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ID PMID Title PublicationDate abstract
12123563 Clinical features of forty patients with primary biliary cirrhosis. 2002 Jun OBJECTIVE: To study the clinical features of patients with primary biliary cirrhosis (PBC) in order to improve the doctors' awareness of the disease. METHODS: General status, clinical manifestations and laboratory findings of 40 patients with PBC were reviewed.Thirty-seven patients were females (37/40), and the mean age at diagnosis was 50.5 +/- 7.8 years. The time interval from initial symptoms or preliminary diagnosis to final diagnosis was 24.0 +/- 23.6 months. RESULTS: The most frequently reported symptoms were fatigue (67.5%, 27/40), jaundice (60%, 24/40) and pruritus (32.5%, 17/40). Eight patients (20%) had associated auto-immune diseases (Sjogren's syndrome and/or rheumatoid a(c)arthritis). Serum alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (gamma-GT) levels were markedly elevated (520.3 +/- 382.3 IU/L and 648.6 +/- 529.1 IU/L, respectively) in all patients, while alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were mildly elevated (82.6 +/- 54.5 IU/L and 100.7 +/- 47.2 IU/L, respectively). Twenty-four patients (60%) had a total bilirubin level >/= 34.2 micromol/L. Thirty-five patients (87.5%) had elevated serum immunoglobin M,and 97.5% of patients (39/40 ) were anti-mitochondrial antibody (AMA)/AMA-M2 positive. CONCLUSION: Elevated serum ALP and gamma-GT levels, together with a positive AMA/AMA-M2, can help the diagnosis of PBC. Liver biopsy is useful to confirm the diagnosis and to differentiate histopathological stages.
15220345 Group IB secretory phospholipase A2 promotes matrix metalloproteinase-2-mediated cell migr 2004 Aug 27 Secretory phospholipase A(2) (sPLA(2)), abundantly expressed in various cells including fibroblasts, is able to promote proliferation and migration. Degradation of collagenous extracellular matrix by matrix metalloproteinase (MMP) plays a role in the pathogenesis of various destructive disorders, such as rheumatoid arthritis, tumor invasion, and metastasis. Here we show that group IB PLA(2) increased pro-MMP-2 activation in NIH3T3 fibroblasts. MMP-2 activity was stimulated by group IB PLA(2) in a dose- and time-dependent manner. Consistent with MMP-2 activation, sPLA(2) decreased expression of type IV collagen. These effects are due to the reduction of tissue inhibitor of metalloproteinase-2 (TIMP-2) and the activation of the membrane type1-MMP (MT1-MMP). The decrease of TIMP-2 levels in conditioned media and the increase of MT1-MMP levels in plasma membrane were observed. In addition, treatment of cells with decanoyl Arg-Val-Lys-Arg-chloromethyl ketone, an inhibitor of pro-MT1-MMP, suppressed sPLA(2)-mediated MMP-2 activation, whereas treatment with bafilomycin A1, an inhibitor of H(+)-ATPase, sustained MMP-2 activation by sPLA(2). The involvement of phosphatidylinositol 3-kinase (PI3K) and Akt in the regulation of MMP-2 activity was further suggested by the findings that PI3K and Akt were phosphorylated by sPLA(2). Expression of p85alpha and Akt mutants, or pretreatment of cells with LY294002, a PI3K inhibitor, attenuated sPLA(2)-induced MMP-2 activation and migration. Taken together, these results suggest that sPLA(2) increases the pro-MMP-2 activation and migration of fibroblasts via the PI3K and Akt-dependent pathway. Because MMP-2 is an important factor directly involved in the control of cell migration and the turnover of extracellular matrix, our study may provide a mechanism for sPLA(2)-promoted fibroblasts migration.
14996519 Renal effects of etoricoxib and comparator nonsteroidal anti-inflammatory drugs in control 2004 Jan BACKGROUND: Based on the experience with selective cyclooxygenase (COX)-2 inhibitors, including rofecoxib, valdecoxib, and celecoxib, it was anticipated that etoricoxib, a new selective COX-2 inhibitor, would display mechanism-based, dose-dependent renal adverse effects (AEs) similar to those observed with nonselective non-steroidal anti-inflammatory drugs (NSAIDs) in long-term treatment. OBJECTIVE: The present analysis examined pooled safety data from the etoricoxib clinical development program with the aim of comparing the renal AE profiles of etoricoxib 60, 90, and 120 mg/d with those of approved therapeutic dosages of the comparator nonselective NSAIDs, naproxen 1000 mg/d and ibuprofen 2400 mg/d, and with that of placebo. METHODS: The etoricoxib program database included data from 8 placebo-controlled Phase III studies of osteoarthritis, rheumatoid arthritis, and chronic low back pain. As part of the program-wide assessment of etoricoxib, the investigator-reported incidence of and discontinuations due to renal AEs, including hypertension, lower-extremity edema (LEE), elevated serum creatinine concentration (SCC), and congestive heart failure (CHF) were examined. RESULTS: Data from 4770 patients were included in the analysis. Most patients were women (69.0%-80.3%), and most were white (68.0%-83.3%). The mean (SD) age at baseline ranged from 53.6 (12.1) to 62.2 (8.4) years. Overall, the incidence of renal AEs was low and generally similar between the active-treatment groups. In the placebo; etoricoxib 60-, 90-, and 120-mg; naproxen, and ibuprofen groups, the incidences of hypertension were 2.0%, 4.0%, 3.4%, 4.7%, 2.9%, and 6.6%, respectively, and the incidences of LEE were 1.9%, 3.2%, 1.5%, 1.3%, 2.3%, and 1.8%, respectively. The only significant difference found was the incidence of hypertension with etoricoxib 90 mg/d versus that with placebo (P=0.001); however, the rates of hypertension observed with etoricoxib at any dosage were not clinically meaningfully different versus comparator NSAIDs. Also, LEE was rarely of clinical significance with etoricoxib or comparator NSAIDs; related discontinuations were infrequent in all treatment groups. In addition, the incidences of elevated SCC and CHF were low among active-treatment groups (0.0% to 0.8% and 0.0% to 0.2%, respectively). CONCLUSIONS: Based on this combined data review, the risks for renal AEs (i.e., hypertension, LEE, elevated SCC changes, and CHF) with etoricoxib 60, 90, and 120 mg/d were low, with a shallow dose response, and were generally similar to those found with the comparator NSAIDs naproxen 1000 mg/d and ibuprofen 2400 mg/d.
