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Objective: To describe and compare baseline renal anatomy and renal function in patients with obstetric fistulas, and to evaluate whether preoperative renal testing and imaging may aid with operative decision making.Design: A prospective cohort study.Setting: Fistula Care Centre in Malawi.Population: Women with an obstetric fistula.Methods: Baseline creatinine testing and renal ultrasounds were performed. Surgeons completed a short questionnaire on the usefulness of creatinine and renal ultrasound on operative decision making.Main Outcome Measures: Baseline creatinine and renal ultrasound findings.Results: Four surgeons performed operations on 85 patients. The mean creatinine in patients with vesicovaginal fistulas (VVF) was 0.60 ng/ml versus patients with uretero-vaginal fistulas (UVF) (0.79 ng/ml, P = 0.012). When a grade 3 or more hydronephrosis is absent on renal ultrasound, the negative predictive value of the presence of UVF is 93.3% (95% confidence interval [CI] 88.6-96.2) with a specificity of 97.2% (95% CI 90.3-99.6). In cases of UVF, surgeons found the renal ultrasound results useful or very useful 87.5% of the time, and the creatinine useful or very useful 75% of the time.Conclusion: In this pilot study, most patients with obstetric fistulas presented with a normal creatinine. In the absence of a grade 3 hydronephrosis or above on renal ultrasound, the probability of not having a UVF is 93.3%. Surgeons should consider performing preoperative renal ultrasound testing in all patients with an obstetric fistula, particularly in women with a prior laparotomy, as this population has risk factors for ureterovaginal fistula.Tweetable Abstract: Most patients with obstetric fistulas have normal renal function. Preoperative renal ultrasounds should be performed. [ABSTRACT FROM AUTHOR]

Gynecologic and plastic surgeons collaborate to improve vaginal reconstruction for women with vaginal stenosis and obstetric fistula. As these cases occur typically in low-resource settings, the Singapore flap is a useful technique given its reliability, safety, ease of dissection, and minimal need for additional supplies. The fasciocutaneous flap maintains cutaneous innervation and vasculature and does not require stenting. The surgical collaboration has made it possible to provide functional vaginal reconstruction as a part of the overall care of obstetric fistula patients. The technique shows promise for improving sexual function for women with obstetric fistula and may also enhance healing.Tweetable Abstract: Gynecologic & plastic surgeons collaborate to improve vaginal reconstruction for women with obstetric fistula. [ABSTRACT FROM AUTHOR]

In this article, the authors talk about urinary diversion in women in low resource settings to prevent obstetric fistula after pregnancy and urinary incontinence. Topics discussed include common procedures of urinary diversion like ileal conduit and ureterosig-moidostomy, association of obstructed labour with abscess formation and retroperitoneal fibrosis, and risk of ureteral stenosis complications.

Groupings of Lamb weather types ( LWTs) are used to assess the influence of synoptic meteorology on UK tropospheric column NO2. Composite satellite maps using daily 2005-2011 data show significant NO2 anomalies for each group. Hence, despite large day-to-day variability and significant uncertainty in individual retrievals, the satellite data can be used to determine national-scale column NO2 variations under different meteorological conditions. Under cyclonic conditions, NO2 is reduced, while anticyclonic conditions aid its accumulation, especially during winter, consistent with trapping of surface emissions and slower photochemical processing. This composite dataset can be used to test seasonal simulations of air quality models. [ABSTRACT FROM AUTHOR]

Groupings of Lamb weather types ( LWTs) are used to assess the influence of synoptic meteorology on UK tropospheric column NO2. Composite satellite maps using daily 2005-2011 data show significant NO2 anomalies for each group. Hence, despite large day-to-day variability and significant uncertainty in individual retrievals, the satellite data can be used to determine national-scale column NO2 variations under different meteorological conditions. Under cyclonic conditions, NO2 is reduced, while anticyclonic conditions aid its accumulation, especially during winter, consistent with trapping of surface emissions and slower photochemical processing. This composite dataset can be used to test seasonal simulations of air quality models. [ABSTRACT FROM AUTHOR]

Most of the clinical studies report the incidence of tarsal coalitions (TC) as less than 1% but they disregard the asymptomatic coalitions. TC have been associated with degenerative arthritic changes. After X-rays, computer tomography (CT) is the most commonly used diagnostic test in the detection of TC.The aims of our study were to establish the incidence of TC; the association between TC and accessory tarsal bones and between TC and tarsal arthritis; and to assess the sensitivity of CT as a diagnostic tool in TC. We performed spiral CT scans of 100 cadaver feet (mean age at death 77.7±10.4), which were subsequently dissected. The dissections identified nine non-osseous TC: two talocalcaneal and seven calcaneonavicular. There was no osseous coalition. Tarsal arthritis was identified in 31 cases. Both talocalcaneal coalitions were associated with arthritis while none of the calcaneonavicular coalitions were associated with tarsal arthritis. The CT diagnosed an osseous talocalcaneal coalition and was suspicious of fibrocartilaginous coalitions in eight cases. There was correlation between dissection and CT in two talocalcaneal coalitions and three calcaneonavicular coalitions thus CT identifying 55.5% of the coalitions. CT did not diagnose four non-osseous coalitions and diagnosed errouresly four possible coalitions. In conclusion our study demonstrated that the incidence of non-osseous TC is higher than previously thought (12.72%). The calcaneonavicular coalitions are the most common single type (9.09%) and they do not seem to be associated with arthritic changes in the tarsal bones. Our CT results suggest that spiral CT has a low sensitivity in the detection of non-osseous coalitions and questions if multislice CT should be used routinely when TC are suspected. [Copyright &y& Elsevier]

