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ID PMID Title PublicationDate abstract
10798713 Evidence for oxidised low density lipoprotein in synovial fluid from rheumatoid arthritis 2000 Jun The oxidative modification of human LDL has been implicated in atherosclerosis, but the mechanisms by which such modification occurs in vivo are not fully understood. In the present study, we have isolated LDL from knee-joint synovial fluid of patients with rheumatoid arthritis. We demonstrate that such LDL is oxidatively modified as evidenced by an increased negative charge, distorted particulate nature and more rapid degradation by cultured macrophages. These results indicate that formation of oxidised LDL is associated with the local inflammatory response. Because the cellular interactions in rheumatoid arthritis have analogies with those in atherogenesis, we suggest that the rheumatoid joint is a useful model of atherosclerosis in which the in vivo process of LDL oxidation may be readily studied.
11394667 Primary sclerosing cholangitis associated with rheumatoid arthritis and HLA DR4: is the as 2001 Apr In four cases we describe the unique association of primary sclerosing cholangitis (PSC) and rheumatoid arthritis (RA). In three of the cases the liver disease was unusually progressive, proceeding to cirrhosis in 14, 18 and 48 months from diagnosis. The three cases with progressive liver disease and ulcerative colitis were all HLA type DR4. The fourth patient also suffered from coeliac disease in addition to PSC and RA and has remained asymptomatic over 7 years of follow-up. RA in association with PSC may serve as a clinical marker of patients at high risk of progression to cirrhosis who need to be kept under particularly close observation. In addition, PSC needs to be considered in the differential diagnosis of all patients with RA and cholestatic liver function tests. This is especially important given the link between PSC and an increased risk of colonic carcinoma, and thus the need for surveillance colonoscopy.
10925599 [Bilateral breast masses]. 2000 Jun A 76 year old woman is hospitalized for bilateral breast masses and neurological impairment. Her medical history is marked by rheumatoid arthritis treated with gold salts and methylprednisolone. Blood tests reveal pancytopenia; the MRI scan of the brain is suggestive of a CNS lymphoma. The pathologic examination of a breast mass specimen confirms the lymphoid nature of the neoplasm. This case report highlights the multifocal or systemic nature of non hodgkin's lymphoma and the diagnostic pitfalls of breast lymphomas. Rheumatoid arthritis and its medical management are reviewed for their possible roles in oncogenesis.
9081245 Temporomandibular joint involvement in generalized osteoarthritis and rheumatoid arthritis 1997 Feb Twenty patients having generalized osteoarthritis (GOA) and symptomatic temporomandibular joints (TMJs) were compared with 22 patients having rheumatoid arthritis (RA) and TMJ symptoms, and also with an age-matched reference tissue material obtained at autopsy from 17 TMJs. Muscle tenderness was commoner in GOA. Arthroscopically, high frequencies of synovitis, degenerative changes, and fibrosis were observed in both groups, with more pronounced inflammatory and degenerative changes in RA patients, despite a shorter duration of TMJ symptoms. A correlation was noted between lateral joint tenderness and pronounced synovitis in RA patients. Histologic and immunohistochemical examinations added useful information to arthroscopy and showed similarly high frequencies of synovial inflammation in GOA and RA patients, differing clearly from those in the reference material. Connective-tissue degeneration was commoner in GOA patients. GOA and RA probably have different causes, but, interestingly, the tissue reaction was similar in the TMJs, although pronounced inflammatory and degenerative changes seemed to develop faster in RA.
11845474 The migratory and phagocytic activity of polymorphonuclear leukocytes in rheumatoid arthri 2000 Jan Polymorphonuclear neutrophils (PMN) play a central role in the elimination of most extracellular pathogenic microorganisms and any impairment of their functions therefore predisposes to defect immune defence. We investigated the migratory and phagocytic functions of the PMNs isolated from peripheral blood and synovial fluid of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The results suggest that in RA the number and the migratory but not phagocytic capacity of synovial fluid (SF) neutrophils were enhanced, while in OA they were significantly decreased in synovial fluid cells comparatively with peripheral blood (PB). The migratory function of both PB and SF cells from RA patients was increased comparatively with that of the cells from OA patients. We found the different abnormal functions in synovial fluid neutrophils from RA and OA patients. These results may help to elucidate the underlying mechanism which leads to severe joint destruction and different susceptibility to infectious diseases in patients with rheumatic disorders.