14513268 Superiority of alfacalcidol over plain vitamin D in the treatment of glucocorticoid-induce 2004 Mar Supplementation therapy with plain vitamin D plus calcium is in general regarded as effective prevention or first-step treatment of glucocorticoid-induced osteoporosis (GIOP). The aim of our study was to compare the therapeutic efficacy of the D-hormone analog alfacalcidol with plain vitamin D in patients with established GIOP with or without vertebral fractures. Patients on long-term glucocorticoid (GC) therapy were included as matched pairs to receive randomly either 1 microg alfacalcidol plus 500 mg calcium per day (group A, n=103) or 1000 IU vitamin D3 plus 500 mg calcium (group B, n=101). The two groups were well matched in terms of mean age, sex ratio, mean height and weight, daily dosage, and duration of GC therapy, and the percentages of the three underlying diseases included chronic obstructive pulmonary disease, rheumatoid arthritis, and polymyalgia rheumatica. The baseline mean bone mineral density (BMD) values at the lumbar spine for the two groups were -3.26 (alfacalcidol) and -3.25 (vitamin D(3)) and, at the femoral neck, -2.81 and -2.84, respectively (T scores). Rates of prevalent vertebral and nonvertebral fractures did not differ between groups. During the 3-year study, we observed a median percentage increase of BMD at the lumbar spine of 2.4% in group A and a loss of 0.8% in group B ( P<0.0001). There also was a larger median increase at the femoral neck in group A (1.2%) than in group B (0.8%) ( P<0.006). The 3-year rates of patients with at least one new vertebral fracture were 9.7% among those assigned to the alfacalcidol group and 24.8% in the vitamin D group (risk reduction 0.61, 95% CI 0.24-0.81, P=0.005). The 3-year rates of patients with at least one new nonvertebral fracture were 15% in the alfacalcidol group and 25% in the vitamin D group (risk reduction 0.41, 95% CI 0.06-0.68, P=0.081). The 3-year rates of patients with at least one new fracture of any kind were 19.4% among those treated with alfacalcidol and 40.65% with vitamin D (risk reduction 0.52, 95% CI 0.25-0.71, P=0.001). In accordance with the observed fracture rates, the alfacalcidol group showed a substantially larger decrease in back pain than the plain vitamin D group ( P<0.0001). Generally, side effects in both groups were mild, and only three patients in the alfacalcidol group and two in the vitamin D group had moderate hypercalcemia. We conclude that alfacalcidol plus calcium is highly superior to plain vitamin D3 plus calcium in the treatment of established GIOP.
12577299 Inflammatory T cells rapidly induce differentiation of human bone marrow stromal cells int 2003 Mar 1 Activated T cells secrete multiple osteoclastogenic cytokines which play a major role in the bone destruction associated with rheumatoid arthritis. While the role of T cells in osteoclastogenesis has received much attention recently, the effect of T cells on osteoblast formation and activity is poorly defined. In this study, we investigated the hypothesis that in chronic inflammation activated T cells contribute to enhanced bone turnover by promoting osteoblastic differentiation. We show that T cells produce soluble factors that induce alkaline phosphatase activity in bone marrow stromal cells and elevated expression of mRNA for Runx2 and osteocalcin. This data indicate that T cell derived factors have the capacity to stimulate the differentiation of bone marrow stromal cells into the osteoblast phenotype. RANKL mRNA was undetectable under any conditions in highly purified bone marrow stromal cells. In contrast, RANKL was constitutively expressed in primary osteoblasts and only moderately up-regulated by activated T cell conditioned medium. Interestingly, both bone marrow stromal cells and osteoblasts expressed mRNA for RANK, which was strongly up-regulated in both cell types by activated T cell conditioned medium. Although, mRNA for the RANKL decoy receptor, osteoprotegerin, was also up-regulated by activated T cell conditioned medium, it's inhibitory effects may be mitigated by a simultaneous rise in the osteoprotegerin competitor TNF-related apoptosis-inducing ligand. Based on our data we propose that during chronic inflammation, T cells regulate bone loss by a dual mechanism involving both direct stimulation of osteoclastogenesis, by production of osteoclastogenic cytokines, and indirectly by induction of osteoblast differentiation and up-regulation of bone turnover via coupling.