The model is motivated by data showing that the Australian production of local manufactures is hurt by depreciations and invigorated by appreciations. The paper briefly presents such evidence and then proceeds to a theoretical analysis. The model aims to capture short–to–medium run exchange rate effects in an economy with goods and services aggregated into four commodities: (i) imports; (ii) local manufactures; (iii) services; and (iv) rural goods (agricultural, pastoral, forestry, finishing and mining products). With the exception of rural goods, each commodity comprises consumer goods as well as inputs into the other sectors. Rural goods enter consumption only indirectly after processing by the manufacturing sector. Exports are exclusively rural goods. The model has a Keynesian flavour in that the production of local manufactures and services is not constrained by the availability of resources and of labour. Variable inputs per unit of output are assumed to be constant. There are also fixed inputs. Variable inputs are imports in the case of the import sector; rural goods and imports in the case of the local manufacturing sector; and labour in the case of the services sector. The prices of imports, local manufactures and services are set by constant mark–up factors on variable costs. This assumption is based on a picture of imperfect competition with constant elasticity of demand at the firm level. The extreme capital intensity of rural goods production is taken into account by modelling total production of rural goods as an exogenous parameter. The price of rural goods is determined in the export market. It falls with increasing exports. The economy is not assumed to be small in its export market. The domestic consumption demand schedule is modelled as predetermined in the sense that in the time span under consideration the relationship between quantities consumed and nominal prices is not affected by the exchange rate. The nominal wage rate is assumed to be predetermined in the same sense. No specific functional form is imposed on the consumption demand schedule: the analysis is based on general assumptions, mainly non–inferiority and gross substitutability. In view of gross substitutability, there is a competitive relationship between imports and local manufactures. A depreciation raises the price of imports and ceteris paribus such an increase raises the consumption of manufactures. However, the analysis shows that this enhancing influence of a depreciation on manufacturing is weaker than other causal channels that work in the opposite direction. An increase in the price of imports (and exportables)raises variable costs and thereby the price of local manufactures. This leads to a decrease in the output of local manufactures. In the course of the analysis, it is first shown that a uniquely determined equilibrium exists for every exchange rate above a lower bound. Then the effects of a change in the exchange rate are investigated. In most cases the results are unambiguous. In particular this is true for the output and the price of local manufactures. Other conclusions are that a depreciation increases exports and the amount of services provided. In some cases unequivocal results can be obtained only with the help of further assumptions. This concerns the domestic price of rural goods, the balance of trade in domestic prices and import penetration. [ABSTRACT FROM AUTHOR]

The infection of channel catfish ovarian cells with channel catfish virus results in the redistribution of all cytoskeletal elements during virus-induced syncytium formation. Actin filaments are normally arranged as large stress fibres, even during early stages of infection, but become redistributed as densely staining regions near the centre of the syncytium in latent infection. Microtubules and vimentin filaments (easily visible in early infection) lose all visible organization during syncytium formation. Stabilization of microtubules with taxol results in the production of elongate syncytia with regularly organized microtubules. Conversely, disruption of microtubules with nocodazole inhibits cell fusion and causes a reduction in infectious virus production. This reduction upon treatment with nocodazole, and the subsequent rescue of virus production upon addition of taxol indicates that viral replication relies upon the presence of microtubules. [ABSTRACT FROM AUTHOR]

A detailed examination of the epitopes recognized by autoantibodies (aAbs) to the thyroid microsomal antigen/thyroid peroxidase (TMA/TPO) in patients with thyroid autoimmune disease has been made using a combination of immunochemical and enzymatic techniques. Our results demonstrate the the autoimmune response to thyroid microsomal antigen/thyroid peroxidase (TMA/TPO) is multifocal and far more heterogenous than hitherto recognized. By immunoblotting with aAbs, antigenic determinants on the TMA/TPO have been recognized that are either susceptible to polypeptide denaturation and/or sensitive to the effects of reducing agents. Furthermore, these aAbs can inhibit, to varying degrees, the enzymatic activity of solubilized preparations of TPO in microsomes, as ascertained by peroxidation of guaiacol and iodide. A large proportion of the autoimmune response is directed to the guaiacol peroxidation site. The data support the view that the autoimmune reactivity to the TMA/TPO is a specific polyclonal response with a minimum of six distinct, independent determinants that are recognized by aAbs. [ABSTRACT FROM AUTHOR]