11094433 Association of MHC and rheumatoid arthritis. Association of RA with HLA-DR4: the role of r 2000 Most patients with rheumatoid arthritis (RA) express HLA-DR4, HLA-DR1 or HLA-DR10. These alleles share a common amino acid motif in their third hypervariable regions: the shared epitope. In normals and patients with RA, HLA-DR genes exert a major influence on the CD4 alpha beta T-cell repertoire, as shown by studies of AV and BV gene usage and by BV BJ gene usage by peripheral blood CD4 alpha beta T-cells. However, the rheumatoid T-cell repertoire is not entirely under HLA-DR influence, as demonstrated by discrepancies in VB JB gene usage between identical twins discordant for RA and by contraction of the CD4 alpha beta T-cell repertoire in RA patients. Shared epitope positive HLA-DR alleles may shape the T-cell repertoire by presenting self peptides to CD4 T cells in the thymus. Peptides processed from HLA-DR molecules and encompassing the shared epitope may also be presented by HLA-DQ and select CD4 alpha beta T cells in the thymus. Thus, shared epitope-positive alleles impose a frame on the T-cell repertoire. This predisposing frame is further modified (by unknown factors) to obtain the contracted rheumatoid repertoire.
15359509 Ultrasonographic evaluation of knee joint cartilage in rheumatoid arthritis patients. 2000 The non-invasive methods used to study joint cartilage are restricted in their scope. No direct visualization of the joint cartilage is possible in conventional radiology and tomography and the decrease in joint space is only indirect evidence for joint destruction. CT is a radiologic method for direct visualization of joint cartilage but its diagnostic precision in the evaluation of early cartilage lesions is limited because it can not produce an image in a plane other than the transversal plane perpendicular to the direction of the main axis of the body and because it has limited spatial resolution. Other methods for direct visualization of joint cartilage are arthrography and arthroscopy which are little used in clinical practice because of their invasiveness and limited indications. MRI is a promising technique but its usage is limited by the high price and limited accessibility. Our object in the present study was to evaluate the significance of arthro-sonography in the diagnosis of early arthritic lesions of knee cartilage, based on the ultrasonographic assessment of the joint surface and cartilage thickness. Femoral cartilage was our choice for the study as there is statistically well documented high incidence of early arthritic changes in this area; moreover, the area is easily accessible for ultrasound evaluation using a scan perpendicular to the articular surface, incl. the cases with complete flexion of the knee joint, where the pressure areas of the condyles are apositioned to the tibial plateau. Using a 7.5 MHz transducer we managed to measure and document early arthritic changes in joint thickness and the contour of the joint surfaces before they can be detected using routine radiologic methods.
11312385 Mortality in rheumatoid arthritis: relationship to single and composite measures of diseas 2001 Apr BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous disease characterized by a variable course of remissions and relapses. Single measures of disease activity at only one point in time may not reflect the overall control of disease activity. OBJECTIVE: The aim was to determine (i) the predictive value of 20 baseline demographic and disease variables on mortality, and (ii) the relationship between serial measures of the Stoke index (SI; a validated index of disease activity in RA) and mortality in RA. METHODS: Mortality in 309 RA patients followed up for a median of 14 yr was analysed retrospectively. The standardized mortality ratio (SMR) was calculated for all causes of death. The predictive values of baseline and time-integrated variables were assessed using multivariate Cox proportional hazards regression analysis. RESULTS: The SMR was 1.65. At baseline, only nodules, erosions, RA latex titre, white cell count and globulin level were predictive of mortality after correction for age, sex and disease duration. Using a stepwise Cox proportional hazards regression model, the most powerful predictors of mortality were age, nodules and RA latex titre. Individual measures of disease activity and the SI at baseline were not predictive of mortality. However, the mean level of the SI over 12 months was related to mortality (P=0.039). CONCLUSIONS: At baseline, the demographic and disease variables most significantly related to mortality in RA are age, nodules and RA latex titre. Individual measures of disease activity at a single point in time are poor predictors of mortality in RA. However, measurement of the mean level of disease activity over time using the composite SI has a significant relationship with mortality. A high level of sustained inflammation appears to be an important predictor of premature death.