12171295 Comparative reactivity of human sera to recombinant VlsE and other Borrelia burgdorferi an 2002 Aug A comparative study of human sera was conducted to determine which purified preparations of 11 recombinant antigens of Borrelia burgdorferi sensu stricto were diagnostically most important in enzyme-linked immunosorbent assays (ELISAs). To assess sensitivity, 20 serum samples obtained 1-6 weeks after onset of illness from 20 persons who had physician-diagnosed erythema migrans (EM) were tested for IgM and IgG antibodies. In tests for IgM antibody, seropositivity of > or = 25% was recorded when ELISAs had separate preparations of protein (p) 37, p41-G, outer-surface protein (Osp) C, OspE, OspF or VlsE antigens. Sera reacted most frequently (80% positive) with VlsE antigen in analyses for IgG antibodies. When results of both class-specific assays were considered for VlsE, OspC or OspF, 90% of the EM cases were serologically confirmed. Results of specificity testing with a further 59 sera from persons who had syphilis, louse-borne relapsing fever, oral infections, rheumatoid arthritis or human granulocytic ehrlichiosis and 28 normal sera indicated no false positive reactions when VlsE antigen was used in tests for IgM antibody. One of the 11 louse-borne relapsing fever sera cross-reacted with VlsE antigen in tests for IgG antibodies. Minor cross-reactivity also occurred when p37, OspC, OspE or OspF antigens were used. Overall, VlsE was the most suitable antigen for laboratory diagnosis of Lyme borreliosis during the early weeks of B. burgdorferi infection because of its high sensitivity and specificity.
11857637 Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and 2002 Mar This review focuses on providing insights into the structural basis and clinical relevance of LFA-1 and VLA-4 inhibition by peptides and small molecules as adhesion-based therapeutic strategies for inflammation and autoimmune diseases. Interactions of cell adhesion molecules (CAM) play central roles in mediating immune and inflammatory responses. Leukocyte function-associated antigen (LFA-1, alpha(L)beta(2), and CD11a/CD18) and very late antigen (VLA-4, alpha(4)beta(1), and CD49d/CD29) are members of integrin-type CAM that are predominantly involved in leukocyte trafficking and extravasation. LFA-1 is exclusively expressed on leukocytes and interacts with its ligands ICAM-1, -2, and -3 to promote a variety of homotypic and heterotypic cell adhesion events required for normal and pathologic functions of the immune systems. VLA-4 is expressed mainly on lymphocyte, monocytes, and eosinophils, but is not found on neutrophils. VLA-4 interacts with its ligands VCAM-1 and fibronectin (FN) CS1 during chronic inflammatory diseases, such as rheumatoid arthritis, asthma, psoriasis, transplant-rejection, and allergy. Blockade of LFA-1 and VLA-4 interactions with their ligands is a potential target for immunosuppression. LFA-1 and VLA-4 antagonists (antibodies, peptides, and small molecules) are being developed for controlling inflammation and autoimmune diseases. The therapeutic intervention of mostly mAb-based has been extensively studied. However, due to the challenging relative efficacy/safety ratio of mAb-based therapy application, especially in terms of systemic administration and immunogenic potential, strategic alternatives in the forms of peptide, peptide mimetic inhibitors, and small molecule non-peptide antagonists are being sought. Linear and cyclic peptides derived from the sequences of LFA-1, ICAM-1, ICAM-2, VCAM-1, and FN C1 have been shown to have inhibitory effects in vitro and in vivo. Finally, understanding the mechanism of LFA-1 and VLA-4 binding to their ligands has become a fundamental basis in developing therapeutic agents for inflammation and autoimmune diseases.