The reactions of a series of monocyclic and bicyclic arenes with early transition metal ions (Sc+, Y+, Nb+ and Ta+) and their oxides and dioxides were studied in a Fourier transform ion cyclotron resonance mass spectrometer. Ring cleavage of the nitrogen-containing heterocycles results in loss of HCN as the dominant pathway. Thermochemical considerations, secondary reactions and correlations with solution cyclotrimerization reactions indicate that the MC4H4+ product is a metallacyclopentadiene. Based on correspondence between the reactivities of a series of early metals with their valence electron counts, the reactivities of quinoline and isoquinoline and the decomposition behavior of the products, a metallacycloheptatriene intermediate is proposed for the heteroaromatic ring cleavage reaction. These results are compared to metal complexes in solution which catalyze the [2 + 2 + 2] cyclotrimerization of alkynes and nitriles. [ABSTRACT FROM AUTHOR]

The partitioning of reaction exothermicity into relative translational energy of the products of gas-phase SN2 (F− + CH3Cl) and nucleophilic aromatic substitution (F− + C6H5Cl) reactions has been investigated using kinetic energy release Fourier transform ion cyclotron resonance spectroscopy. The chloride product ion is observed to be highly translationally excited for the SN2 reaction, indicating a cold internal energy distribution for the products. For the chlorobenzene reaction the products are not generated with large translational energies. The results are compared with a statistical model. Ion-intensity profiles for the CH3Cl reaction deviate significantly from the statistical model whereas the chlorobenzene results are consistent with this model. The kinetic energy release for the CH3C1 reaction is compared with energy-disposal results for the photodissociation and dissociative electron-attachment processes of halomethanes. In all three cases a node in the molecular orbital between the carbon atom and the departing halogen results in a repulsive energy release. Ion-retention curves for the nucleophilic aromatic substitution reaction are consistent with the existence of a long-lived ion-dipole complex on the exit channel for this reaction. [ABSTRACT FROM AUTHOR]

Earlier studies demonstrated enhanced proliferative responses to an acetone precipitable Mycobacterium tuberculosis (AP-MT) antigenic complex by T lymphocytes from the synovial fluid, compared with the peripheral blood, of patients with inflammatory synovitis, including rheumatoid arthritis. In contrast, decreased proliferation and interleukin 2 (IL-2) production in response to mitogens by synovial fluid lymphocytes from patients with rheumatoid arthritis has been demonstrated. In order to determine if IL-2 was produced in response to AP-MT, the peripheral blood and synovial fluid of patients with inflammatory arthritis were analysed by measuring proliferation and IL-2 production in response to AP-MT and tetanus toxoid. A reduction of IL-2 production relative to proliferation was observed in some, but not all, synovial fluids of patients who responded to the AP-MT. Nevertheless, antibodies to IL-2 as well as interleukin 4(IL-4), significantly inhibited proliferation of synovial fluid lymphocytes by AP-MT. There was no inhibition by antibodies to interleukin 6 (IL-6). We conclude that AP-MT induced proliferation by synovial fluid lymphocytes is mediated by both IL-2 and IL-4. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cell activity and its regulation in synovial fluid (SF), synovial tissue (ST), and peripheral blood (PB) was studied in 23 patients with active rheumatoid arthritis (RA). NK activity was reduced in PB (P<0.005), SF (P<0.002), and ST of patients with RA compared to the PB of 28 healthy controls. NK activity in SF was inversely correlated with disease activity as measured by erythrocyte sedimentation rate (r= -0.561; P<0.02). Poly 1:C, an interferon inducer, stimulated NK activity in RA patients' PB and SF and control subjects' PB to similar extents. However, augmentation of NK activity by interleukin-2 was significantly greater in SF than in PB of RA (P<0.02). Preincubation of mononuclear cells with indomethacin significantly increased the NK activity of normal and RA PB but had no effect on that of SF. These observations suggest that the NK activity may be reduced in both PB and SF of RA and that functional differences between populations of cells with NK-like activity and/or differences in the control or modulation of NK activity exist between PB and SF. [ABSTRACT FROM AUTHOR]

. The genus Scymnodes is reviewed both taxonomically and biologically, and its nineteen constituent species placed into two subgenera. S.(Dolinus) Weise is made a subjective synonym of S. (Scymnodes) Blackburn, S.(Apolinus) is proposed as a new name for Platyomus Mulsant (nee Schoenherr) and Rhynchortalia wallacei Crotch is transferred to S. (Scymnodes) as a new combination. S.(S.)bellus, sp.n. is described. Its larva is also described and comparisons made with those of S.(A.)lividigaster and the platynaspine Phymatosternus lewisi (Crotch). Comments are made on the habits of the S.(S.)bellus larva, which was observed to feed on ants. [ABSTRACT FROM AUTHOR]