10023863 Antibodies against macaque monoclonal immunoglobulin G in rheumatoid arthritis. 1999 Jan The presence of rheumatoid factors (RF) in the serum of rheumatoid arthritis (RA) patients is commonly evidenced by agglutination tests: the Waaler-Rose assay, based on the use of human red blood cells (RBCs) coated with rabbit anti-RBC antibodies, and the latex test, which uses latex particles coated with denatured human immunoglobulin G (IgG). The aim of the present study was to characterize the RF able to agglutinate human RBCs coated with macaque antihuman RBC IgG antibodies secreted from macaque-mouse heterohybridomas (two from rhesus monkey and one from crab-eating macaque). Human RBCs coated with macaque monoclonal antibodies (MacMoAbs) were used for agglutination tests and these were carried out in parallel with standard tests (Waaler-Rose and latex agglutination tests) on sera from 82 RA patients, 86 patients with other forms of inflammatory chronic arthritis and 47 healthy human subjects. MacMoAb-coated RBCs identified RF in the sera of 66% patients with RA. By contrast, the frequency of positive sera in other inflammatory diseases was 5% and all 47 healthy controls were negative. Antimacaque IgG antibodies were found to be more specific for RF than standard tests, in the sera of patients with RA.
11764389 Loss of collagen type IV in rheumatoid synovia and cytokine effect on the collagen type-IV 2001 Nov Collagen type IV is a structural matrix protein which contributes to the structural organization of the synovia. In order to characterize the distribution of this protein in synovia with chronic synovitis, collagen type IV was detected by immunochemistry in normal synovia and in synovia from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). A decrease of collagen type IV was observed in synovial layers of rheumatoid synovia, which statistically correlated with the grade of inflammation and with the thickness of the synovial layer. In vitro, we found no differences in the gene expression of collagen type IV in cultures of fibroblast-like synoviocytes (FLS) derived from OA and RA using a reverse-transcriptase polymerase chain reaction. Nevertheless, we observed a downregulating effect of tumor necrosis factor-alpha and interleukin (IL)-1beta on the gene expression of collagen type IV only in FLS isolated from patients with RA. The effect of IL-1beta was dose dependent. In summary, we observed an inflammation-associated decrease of collagen type IV in the synovial layer of rheumatoid synovia. Inflammatory cytokines may play a role in regulating the synthesis of collagen type IV in the rheumatoid process in vivo.
10071584 Total knee replacement: should it be cemented or hybrid? 1999 Feb OBJECTIVE: To compare the complication rates associated with total knee arthroplasty against the types of fixation (hybrid or cemented), using a single total knee design (the anatomic modular knee [AMK] prosthesis). DESIGN: A prospective, nonrandomized, controlled trial. SETTING: University Hospital in London, Ont., a tertiary care teaching centre. PATIENTS: Two groups made up of 484 knees in 395 patients (89 bilateral). INTERVENTIONS: In 260 knees a hybrid configuration (cemented tibia and noncemented femur) was used (group 1). In 224 knees the femoral and tibial components were cemented (group 2). All patellae were cemented in both groups. MAIN OUTCOME MEASURES: Clinical results were assessed by The Knee Society Clinical Rating Scores at 3 months, 6 months and yearly intervals. Radiographic results were determined by 3-foot standing radiographs and at each follow-up visit standing knee radiographs, lateral and skyline views. Radiographs were analysed for alignment, presence or absence of radiolucent lines or changes in the position of the implant. All reoperations and nonoperative complications were recorded. RESULTS: At an average follow-up of 4.8 years, 8 knees (1.6%) required reoperation. An analysis of the complications leading to reoperation demonstrated no difference between the 2 groups. CONCLUSIONS: There was no difference in outcome whether the femoral component was cemented or not. Medium-term results of the AMK are excellent with a very low reoperation rate.