22319801 Cyclo(Cys-Arg-Gly-Asp-Cys)-Gly-Lys-Cy5.5. 2004 Optical fluorescence imaging is increasingly being used to monitor biological functions of specific targets (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the natural background fluorescence interference of biomolecules, providing a high contrast between target and background tissues in small animals. NIR fluorophores have a wider dynamic range and minimal background fluorescence as a result of reduced scattering compared with visible fluorescence detection. NIR fluorophores also have high sensitivity, attributable to low background fluorescence, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is a non-invasive alternative to radionuclide imaging in small animals or with probes in close proximity of the target in humans (4, 5). Among the various optical imaging agents, only indocyanine green (ICG), with NIR fluorescence absorption at 780 nm and emission at 820 nm, is approved by the United States Food and Drug Administration for clinical applications in angiography, blood flow evaluation, and liver function assessment. It is also under evaluation in several clinical trials for other applications, such as optical imaging and mapping of both the lymphatic vessels and lymph nodes in cancer patients for surgical dissection of tumors and endoscopic imaging of the pancreas and colon. Integrins are a family of cell-surface heterodimeric glycoproteins that mediate diverse biological events involving cell–cell and cell–matrix interactions (6). They consist of an α and a β subunit, and they are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor class affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (7-12). The α(v)β(3) integrin is strongly expressed on tumor cells and activated endothelial cells. In contrast, expression of α(v)β(3) integrin is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as anti-tumor and anti-angiogenic agents (9, 13, 14), and the agonists are being studied as angiogenic agents for coronary angiogenesis (15, 16). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (17). Cyclo(RGDyK) was conjugated with Cy5.5 to study in vivo biodistribution of the tracer in tumor-bearing mice. Cy5.5 is a NIR fluorescent dye with an absorbance maximum at 675 nm and an emission maximum at 694 nm, with a high extinction coefficient of 250,000 (mol/L)(–1)cm(–1). c(RGDyK)-Cy5.5 was found to have high and long-lasting accumulation in α(v)β(3)-positve U87MG human glioblastoma tumor cells in nude mice (18). The binding of c(RGDyK)-Cy5.5 to the integrin receptor was found to be specific both in vitro and in vivo. von Wallbrunn et al. (19) performed optical NIR fluorescence imaging studies using a two-dimensional planar fluorescence reflectance imaging system and three-dimensional fluorescence-mediated tomography (FMT) of cyclo(Cys-Arg-Gly-Asp-Cys)-Gly-Lys-Cy5.5 (c(CRGDC)-GK-Cy5.5) in tumor-bearing nude mice.
20641939 (99m)Tc-Regioselectively addressable functionalized template-[cyclo-(Arg-Gly-Asp-d-Phe-Lys 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as anti-tumor and anti-angiogenic agents, and agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A peptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced to image tumors and tumor angiogenesis (10). Most of the cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to the α(v)β(3) integrin (50% inhibition concentration (IC(50)) = 7–40 nM) but not to the α(v)β(5) (IC(50) = 600–4,000 nM) or α(IIb)β(3) (IC(50) = 700–5,000 nM) integrins. Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Hydrazinonicotinic acid (HYNIC) is a coupling agent for (99m)Tc-labeling of peptides that can achieve high specific activities without affecting the receptor-binding ability of the amino acid sequence. (99m)Tc is bound to the hydrazine group, and other coordination sites could be occupied by one or more coligands. Liu et al. (13) reported the success of radiolabeling the cyclo(Arg-Gly-Asp-d-Phe-Lys) (c(RGDfK)) tetramer linked by glutamic acid and conjugated with HYNIC, which displayed high tumor accumulation in nude mice bearing human tumor xenografts. Boturyn et al. (14) generated a versatile molecular regioselectively addressable functionalized template (RAFT) platform with a cyclic decapeptide [c(-Lys(Boc)-Lys(Alloc)-Lys(Boc)-Pro-Gly-Lys(Boc)-Lys(Alloc)-Lys(Boc)-Pro-Gly-)] that had two attachment sides. The upper side is linked to four copies of the c(RGDfK) peptide for integrin α(v)β(3) targeting, and the bottom side is linked to (99m)Tc for single-photon emission computed tomography (SPECT) imaging or other labels for other imaging modalities. Sancey et al. (15) reported that (99m)Tc-RAFT-c(-RGDfK-)(4) efficiently accumulated into tumors in mice. (99m)Tc-RAFT-c(-RGDfK-)(4) is an integrin-targeted molecular imaging agent developed for imaging of tumor vasculature and tumor angiogenesis.
15698379 The Sit & Stand chair. A revolutionary advance in adaptive seating systems. 2004 A major factor governing independence for the elderly and persons with disabilities is the ability to stand from a chair. Factors such as pain, reduced joint range of motion, stiffness, and muscle weakness frequently limit the ability to stand. Sit-to-stand position is even further reduced in patients whose hands and shoulders are afflicted with rheumatoid arthritis. When achieving a sit-to-stand position in the elderly and persons with disabilities, there is considerable risk of the individual falling and sustaining bone fracture. The purposes of this scientific report are to achieve the following goals: (1) to provide a narrative discussion of the senior author's contributions to furniture manufacturing as well as his successful patent application for the SIT & STAND chair, (2) to describe the steps involved in the development of the SIT & STAND prototype, and (3) to examine the performance of the SIT & STAND chair in assisting the elderly or persons with disabilities in achieving a sit-to-stand position. The invention of the SIT & STAND chair by the senior author, Michael Galumbeck, was a culmination of his lifelong interest in adaptive seating systems. His electrically operated chair has the unique ability to assist the occupant to achieve safely a sit-to-stand position. The rear portion of his chair remains in a fixed position to support the buttocks of the user during mechanical lift. The front portion of the seat folds down incrementally as the chair rises to allow the feet of the user to be positioned in a more posterior position firmly on the floor. Using its actuator, the height that the chair rises will vary with the length of the legs of the occupant. Using the drawing program Solid Works (Solid Works, Concord, Massachusetts), drawings of the chair were made. To visualize the operation and performance of the chair, separate drawings were made in the lateral position. The prototype