. Details of wax and wax-producing structures belonging to twenty species of coccinellid larvae, including members of the Scymnini, Ortaliini, Hyperaspini, Coccidulini, Noviini, Cryptognathini, Azyini and Telsimiini are described and/or illustrated with photographs taken by means of the scanning electron microscope. Published records of wax-production by larvae of Telsimiini and Chilocorini are examined and evaluated. The means by which wax precursors reach the outer surface of the epicuticle is discussed. Some of the physical properties of coccinellid and other waxes, such as their adhesiveness and UV reflectance, are recorded and the ecological significance of these factors is discussed. The contribution made by the present study to current opinion concerning the classification and possible phylogeny of the Coccinellidae is discussed and assessed. [ABSTRACT FROM AUTHOR]

. Wing-reduction among the Coccinellidae occurs in less than 100 species. Wing-polymorphism in Rhyzobius lirura (F.), R.chrysorneloides (Herbst) and Subcoccinella 24-punctuta (L.) varies throughout the geographical ranges of the species. The incidence of wing-polymorphism in British Subcoccinella has varied markedly over the last 160 years. Wing-polymorphism in Subcoccinella is not sex-linked and is under complex control, influenced in some way by environmental or population stability. [ABSTRACT FROM AUTHOR]

SUMMARY The average number of brain scans performed in this unit per month is 50. Of these 7H% are reported as normal. A survey has been made of a series of adult Technetium-99m brain scans reported as normal. An attempt lias been made to assess the variations in the normal pattern. The effect of potassium perchlorate in blocking the uptake of 99mTc by the thyroid gland and choroid plexus is evaluated. [ABSTRACT FROM AUTHOR]

SUMMARY A theoretical comparison is made between two different criteria of statistical significance for detecting abnormalities in a scan. Criterion I utilizes as much of the available information content as possible, while Criterion II is applicable to visual reading of a photoscan or colour-scan. The limits of detecting abnormalities with Criterion II is theoretically inferior to that with Criterion I. Using theoretical estimates of contrast for various sized abnormalities, the concentration ratio of 99mTcO4 in cerebral lesions is estimated from a number of scans. The mean concentration ratio was 6-5, assuming a log-normal distribution. [ABSTRACT FROM AUTHOR]

It may be concluded from the work of the committee during the past year that [ABSTRACT FROM AUTHOR]

The article offers information on surgical innovations for obstetric fistula patients. Topics discussed include restoration of the pubo-urethral ligament using a pubococcygeal sling or rectus sheath and recreation of the urethra with bladder smooth muscle, closing defect in bladder so that it can hold sufficient urine and tissue loss of the anterior vagina during surgery.

UK Bonfire Night (BFN) is an annual event on 5 November which celebrates the failed 'gunpowder plot' of Guy Fawkes, who intended to blow up the Houses of Parliament. This event is celebrated with firework and bonfire displays, which reduce visibility and increase air pollutant concentrations. A two- to four-fold increase in particulate matter concentrations was seen at some surface monitoring sites. Satellite measurements of aerosol optical depth found increases of 10-90% between days before and after BFN. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "The World Health Organisation surgical safety checklist," by D. Karamchandani and G. W. McGarry in the 2010 issue.

Objective: Characterise VLS and obstetric considerations among women during pregnancy, parturition and postpartum., Design: Retrospective cross-sectional online survey, 2022., Setting: International, English-speakers., Population: Self-identified individuals aged 18-50 diagnosed with VLS with symptom onset prior to pregnancy., Methods: Participants recruited from social media support groups and accounts, completed a 47-question survey including yes/no, multiple answer, and free-text responses. Data were analysed with frequency, means and the Chi-square test., Main Outcome Measures: VLS symptom severity, mode of delivery, perineal laceration, source and sufficiency of information provided about VLS and obstetrics, anxiety about delivery, and postpartum depression., Results: Of 204 responses, 134 met inclusion criteria, encompassing 206 pregnancies. Mean respondent age was 35 years (SD 6) and mean age of VLS symptom onset, diagnosis and birth, was 22 (SD 8), 29 (SD 7) and 31 (SD 4) years, respectively. Symptoms decreased in 44% (n = 91) of pregnancies and increased during the postpartum period in 60% (n = 123). In all, 67% (n = 137) of pregnancies resulted in vaginal birth and 33% (n = 69) in caesarean birth. Anxiety for delivery due to VLS symptoms was reported by 50% (n = 103); 31% (n = 63) experienced postpartum depression. Of respondents previously diagnosed with VLS, 60% (n = 69) used topical steroids prior to pregnancy, 40% (n = 45) were treated during pregnancy and 65% (n = 75) postpartum. In all, 94% (n = 116) reported receiving an insufficient amount of information on the topic., Conclusion: In this online survey, we found reported symptom severity remained unchanged or decreased during pregnancy, but increased postpartum. Use of topical corticosteroids decreased during pregnancy compared with before and after pregnancy. Half of the respondents reported anxiety regarding VLS and delivery., (© 2023 John Wiley & Sons Ltd.)

