade. Synovial tissue sections were immunostained for RANKL, OPG, RANK, and TRAP and assessed by semiquantitative scoring and digital image analysis.

Results

After extensive validation of the reactivity and specificity of the antibodies, we demonstrated the abundant expression of RANKL and OPG in SpA synovitis. RANKL was expressed by both fibroblast‐like synoviocytes and sublining T lymphocytes. RANK‐positive osteoclast precursors but no mature TRAP‐positive osteoclasts were present in the inflamed tissue. The expression of these mediators was not different between patients with nonpsoriatic SpA, patients with psoriatic SpA, and patients with RA, was not related to the degree of systemic or local inflammation, and was not significantly modulated by highly effective treatment with TNFα blockers. Only the subset of patients with the best systemic response to TNFα blockade had decreased RANKL expression in the intimal lining layer.

Conclusion

The relative protection against bone erosions in SpA cannot be explained by qualitative or quantitative differences in the synovial expression of RANKL, OPG, and RANK. The abundant expression of these factors in SpA peripheral synovitis is largely disconnected from systemic and local inflammation.
Interleukin‐17–producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers
Authors: Nistala Kiran , Moncrieffe Halima , Newton Katy R. , Varsani Hemlata , Hunter Patricia , Wedderburn Lucy R.
Published: March 2008

Objective

To identify interleukin‐17 (IL‐17)–producing T cells from patients with juvenile idiopathic arthritis (JIA), and investigate their cytokine production, migratory capacity, and relationship to Treg cells at sites of inflammation, as well as to test the hypothesis that IL‐17+ T cell numbers correlate with clinical phenotype in childhood arthritis.

Methods

Flow cytometry was used to analyze the phenotype, cytokine production, and chemokine receptor expression of IL‐17–producing T cells in peripheral blood and synovial fluid mononuclear cells from 36 children with JIA, in parallel with analysis of forkhead box P3 (FoxP3)–positive Treg cells. Migration of IL‐17+ T cells toward CCL20 was assessed by a Transwell assay. Synovial tissue was analyzed by immunohistochemistry for IL‐17 and IL‐22.

Results

IL‐17+ T cells were enriched in the joints of children with JIA as compared with the blood of JIA patients (P = 0.0001) and controls (P = 0.018) and were demonstrated in synovial tissue. IL‐17+ T cell numbers were higher in patients with extended oligoarthritis, the more severe subtype of JIA, as compared with patients with persistent oligoarthritis, the milder subtype (P = 0.046). Within the joint, there was an inverse relationship between IL‐17+ T cells and FoxP3+ Treg cells (r = 0.61, P = 0.016). IL‐17+,CD4+ T cells were uniformly CCR6+ and migrated toward CCL20, but synovial IL‐17+ T cells had variable CCR4 expression. A proportion of IL‐17+ synovial T cells produced IL‐22 and interferon‐γ.

Conclusion

This study is the first to define the frequency and characteristics of “Th17” cells in JIA. We suggest that these highly proinflammatory cells contribute to joint pathology, as indicated by relationships with clinical phenotypes, and that the balance between IL‐17+ T cells and Treg cells may be critical to outcome.
H‐2g, a glucose analog of blood group H antigen, mediates mononuclear cell recruitment via Src and phosphatidylinositol 3‐kinase pathways
Authors: Amin M. Asif , Ruth Jeffrey H. , Haas Christian S. , Pakozdi Angela , Mansfield Pamela J. , Haghshenas Jafar , Koch Alisa E.
Published: March 2008

Objective

Monocyte recruitment by proinflammatory cytokines is a hallmark of rheumatoid arthritis (RA). Lewisy‐6 and H (Ley/H) are blood group antigens up‐regulated on RA synovial endothelium. We have previously shown that both soluble Ley/H and a glucose analog of H, H‐2g, are angiogenic and mediateleukocyte–endothelial adhesion via induction of intercellular adhesion molecule 1. We hypothesized that soluble Ley/H plays an important role in monocyte recruitment in RA.

Methods

We examined the role of H‐2g in monocyte chemotaxis in vitro. We used an RA synovial tissue (ST)–SCID mouse chimera model to evaluate the role of H‐2g in monocyte recruitment in vivo. We used Western blots to examine signaling molecules activated by H‐2g in monocytes.

Results

H‐2g induced human monocyte migration in vitro, which was mediated by Src and phosphatidylinositol 3‐kinase (PI 3‐kinase), since inhibitors and antisense oligodeoxynucleotides (ODNs) of Src and PI 3‐kinase significantly decreased H‐2g–induced monocyte migration (P < 0.05). H‐2g significantly increased mononuclear cell (MNC) homing in vivo into an RA ST–SCID mouse chimera (P < 0.05). Transfection of MNCs with Src antisense ODNs blocked H‐2g–induced MNC recruitment into the RA ST–SCID mouse chimera. Additionally, H‐2g induced marked phosphorylation of protein kinase CαI/βII (PKCαI/βII), Src, IκBα, and Akt in monocytes. Src, Akt, and NF‐κB were shown to be downstream targets of PKCαI/βII, since an inhibitor of PKCαI/βII reduced H‐2g–mediated phosphorylation of Src, Akt, and NF‐κB in monocytes.

Conclusion

These data suggest that H‐2g may be a novel mediator of monocyte recruitment in chronic inflammatory diseases like RA.