of the SIT & STAND chair was manufactured with an electric actuator that allows elevation of the back portion of the seat. The design of this chair ensured that there were no pinch points that could endanger the user or assistant. Its framework ensured that it was stable and did not tip over. After the prototype chair is manufactured, it is being sent to Underwriters Laboratory Inc. (Los Angeles, California) for review and certification. The performance of the SIT & STAND chair was determined in a clinical study involving seven elderly or disabled individuals who complained of difficulty in rising from a chair from a seated position. During each performance evaluation, a mechanical chest and shoulder harness attached to an overhead sling encircled the individual to ensure that he/she would not fall. In the first part of the evaluation, these individuals were asked to achieve a standing position after being seated in the SIT & STAND chair without the use of the actuator. Three individuals were unable to achieve a standing position, while four achieved this standing position with considerable difficulty and potential instability. When these participants used the SIT & STAND chair with the use of the electrical actuator, all individuals achieved a standing position without difficulty or instability. All individuals expressed disappointment that the SIT & STAND chair was not commercially available for them to purchase and use in their homes. Because the SIT & STAND chair allows the individual to achieve a standing position without assistance, the SIT & STAND chair has other potential benefits not evaluated in this study. The beneficial effects of standing have been documented by comprehensive scientific studies. These benefits include reduction of seating pressure, decreased bone demineralization, increased bladder pressure, enhanced circulatory regulation, reduction in muscular tone, decrease in upper extremity muscle stress, and participation in activities of daily living. Another irrefutable benefit of the SIT & STAND chair is that the chair eliminates the need for physical assistance from family members or health care personnel, preventing the development of disabling back injuries in personal care assistants. In addition, the SIT & STAND chair entirely removes the risk of pain or harm to the individual, which sometimes occurs with manual assist to stand, such as dislocation or fracture of frail shoulders with the under-axilla lift. Realizing the medical benefits of the SIT & STAND chair, Aetna completed a clinical policy bulletin that states that the seat lift mechanism is a medically necessary durable medical product. On the basis of this extensive product and performance evaluation, we recommend the SIT & STAND chair for the elderly as well as persons with disability to safely achieve a sit-to-stand position.
22171395 (64)Cu-1,4,8,11-Tetraazacyclotetradecane-regioselectively addressable functionalized templ 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A peptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most of the cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (IC(50), 7–40 nM) but not to α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM) integrins. Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Hydrazinonicotinic acid (HYNIC) is a coupling agent for (99m)Tc labeling of peptides that can achieve high specific activities without affecting receptor-binding ability of the amino acid sequence. (99m)Tc is bound to the hydrazine group, and other coordination sites could be occupied by one or more coligands. Liu et al. (13) reported the success of radiolabeling cylco(Arg-Gly-Asp-d-Phe-Lys) (c(RGDfK)) tetramer linked by glutamic acid that was conjugated with HYNIC, which showed high tumor accumulation in nude mice bearing human tumor xenografts. Boturyn et al. (14) generated a versatile molecular “Regioselectively Addressable Functionalized Template” (RAFT) platform with a cyclic decapeptide [c(-Lys(Boc)-Lys(Alloc)-Lys(Boc)-Pro-Gly-Lys(Boc)-Lys(Alloc)-Lys(Boc)-Pro-Gly-)] with two attachment sides. The upper side is linked to four copies of the c(RGDfK) peptide for targeting of integrin α(v)β(3), and the bottom side is linked to (99m)Tc (15) or (111)In (16) for single-photon emission computed tomography imaging or to other labels for other imaging modalities. (99m)Tc-RAFT-c(-RGDfK-)(4) and (111)In-RAFT-c(-RGDfK-)(4) efficiently accumulated in tumors in mice. Jin et al. (17) conjugated RAFT-c(-RGDfK-)(4) with a bifunctional chelator, 1,4,8,11-tetraazacyclotetradecane (cyclam), for radiolabeling with (64)Cu. (64)Cu-Cyclam-RAFT-c(-RGDfK-)(4) is an integrin-targeted molecular imaging agent developed for positron emission tomography (PET) imaging of tumor vasculature and tumor angiogenesis.
15621569 Ongoing immunoglobulin class switch DNA recombination in lupus B cells: analysis of switch 2004 Sep Inflammation and tissue damage in systemic lupus erythematosus (SLE) are mediated by class-switched autoantibodies reactive with nucleic acids, nucleic acid-binding proteins, phospholipids and other self-antigens. While some healthy individuals produce IgM antibodies with specificities similar to those of lupus patients, immunoglobulin class switching to mature downstream isotypes appears to be required for the generation of pathogenic autoantibodies. To characterize the cellular and molecular basis of pathogenic autoantibody production in SLE, we studied the capacity of peripheral blood B cells of naive phenotype from patients with SLE, rheumatoid arthritis (RA) or healthy control subjects to spontaneously switch to IgG and IgA. In addition, we determined the DNA sequences of the upstream evolutionary conserved sequence (ECS)-Igamma promoter regulatory regions that control germline IH-CH transcription and class switch DNA recombination (CSR) to IgG1, IgG2 and IgG4. IgM+IgD+ B cells from patients with SLE, but not those from RA or healthy control subjects, underwent spontaneous CSR, as assessed by expression of germline Igamma1-Cgamma1, Igamma2-Cgamma2, Igamma3-Cgamma3, Igamma4-Cgamma4 and Ialpha1-Calpha1 transcripts, mature (switched) VHDJH-Cgamma1, VHDJH-Cgamma2, VHDJH-Cgamma3 and VHDJH-Calpha1 transcripts and secreted IgG and IgA. Although polymorphic DNA sequences were identified in the ECS-Igamma1, ECS-Igamma2 and ECS-Igamma4 promoter regions, the transcription factor-binding sites that mediate germline Igamma-Cgamma transcription were conserved in patients and controls. However, distinct patterns of nuclear protein binding to an ECS-Igamma promoter sequence that contains both positive and negative regulatory elements were observed in SLE patients and controls. These results support a role for exogenous signals, such as through CD40 ligation, rather than altered genomic sequence, in the increased production of class switched autoantibodies in SLE.