Objective: To describe and compare baseline renal anatomy and renal function in patients with obstetric fistulas, and to evaluate whether preoperative renal testing and imaging may aid with operative decision making., Design: A prospective cohort study., Setting: Fistula Care Centre in Malawi., Population: Women with an obstetric fistula., Methods: Baseline creatinine testing and renal ultrasounds were performed. Surgeons completed a short questionnaire on the usefulness of creatinine and renal ultrasound on operative decision making., Main Outcome Measures: Baseline creatinine and renal ultrasound findings., Results: Four surgeons performed operations on 85 patients. The mean creatinine in patients with vesicovaginal fistulas (VVF) was 0.60 ng/ml versus patients with uretero-vaginal fistulas (UVF) (0.79 ng/ml, P = 0.012). When a grade 3 or more hydronephrosis is absent on renal ultrasound, the negative predictive value of the presence of UVF is 93.3% (95% confidence interval [CI] 88.6-96.2) with a specificity of 97.2% (95% CI 90.3-99.6). In cases of UVF, surgeons found the renal ultrasound results useful or very useful 87.5% of the time, and the creatinine useful or very useful 75% of the time., Conclusion: In this pilot study, most patients with obstetric fistulas presented with a normal creatinine. In the absence of a grade 3 hydronephrosis or above on renal ultrasound, the probability of not having a UVF is 93.3%. Surgeons should consider performing preoperative renal ultrasound testing in all patients with an obstetric fistula, particularly in women with a prior laparotomy, as this population has risk factors for ureterovaginal fistula., Tweetable Abstract: Most patients with obstetric fistulas have normal renal function. Preoperative renal ultrasounds should be performed., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Objective: A number of non-HLA loci that have shown evidence (P < 0.05) for linkage with rheumatoid arthritis (RA) have been previously identified. The present study attempts to confirm these findings., Methods: We performed a second genome-wide screen of 256 new multicase RA families recruited from across the United States by the North American Rheumatoid Arthritis Consortium. Affected sibling pair analysis on the new data set was performed using SIBPAL. We subsequently combined our first and second data sets in an attempt to enhance the evidence for linkages in a larger sample size. We also evaluated the impact of covariates on the support for linkage, using LODPAL., Results: Evidence of linkage at 1p13 (D1S1631), 6p21.3 (the HLA complex), and 18q21 (D18S858) (P < 0.05) was replicated in this independent data set. In addition, there was new evidence for linkage at 9p22 (D9S1121 [P = 0.001]) and 10q21 (D10S1221 [P = 0.0002] and D10S1225 [P = 0.0038]) in the current data set. The combined analysis of both data sets (512 families) showed evidence for linkage at the level of P < 0.005 at 1p13 (D1S1631), 1q43 (D1S235), 6q21 (D6S2410), 10q21 (D10S1221), 12q12 (D12S398), 17p13 (D17S1298), and 18q21 (D18S858). Linkage at HLA was also confirmed (P < 5 x 10(-12)). Inclusion of DRB1*04 as a covariate significantly increased the probability of linkage on chromosome 6. In addition, some linkages on chromosome 1 showed improved significance when modeling DRB1*04 or rheumatoid factor positivity as covariates., Conclusion: These results provide a rational basis for pursuing high-density linkage and association studies of RA in several regions outside of the HLA region, particularly on chromosomes 1p, 1q, and 18q.

Objective: In patients with rheumatoid arthritis (RA), chemokines and their receptors are important for lymphocyte trafficking into the inflamed joint. This study was undertaken to characterize the expression of chemokine receptors CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CXCR3, and CX3CR1 in normal (NL) peripheral blood (PB), RA PB, and RA synovial fluid (SF)., Methods: Using flow cytometry, immunohistochemistry, and 2-color immunofluorescence, we defined the expression of chemokine receptors on CD3+ T lymphocytes in RA synovial tissue (ST), RA SF, RA PB, and NL PB., Results: The percentage of CD3+ lymphocytes expressing CCR2, CCR4, CCR5, and CX3CR1 was significantly elevated in RA PB compared with that in NL PB, while the percentage of CD3+ lymphocytes expressing CCR5 was significantly enhanced in RA SF compared with that in NL and RA PB. In contrast, similar percentages of CD3+ lymphocytes in NL PB, RA PB, and RA SF expressed CCR6 and CXCR3. Immunohistochemistry of RA ST showed lymphocyte expression of CCR4, and 2-color immunofluorescence staining revealed RA ST CD3+ lymphocytes intensely immunoreactive for CXCR3, suggesting that these 2 receptors may be particularly important for CD3+ lymphocyte trafficking to the inflamed joint. In comparisons of chemokine receptor expression on naive (CD45RA+) and memory (CD45RO+) CD3+ lymphocytes, there were greater percentages of memory CD3+/CD4+ lymphocytes expressing CCR4, CCR5, and CXCR3 than naive CD3+/CD4+ lymphocytes in RA PB and RA SF, and greater percentages of memory CD3+/CD8+ lymphocytes expressing CCR4, CCR5, and CXCR3 than naive CD3+/CD8+ lymphocytes in RA SF, suggesting receptor up-regulation upon lymphocyte activation. In contrast, percentages of CD3+/CD8+ memory lymphocytes expressing CX3CR1 were significantly less than percentages of naive CD3+/CD8+ lymphocytes in RA PB, suggesting that this receptor may be down-regulated upon lymphocyte activation. A major difference between the RA PB and NL PB groups was significantly more CCR4+ memory leukocytes and memory CCR5+/ CD3+/CD8+ lymphocytes in RA PB than NL PB, further suggesting that these receptors may be particularly important for lymphocyte homing to the RA joint., Conclusion: These results identify CCR4, CCR5, CXCR3, and CX3CR1 as critical chemokine receptors in RA.