9417760 [Follow-up studies after bicondylar superficial replacement of rheumatoid knee joint destr 1997 Jul This study documents prospectively the Knee Society knee- and function score of 28 patients with rheumatoid arthritis with 34 PFC unconstrained total knee arthroplasties from preoperative values on at yearly intervals. The average follow-up period was 3.4 years (range 2-5.5 y). At last follow-up over 80% of the knees were painfree. All but one patient could walk more than 500 m. Knee and function score increased significantly from 30.1 resp. 35.0 to 83.8 resp. 74.6 (P < 0.000001). Postoperatively the knee score rose soon to a constant level whereas the function score showed a continuous slow increase up to 5 years. We observed one deep venous thrombosis and one subluxation. At an intermediate follow-up rheumatoid knees are clinically and functionally successfully operated on using an unconstrained TKA. Pain relief is excellent. We recommend the use of a scoring system assessing knee and functional results separately.
10855291 [Radiographic course of 39 rheumatoid wrists after synovectomy and stabilization]. 1998 Between 1984 and 1995, 39 patients underwent wrist synovectomy-stabilisation. Among these patients, 5 had died and 2 could not rectum for review. These 7 patients were excluded from the study. 32 patients were therefore included in the study. These patients had an average age of 50 years, with an average follow-up of 65 months. We used the Larsen classification to assess wrist osteo-articular involvement. To evaluate carpal instability, we measured: the carpal height with the Mac Murtry index, Shapiro's angle and the modified Shapiro's angle (the angle between the radial diaphysis and the second metacarpal diaphysis), the angle of finger ulnar deviation, the carpal ulnar deviation with the ulnar deviation index of the carpus, the radial deviation with the radial deviation index of the carpus, the carpal frontal dislocation. Carpitis continued to develop and Larsen's grade deteriorated in 50% wrists despite surgery. The average value of the radial sliding index of the carpus increased from 0.11 to 0.15: this showed an average ulnar sliding of 2.2 mm. The average Shapiro's angle increased from 118.2 degrees to 125 degrees. At follow-up, we observed anterior translation of the carpal bones and an increased distance between the proximal and distal carpal rows. The distance between the proximal and distal rows of the carpus appeared to be corrected by extensive synovectomy. Radio-carpal and mid-carpal synovectomy increased the carpal ulnar sliding. The modified Shapiro's angle was corrected by transfer of the extensor carpi radialis longus onto the extensor carpi radialis brevis. In contrast with other operations without stabilisation, the Sauvé-Kapandji procedure limited ulnar sliding and radial tilting of the carpus. Stabilisation of the carpus therefore participates in control of ulnar deviation of the long fingers. Transfer of the extensor carpi radialis longus onto the extensor carpi radialis brevis seems effective on wrist relaxation, by medialization of the traction force of the extensor carpi radialis longus. Our results with of Larsen stage IV were encouraging. The indication for wrist arthrodesis could be limited to stage IV with radio-carpal dislocation or stage V.
10648863 Analysis of immune system gene expression in small rheumatoid arthritis biopsies using a c 2000 Jan 13 Subtractive hybridization of cDNAs generated from synovial RNA which had been isolated from patients with rheumatoid arthritis (RA) or normal controls was used in conjunction with high-density array hybridization to identify genes of immunological interest. The method was designed to detect gene expression in small needle biopsy specimens by means of a prior amplification of nanogram amounts of total RNA to full-length cDNA using PCR. The latter was cut with Rsa I, ligated with adapters, hybridized with unmodified driver cDNA, and subjected to suppression subtraction PCR. Differentially expressed products were cloned into E. coli and picked into 384 well plates. Inserts were obtained by PCR across the multiple cloning site, and the products arrayed at high density on nylon filters. The subtracted cDNAs were also labelled by random priming for use as probes for library screening. The libraries chosen were the subtracted one described above and a set of 45,000 ESTs from the I.M. A.G.E consortium. Clones showing positive hybridization were identified by sequence analysis and homology searching. The results showed that the subtracted hybridization approach could identify many gene fragments expressed at different levels, the most abundant being immunoglobulins and HLA-DR. The expression profile was characteristic of macrophage, B cell and plasma cell infiltration with evidence of interferon induction. In addition, a significant number of sequences without matches in the nucleotide databases were obtained, this demonstrates the utility of the method in finding novel gene fragments for further characterisation as potential members of the immune system. Although RA was studied here, the technology is applicable to any disease process even in cases where amounts of tissue may be limited.