12730964 Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocyte 2003 Jun Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E(2) (PGE(2)), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE(2) production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE(2) production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE(2) production by OSM and IL-1beta treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE(2) synthesis. Of the enzymes involved in PGE(2) biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1beta. Nuclear run-on assays demonstrate that OSM and IL-1beta synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1beta. To effect synergy on the PGE(2) level, OSM signals in part through its gp130/OSMRbeta receptor, since neutralizing antibodies against gp130 and OSMRbeta, but not LIFRbeta, decrease PGE(2) production in response to OSM plus IL-1beta. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1beta and OSM upregulation of COX-2 and PGE(2), indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE(2) amplification may be active in brain pathologies where both OSM and IL-1beta are present, such as glioblastomas and multiple sclerosis.
12531797 Beta 2-microglobulin as a negative regulator of the immune system: high concentrations of 2003 May 15 Two common features in human immunodeficiency virus infection and acquired immunodeficiency syndrome, rheumatoid arthritis, and hematologic malignancies including multiple myeloma are elevated serum levels of beta(2)-microglobulin (beta(2)M) and activation or inhibition of the immune system. We hypothesized that beta(2)M at high concentrations may have a negative impact on the immune system. In this study, we examined the effects of beta(2)M on monocyte-derived dendritic cells (MoDCs). The addition of beta(2)M (more than 10 microg/mL) to the cultures reduced cell yield, inhibited the up-regulation of surface expression of human histocompatibility leukocyte antigen (HLA)-ABC, CD1a, and CD80, diminished their ability to activate T cells, and compromised generation of the type-1 T-cell response induced in allogeneic mixed-lymphocyte reaction. Compared with control MoDCs, beta(2)M-treated cells produced more interleukin-6 (IL-6), IL-8, and IL-10. beta(2)M-treated cells expressed significantly fewer surface CD83, HLA-ABC, costimulatory molecules, and adhesion molecules and were less potent at stimulating allospecific T cells after an additional 48-hour culture in the presence of tumor necrosis factor-alpha and IL-1beta. During cell culture, beta(2)M down-regulated the expression of phosphorylated mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), and mitogen-induced extracellular kinase (MEK), inhibited nuclear factor-kappaB (NF-kappaB), and activated signal transducer and activator of transcription-3 (STAT3) in treated cells, all of which are involved in cell differentiation and proliferation. Thus, our study demonstrates that beta(2)M at high concentrations retards the generation of MoDCs, which may involve down-regulation of major histocompatibility complex class I molecules, inactivation of Raf/MEK/ERK cascade and NF-kappaB, and activation of STAT3, and it merits further study to elucidate the underlying mechanisms.
12403738 Community-based exercise program reduces risk factors for falls in 65- to 75-year-old wome 2002 Oct 29 BACKGROUND: Exercise programs improve balance, strength and agility in elderly people and thus may prevent falls. However, specific exercise programs that might be widely used in the community and that might be "prescribed" by physicians, especially for patients with osteoporosis, have not been evaluated. We conducted a randomized controlled trial of such a program designed specifically for women with osteoporosis. METHODS: We identified women 65 to 75 years of age in whom osteoporosis had been diagnosed by dual-energy X-ray absorptiometry in our hospital between 1996 and 2000 and who were not engaged in regular weekly programs of moderate or hard exercise. Women who agreed to participate were randomly assigned to participate in a twice-weekly exercise class or to not participate in the class. We measured baseline data and, 20 weeks later, changes in static balance (by dynamic posturography), dynamic balance (by a timed figure-eight run) and knee extension strength (by dynamometry). RESULTS: Of 93 women who began the trial, 80 completed it. Before adjustment for covariates, the intervention group tended to have greater, although nonsignificant, improvements in static balance (mean difference 4.8%, 95% confidence interval [CI] -1.3% to 11.0%), dynamic balance (mean difference 3.3%, 95% CI -1.7% to 8.4%) and knee extension strength (mean difference 7.8%, 95% CI -5.4% to 21.0%). Mean crude changes in the static balance score were -0.85 (95% CI -2.91 to 1.21) for the control group and 1.40 (95% CI -0.66 to 3.46) for the intervention group. Mean crude changes in figure-eight velocity (dynamic balance) were 0.08 (95% CI 0.02 to 0.14) m/s for the control group and 0.14 (95% CI 0.08 to 0.20) m/s for the intervention group. For knee extension strength, mean changes were -0.58 (95% CI -3.02 to 1.81) kg/m for the control group and 1.03 (95% CI -1.31 to 3.34) kg/m for the intervention group. After adjustment for age, physical activity and years of estrogen use, the improvement in dynamic balance was 4.9% greater for the intervention group than for the control group (p = 0.044). After adjustment for physical activity, cognitive status and number of fractures ever, the improvement in knee extension strength was 12.8% greater for the intervention group than for the control group (p = 0.047). The intervention group also had a 6.3% greater improvement in static balance after adjustment for rheumatoid arthritis and osteoarthritis, but this difference was not significant (p = 0.06). INTERPRETATION: Relative to controls, participants in the exercise program experienced improvements in dynamic balance and strength, both important determinants of risk for falls, particularly in older women with osteoporosis.