Objective: To examine the relationship between apoptosis and the expression of antiapoptotic proteins in the pathogenesis of experimental inflammatory arthritis., Methods: Clinical and histologic assessment of adjuvant-induced arthritis (AIA) was performed over a 42-day period. The induction of apoptosis was measured by TUNEL analysis, and the antiapoptotic proteins, Bcl-2 and FLIP, were examined by immunohistochemistry with the use of monospecific antibodies. The percentage of Bcl-2- and FLIP-positive cells was correlated with histologic markers of AIA., Results: Arthritis developed by day 14 following adjuvant injection. Few TUNEL-positive cells were observed between days 0 and 21, indicating that apoptosis did not occur at these time points. An increase in the number of TUNEL-positive cells was observed at day 28, particularly outside sites of cartilage or bone erosion, which dramatically declined by day 35. Immunohistochemical analyses of Bcl-2 and FLIP revealed that the synovium was positive for Bcl-2 and FLIP on day 0. On day 14, Bcl-2 was present at the sites of early erosions and correlated with the erosion and inflammation scores. FLIP was also highly expressed at sites of erosion and was localized to the pannus starting on day 21. Although TUNEL positivity peaked at day 28, a time point in which Bcl-2 and FLIP were present, the areas that displayed intense positivity for expression of Bcl-2 and FLIP were TUNEL negative. In addition, the number of neutrophils in the synovial lining and pannus significantly decreased from day 28 to day 35, suggesting that the cells undergoing apoptosis were neutrophils. Furthermore, at day 42 when TUNEL-positive cells were absent, Bcl-2 expression was diminished, while FLIP remained highly expressed in the pannus., Conclusion: The overall percentage of TUNEL-positive cells in the ankle was <1% except on days 28 and 35 post-adjuvant injection, suggesting that in AIA, similar to rheumatoid arthritis, a lack of apoptosis may contribute to disease progression. Furthermore, Bcl-2 and FLIP are temporally and differentially expressed during the pathogenesis of AIA. Inhibition of these molecules may augment synovial apoptosis and ameliorate the disease.

Objective: Since it is likely that monocytes utilize chemokines to migrate to the rheumatoid arthritis (RA) joint, we investigated the expression of C-C chemokine receptors (CCR) 1-6 and C-X-C receptor 3 (CXCR3) in the peripheral blood (PB), synovial fluid (SF), and synovial tissue of patients with RA as well as in the PB of normal subjects., Methods: We compared chemokine receptor expression on CD14+ monocytes from normal PB, RA PB, and RA SF using 2-color flow cytometry. Correlations with patient clinical data were determined. Chemokine and receptor expression were investigated in RA synovial tissue by immunohistochemistry and 2-color immunofluorescence to identify CD68+ macrophages., Results: Most normal PB monocytes expressed CCR1 (87%) and CCR2 (84%), but not CCRs 3, 4, 5, or 6 or CXCR3. RA PB monocytes expressed CCR1 (56%) and CCR2 (76%), with significantly more expressing CCR3 (18%), CCR4 (38%), and CCR5 (17%) compared with normal PB monocytes. Significantly fewer SF monocytes from RA patients expressed CCR1 (17%), CCR2 (24%), and CCR4 (6%) while significantly more expressed CCR3 (35%) and CCR5 (47%) compared with RA and normal PB monocytes; CCR6 and CXCR3 were rarely detected. Clinically, the erythrocyte sedimentation rate was inversely correlated with the expression of CCR1 and CCR4 by RA PB, and CCR5 expression by RA SF was correlated with the SF white blood cell count. CCR1-, CCR2-, and CCR5-immunoreactive cells were found in RA synovial tissue and colocalized with CD68+ macrophages. RA synovial tissue RANTES (regulated upon activation, normally T cell expressed and secreted chemokine)- and monocyte chemoattractant protein 1-immunoreactive cells colocalized with CCR1 and CCR2, respectively, on serial sections. Macrophage inflammatory protein 1alpha (MIP-1alpha) was principally restricted to vascular endothelium, and MIP-1beta+ macrophages were found throughout the sections., Conclusion: Monocytes mainly express CCR1 and CCR2 in normal and RA PB, CCR3 and CCR5 in RA PB and RA SF, and CCR4 in RA PB. The differential expression of chemokine receptors suggests that certain receptors aid in monocyte recruitment from the circulation while others are important in monocyte retention in the joint.