10600330 Mechanism of action for leflunomide in rheumatoid arthritis. 1999 Dec Leflunomide (Arava) has recently been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis (RA). This approval was based on data from a double-blind, multicenter trials in the United States (leflunomide versus methotrexate versus placebo) in which leflunomide was superior to placebo and similar to methotrexate (Strand et al., Arch. Intern. Med., in press, 1999). In a multicenter European trial, leflunomide was similar to sulfasalazine in efficacy and side effects (Smolen et al., Lancet 353, 259-266, 1999). Both methotrexate and leflunomide retarded the rate of radiolographic progression, entitling them to qualify as disease-modifying agents (Strand et al., Arch. Intern. Med., in press, 1999). Leflunomide is an immunomodulatory drug that may exert its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHODH by A77 1726, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of RA. We propose that leflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with the cell cycle progression due to inadequate production of rUMP and utilizing mechanisms involving p53. The relative lack of toxicity of A77 1726 on nonlymphoid cells may be due to the ability of these cells to fulfill their ribonucleotide requirements by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis.
9060847 Pannocytes: distinctive cells found in rheumatoid arthritis articular cartilage erosions. 1997 Mar A distinctive cell was identified from sites of rheumatoid arthritis cartilage injury. Similar cells are not found in lesions of osteoarthritis cartilage. We have designated them as pannocytes (PCs). Their rhomboid morphology differs from the bipolar shape of fibroblast-like synoviocytes or the spherical configuration of primary human articular chondrocytes. Chondrocytes are short-lived, whereas the original PC line grew for 25 passages before becoming senescent. Features in common with cultured primary chondrocytes include maximal proliferation in response to transforming growth factor-beta a catabolic response to interleukin-1 beta, collagenase production, and mRNA for the induced lymphocyte antigen and inducible nitric oxide synthase. Despite the presence of the inducible nitric oxide synthase message, PCs do not produce NO either constitutively or when cytokine stimulated. Each of the mesenchymal cells, fibroblast-like synoviocytes, primary chondrocytes, and PCs have the gene for type I collagen, but the type II collagen gene is detected only in primary chondrocytes. PCs can be distinguished from fibroblast-like synoviocytes and primary chondrocytes by their morphology, bright VCAM-1 staining, and growth response to cytokines and growth factors. Their prolonged life span in vitro suggests that PCs might represent an earlier stage of mesenchymal cell differentiation, and they could have a heretofore unrecognized role in rheumatoid arthritis joint destruction.
10442966 Rheumatoid arthritis-affected temporomandibular joint pain analgesia by linear polarized n 1999 Jul PURPOSE: To describe a new short-term treatment for pain in rheumatoid arthritis (RA)-affected temporomandibular joint (TMJ). CLINICAL FEATURES: We investigated four female patients (age 42.8+/-26.0 yr) with chronic rheumatoid arthritis affecting a single TMJ. Patients had received antirheumatic drugs such as sodium aurothiomalate, and as a result showed no symptoms in other body joints. Linear polarized near infrared radiation using Super Lizer was applied weekly with and/or without jaw movement to the unilateral skin areas overlying the mandibular fossa, anterior articular tubercle, masseter muscle and posterior margin of the ramus of the mandible. The duration of irradiation to each point was two seconds on and ten seconds off per cycle and the intensity at each point was approximately 138 J x cm(-2) at a wavelength of 830 nm. Interincisal distance was measured with maximal mouth opening in the absence and presence of pain before and after each treatment. Additionally, subjective TMJ pain scores assessed using a visual analog scale were performed for painful maximal mouth opening before and after each irradiation. TMJ pain disappeared after only four treatments. Moreover, painless maximal mouth opening without pain after irradiation in three patients was on average improved to 5.3+/-2.1 mm. However, one case was observed where the opening length prior to irradiation did not improve, despite the fact that the RA-affected TMJ pain had disappeared. CONCLUSION: Application of linear polarized near infrared irradiation to patients with RA-affected TMJ pain is an effective and non-invasive short-term treatment.