Objective: The chronic inflammation and progressive joint destruction observed in rheumatoid arthritis (RA) are mediated in part by macrophages. A paucity of apoptosis has been observed in RA synovial tissues, yet the mechanism remains unknown. The present study sought to characterize the expression of Fas, Fas ligand (FasL), and Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (FLIP), and to quantify the apoptosis induced by agonistic anti-Fas antibody, using mononuclear cells (MNC) isolated from the peripheral blood (PB) and synovial fluid (SF) of RA patients., Methods: The expression of Fas, FasL, and FLIP and apoptosis induced by agonistic anti-Fas antibody in MNC from the PB and SF of RA patients were determined by flow cytometry. Immunohistochemistry employing a monospecific anti-FLIP antibody was performed on RA and osteoarthritis (OA) synovial tissue., Results: CD14-positive monocyte/macrophages from normal and RA PB and from RA SF expressed equivalent levels of Fas and FasL. Furthermore, unlike the CD14-positive PB monocytes, RA SF monocyte/macrophages were resistant to the addition of agonistic anti-Fas antibody. In contrast, both CD14-positive PB and SF monocyte/macrophages were sensitive to apoptosis mediated by a phosphatidylinositol 3-kinase inhibitor. Intracellular staining of the caspase 8 inhibitor, FLIP, in CD14-positive SF monocyte/macrophages revealed a significant up-regulation of FLIP compared with normal and RA PB monocytes. Immunohistochemical analysis of synovial tissue from RA and OA patients revealed increased FLIP expression in the RA synovial lining compared with the OA synovial lining. Furthermore, FLIP expression was observed in the CD68positive population in the RA synovial lining. Forced reduction of FLIP by a chemical inhibitor resulted in RA SF macrophage apoptosis that was enhanced by agonistic anti-Fas antibody, indicating that FLIP is necessary for SF macrophage survival., Conclusion: These data suggest that up-regulation of FLIP in RA macrophages may account for their persistence in the disease. Thus, the targeted suppression of FLIP may be a potential therapeutic strategy for the amelioration of RA.

Objective: To determine the expression of matrix metalloproteinase 9/gelatinase B (MMP-9) in synovial fluid (SF), plasma, and synovial tissue from individuals with rheumatoid arthritis (RA), inflammatory arthritis (IA), and osteoarthritis (OA), using specific monoclonal antibody reagents., Methods: Gelatinolytic activity in the SF and plasma of patients with RA, IA, and OA was assessed by gelatin zymography. A mouse monoclonal antiserum, 277.13, which selectively recognizes soluble latent forms of human MMP-9, was used to quantitate MMP-9 levels in patient synovial effusions, plasma, and synovial tissue with a capture sandwich enzyme-linked immunosorbent assay (ELISA). Fifty-one SF samples (31 RA, 9 OA, 11 IA) were analyzed. Immunolocalization of MMP-9 in RA, OA, and normal synovium was investigated using MMP-9-specific antisera., Results: MMP-9 antigen levels in synovial effusions were elevated 67-fold in RA samples compared with OA samples. In addition, although MMP-9 antigen levels in IA synovial effusions were 2.7-fold less than the values in RA samples, they were elevated 34-fold over the values in OA samples. These data indicate an association between increased MMP-9 levels and inflammatory arthritis. A predominant 92-kd gelatinolytic activity (specifically inhibited by EDTA) was evident in RA and IA samples, but no activity was observed in OA samples. Among 86 plasma samples (17 RA, 9 IA, 60 normal controls) analyzed for MMP-9 antigen levels by immunocapture ELISA, MMP-9 antigen levels were elevated 7-fold in RA plasma compared with normal plasma. RA synovial tissue extracts demonstrated elevated levels of MMP-9 antigen compared with OA synovial tissue. MMP-9 immunolocalization studies demonstrated expression in infiltrating leukocytes (neutrophils and macrophages), endothelial cells, and synovial fibroblasts in RA synovium., Conclusion: Latent MMP-9 and/or MMP-9-tissue inhibitor of metalloproteinases 1 (TIMP-1) complexes are elevated in RA and IA SF compared with OA SF. In addition, MMP-9 is increased in RA plasma versus normal control plasma. Synovial tissue levels of MMP-9 antigen are also elevated in RA versus OA. The tissue distribution of MMP-9 within RA synovium is localized to sites of inflammation comprising surface synovial lining cells, endothelium, and leukocytes. Taken together, these observations suggest that connective tissue turnover occurs as a result of excessive MMP activity over TIMP action in the invading pannus, periarticular tissue, or SF. Further studies such as those used in the present investigation will help elucidate the role of a number of different enzymes and inhibitors in the destructive arthropathies.

Objective: Angiogenesis is an integral component of the vasculoproliferative phase of rheumatoid arthritis (RA). Recently, a heparin-binding cytokine termed hepatocyte growth factor (HGF), or scatter factor (due to its ability to disperse cohesive epithelial colonies), was described. We conducted this study to investigate the hypothesis that this cytokine was present in the milieu of the inflamed joint, and that it contributed to the chemotaxis of endothelial cells in the synovial tissue., Methods: We examined synovial fluid, synovial tissue, and peripheral blood from 91 patients with RA and other arthritides. We used 83 total samples in an enzyme-linked immunosorbent assay to quantitate the HGF in synovial fluids and peripheral blood. To determine whether the HGF was biologically active, an epithelial scatter factor assay was performed. Immunohistochemical analysis was used to determine localization in synovial tissues. To define a function for synovial HGF, we preincubated rheumatoid synovial fluids with neutralizing anti-HGF and measured the ability of these synovial fluids to induce endothelial chemotaxis., Results: Synovial fluid from patients with RA contained a mean +/- SEM HGF concentration of 2.0 +/- 0.3 ng/ml, while synovial fluid from patients with other arthritides (including inflammatory arthritis) contained 2.4 +/- 0.7 ng/ml HGF. Osteoarthritis (OA) patient samples contained the smallest quantities of synovial fluid HGF at 0.9 +/- 0.1 ng/ml. RA synovial fluid contained significantly more HGF than did RA peripheral blood (1.1 +/- 0.2 ng/ml) (P < 0.05). Rheumatoid synovial fluids induced more scattering of cells than did OA synovial fluids, suggesting a role for this cytokine in rheumatoid joint destruction. Interleukin-1 beta induced expression of rheumatoid synovial tissue fibroblast antigenic HGF and scatter factor activity. Immunohistochemically, HGF, as well as the HGF receptor (the met gene product), localized to significantly more rheumatoid synovial tissue lining cells than normal lining cells (P < 0.05). Both HGF and its receptor immunolocalized to subsynovial macrophages as well. Levels of synovial tissue immunoreactive HGF correlated positively with the number of synovial tissue blood vessels. Anti-HGF neutralized a mean of 24% of the chemotactic activity for endothelial cells found in 10 rheumatoid synovial fluid samples., Conclusion: These results indicate that synovial HGF may contribute to the vasculoproliferative phase of inflammatory arthritides such as RA, by inducing HGF-mediated synovial neovascularization. These findings point to a newly described role for HGF in the fibroproliferative phase of RA-associated synovitis.

Objective: To determine the safety and efficacy of recombinant soluble human interleukin-1 receptor type I (rHuIL-1RI) administered subcutaneously in patients with active rheumatoid arthritis (RA)., Methods: Twenty-three patients with active RA (>5 swollen joints) were enrolled into a randomized, double-blind, 2-center study. Patients received subcutaneous doses of rHuIL-1RI or placebo for 28 consecutive days. Patients were treated with 125, 250, 500, or 1,000 micrograms/m2/day of rHuIL-1RI. Physical examinations and laboratory assessments were performed at baseline (day 1), and 8, 15, 22, 29, 43, and 57 days after the start of the study. Analysis of peripheral blood by flow cytometry was performed on days 1 and 29 to determine the effects of rHuIL-1RI on the distribution and phenotypic characteristics of circulating inflammatory cells., Results: Four of 8 patients who received rHuIL-1RI at 1,000 micrograms/m2/day demonstrated improvement in at least 1 of 8 individual measures of disease activity; however, only 1 of these 4 patients experienced clinically relevant improvement as defined by predetermined criteria. None of the patients treated with smaller doses of rHuIL-1RI, and none of the placebo-treated control patients, experienced any improvement as defined by the predetermined criteria. Monocyte cell surface IL-1alpha was significantly reduced following treatment with rHuIL-1RI at each dosage. Administration of rHuIL-1RI was stopped prematurely because of dose-limiting rashes in 2 patients treated with 1,000 micrograms/m2/day. No other adverse events prevented completion of the study., Conclusion: Only 1 patient, who was treated with the highest concentration of rHuIL-1RI employed (1,000 micrograms/m2/day), demonstrated clinically relevant improvement in this phase I study on this small group of patients with active RA. Dose-limiting toxicity was also observed in 2 patients treated with this highest concentration of rHuIL-1RI. Treatment with rHuIL-1RI did result in a reduction of monocyte cell surface IL-1alpha, which indicates that the dosages of rHuIL-1RI employed were functional.