9546355 Identification of cell types responsible for bone resorption in rheumatoid arthritis and j 1998 Apr Focal resorption of bone at the bone-pannus interface is common in rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) and can result in significant morbidity. However, the specific cellular and hormonal mechanisms involved in this process are not well established. We examined tissue sections from areas of bone erosion in patients with RA and JRA. Multinucleated cells (MNCs) were present in resorption lacunae in areas of calcified cartilage and in subchondral bone immediately adjacent to calcified cartilage, as previously described. mRNA for the calcitonin receptor (CTR) was localized to these MNCs in bone resorption lacunae, a finding that definitively identifies these cells as osteoclasts. These MNCs were also positive for tartrate-resistant acid phosphatase (TRAP) mRNA and TRAP enzymatic activity. Occasional mononuclear cells on the bone surface were also CTR positive. Mononuclear cells and MNCs not on bone surfaces were CTR negative. The restriction of CTR-positive cells to the surface of mineralized tissues suggests that bone and/or calcified cartilage provide signals that are critical for the differentiation of hematopoietic osteoclast precursors to fully differentiated osteoclasts. Some MNCs and mononuclear cells off bone and within invading tissues were TRAP positive. These cells likely represent the precursors of the CTR-TRAP-positive cells on bone. Parathyroid hormone receptor mRNA was present in cells with the phenotypic appearance of osteoblasts, in close proximity to MNCs, and in occasional cells within pannus tissue, but not in the MNCs in bone resorption lacunae. These findings demonstrate that osteoclasts within the rheumatoid lesion do not express parathyroid hormone receptor. In conclusion, the resorbing cells in RA exhibit a definitive osteoclastic phenotype, suggesting that pharmacological agents that inhibit osteoclast recruitment or activity are rational targets for blocking focal bone erosion in patients with RA and JRA.
11580858 Polymorphism in codon 17 of the CTLA-4 gene (+49 A/G) is not associated with susceptibilit 2001 Jul The role of the CTLA-4 antigen in the development of autoimmune diseases is well documented, with several autoimmune disorders showing association or linkage with the CTLA-4 locus. Its role in the aetiology of rheumatoid arthritis (RA) however, remains unclear, as the functional studies of the B7-CTLA-4 pathway in mouse models of RA and genetic studies in humans have given contrasting results. We have studied the single nucleotide polymorphism at position +49 (A/G) of the CTLA-4 gene, in a cohort of 421 RA cases and 452 healthy controls from the UK. Despite the high statistical power to detect even a weak susceptibility effect, no significant association was found. We also analysed the distribution of the allele and genotype frequencies with respect to the presence of the shared epitope (a known RA susceptibility factor) and found no statistically significant differences. We conclude that, although the importance of the B7-CTLA-4 interaction in the development of RA can not be excluded, the CTLA-4 gene is unlikely to be a predisposing factor to this disease.
9519864 Decreased expression of signal-transducing CD3 zeta chains in T cells from the joints and 1998 Mar Although T cells from patients with rheumatoid arthritis (RA) have previously been determined to have poor proliferative responses to a variety of stimuli, the underlying mechanism is not known. We have investigated the expression of the signal-transducing zeta molecule in subsets of T cells and natural killer (NK) cells derived from the peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) of RA patients using quantitative flow cytometry, Western blot analysis and immunohistochemistry. A decrease of zeta expression was apparent in all investigated lymphocyte subsets from the PBMC and SFMC of RA patients, as compared to the corresponding subsets from healthy age- and sex-matched controls. A less pronounced reduction of cell surface-located CD3 epsilon, CD4 and CD8 was also located in T cells from SFMC as compared to PBMC from RA patients. Biochemical demonstration of the low or absent CD3 zeta in PBMC from patients with RA was achieved by Western blot analysis. Immunohistochemical staining and image analysis also confirmed the low expression of zeta chains in synovial tissue of RA patients. The possibility that the decreased expression of zeta and of immune functions of T cells from RA patients may be related to the presence of free oxygen radicals, as we have previously reported in cancer patients, should be considered.