15496230 Age-related changes in serum growth hormone, insulin-like growth factor-1 and somatostatin 2004 Oct 20 BACKGROUND: Systemic lupus erythematosus is an age- and gender-associated autoimmune disorder. Previous studies suggested that defects in the hypothalamic/pituitary axis contributed to systemic lupus erythematosus disease progression which could also involve growth hormone, insulin-like growth factor-1 and somatostatin function. This study was designed to compare basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels in female systemic lupus erythematosus patients to a group of normal female subjects. METHODS: Basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels were measured by standard radioimmunoassay. RESULTS: Serum growth hormone levels failed to correlate with age (r2 = 3.03) in the entire group of normal subjects (i.e. 20 - 80 years). In contrast, serum insulin-like growth factor-1 levels were inversely correlated with age (adjusted r2 = 0.092). Of note, serum growth hormone was positively correlated with age (adjusted r2 = 0.269) in the 20 - 46 year range which overlapped with the age range of patients in the systemic lupus erythematosus group. In that regard, serum growth hormone levels were not significantly higher compared to either the entire group of normal subjects (20 - 80 yrs) or to normal subjects age-matched to the systemic lupus erythematosus patients. Serum insulin-like growth factor-1 levels were significantly elevated (p < 0.001) in systemic lupus erythematosus patients, but only when compared to the entire group of normal subjects. Serum somatostatin levels differed from normal subjects only in older (i.e. >55 yrs) systemic lupus erythematosus patients. CONCLUSIONS: These results indicated that systemic lupus erythematosus was not characterized by a modulation of the growth hormone/insulin-like growth factor-1 paracrine axis when serum samples from systemic lupus erythematosus patients were compared to age- matched normal female subjects. These results in systemic lupus erythematosus differ from those previously reported in other musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, fibromyalgia, diffuse idiopathic skeletal hyperostosis and hypermobility syndrome where significantly higher serum growth hormone levels were found. Somatostatin levels in elderly systemic lupus erythematosus patients may provide a clinical marker of disease activity in these patients.
12804509 Physiotherapy interventions for shoulder pain. 2003 BACKGROUND: The prevalence of shoulder disorders has been reported to range from seven to 36% of the population (Lundberg 1969) accounting for 1.2% of all General Practitioner encounters in Australia (Bridges Webb 1992). Substantial disability and significant morbidity can result from shoulder disorders. While many treatments have been employed in the treatment of shoulder disorders, few have been proven in randomised controlled trials. Physiotherapy is often the first line of management for shoulder pain and to date its efficacy has not been established. This review is one in a series of reviews of varying interventions for shoulder disorders, updated from an earlier Cochrane review of all interventions for shoulder disorder. OBJECTIVES: To determine the efficacy of physiotherapy interventions for disorders resulting in pain, stiffness and/or disability of the shoulder. SEARCH STRATEGY: MEDLINE, EMBASE, the Cochrane Clinical Trials Regiter and CINAHL were searched 1966 to June 2002. The Cochrane Musculoskeletal Review Group's search strategy was used and key words gained from previous reviews and all relevant articles were used as text terms in the search. SELECTION CRITERIA: Each identified study was assessed for possible inclusion by two independent reviewers. The determinants for inclusion were that the trial be of an intervention generally delivered by a physiotherapist, that treatment allocation was randomised; and that the study population be suffering from a shoulder disorder, excluding trauma and systemic inflammatory diseases such as rheumatoid arthritis. DATA COLLECTION AND ANALYSIS: The methodological quality of the included trials was assessed by two independent reviewers according to a list of predetermined criteria, which were based on the PEDro scale specifically designed for the assessment of validity of trials of physiotherapy interventions. Outcome data was extracted and entered into Revman 4.1. Means and standard deviations for continuous outcomes and number of events for binary outcomes were extracted where available from the published reports. All standard errors of the mean were converted to standard deviation. For trials where the required data was not reported or not able to be calculated, further details were requested from first authors. If no further details were provided, the trial was included in the review and fully described, but not included in the meta-analysis. Results were presented for each diagnostic sub group (rotator cuff disease, adhesive capsulitis, anterior instability etc) and, where possible, combined in meta-analysis to give a treatment effect across all trials. MAIN RESULTS: Twenty six trials met inclusion criteria. Methodological quality was variable and trial populations were generally small (median sample size = 48, range 14 to 180). Exercise was demonstrated to be effective in terms of short term recovery in rotator cuff disease (RR 7.74 (1.97, 30.32), and longer term benefit with respect to function (RR 2.45 (1.24, 4.86). Combining mobilisation with exercise resulted in additional benefit when compared to exercise alone for rotator cuff disease. Laser therapy was demonstrated to be more effective than placebo (RR 3.71 (1.89, 7.28) for adhesive capsulitis but not for rotator cuff tendinitis. Both ultrasound and pulsed electromagnetic field therapy resulted in improvement compared to placebo in pain in calcific tendinitis (RR 1.81 (1.26, 2.60) and RR 19 (1.16, 12.43) respectively). There is no evidence of the effect of ultrasound in shoulder pain (mixed diagnosis), adhesive capsulitis or rotator cuff tendinitis. When compared to exercises, ultrasound is of no additional benefit over and above exercise alone. There is some evidence that for rotator cuff disease, corticosteroid injections are superior to physiotherapy and no evidence that physiotherapy alone is of benefit for Adhesive Capsulitis REVIEWER'S CONCLUSIONS: The small sample sizes, variable methodological quality and heterogeneity in terms of population studied, physiotherapy intervention employed and length of follow up of randomised controlled trials of physiotherapy interventions results in little overall evidence to guide treatment. There is evidence to support the use of some interventions in specific and circumscribed cases. There is a need for trials of physiotherapy interventions for specific clinical conditions associated with shoulder pain, for shoulder pain where combinations of physiotherapy interventions, as well as, physiotherapy interventions as an adjunct to other, non physiotherapy interventions are compared. This is more reflective of current clinical practice. Trials should be adequately powered and address key methodological criteria such as allocation concealment and blinding of outcome assessor.
15476906 Effects of valdecoxib in the treatment of chronic low back pain: results of a randomized, 2004 Aug BACKGROUND: Valdecoxib, a cyclooxygenase (COX)-2 specific inhibitor, is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and primary dysmenorrhea. Therapeutic doses of COX-2 specific inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory drugs in reducing inflammatory pain while sparing the gastrointestinal and platelet toxicity associated with nonspecific COX-1 inhibition. OBJECTIVE: The aim of this study was to assess the analgesic efficacy and tolerability of valdecoxib 40 mg/d compared with placebo in the treatment of chronic low back pain. METHODS: This 4-week, prospective, randomized, double-blind placebo-controlled, parallel-group study was conducted at 37 centers across the United States and 5 centers in Canada. Patients aged > or =18 years with chronic low back pain in flare were enrolled. Patients were randomized to receive valdecoxib 40-mg/d or placebo tablets, once daily for 4 weeks. Patients rated low back pain intensity on a visual analog scale and completed the Roland-Morris Disability Questionnaire and the modified Brief Pain Inventory-Short Form (mBPI-SF) at each visit. RESULTS: Two hundred ninety-three patients were enrolled. The valdecoxib group comprised 148 patients (81 women, 67 men; mean [SD] age, 48.6 [13.3] years; mean [SD] body weight, 86.6 [20.9] kg), and the placebo group included 145 patients (85 women, 60 men; mean [SD] age, 48.7 [12.6] years; mean [SD] body weight, 85.6 [19.9] kg). Of the enrolled patients, 249 completed the study: 134 patients (91%) who received valdecoxib and 115 patients (79%) who received placebo. No statistically significant differences in patient baseline characteristics were noted between treatment groups, except in response to 1 mBPI-SF question; patients in the valdecoxib group reported significantly greater interference in relations with other people due to pain than did those in the placebo group (P = 0.048). Changes from baseline in low back pain intensity were significantly greater in valdecoxib-treated patients at each assessment (all, P < 0.001 vs placebo). Pain scores on the mBPI-SF indicated significantly greater pain relief with valdecoxib at each assessment (all, P < or = 0.014 vs placebo). Improvements in mean Roland-Morris Disability Questionnaire score with valdecoxib were significantly greater than with placebo at each assessment (all, P < or = 0.003). Although the overall incidence of adverse events (AEs) was significantly higher among patients receiving valdecoxib than those receiving placebo (35.1% vs 24.1%, respectively; P = 0.042), no significant differences were found between groups for the incidence of any individual AE. Most AEs (89% [77/87 total events]) were mild or moderate in severity. CONCLUSIONS: In this study of patients with chronic low back pain, valdecoxib 40 mg/d provided rapid relief (within 1 week) and consistent relief (over 4 weeks). In addition, significant improvement in function and decreased disability were found with valdecoxib compared with placebo.
15280569 A novel mutation (T61I) in the gene encoding tumour necrosis factor receptor superfamily 1 2004 Oct OBJECTIVE: To identify potential mutations in the tumour necrosis factor receptor superfamily 1A gene (TNFRSF1A) in a Japanese female patient with recurrent fever complicated by systemic lupus erythematosus (SLE), and in her family members. METHODS: DNA sequencing of exons 1-10 of the TNFRSF1A gene was performed to determine mutations that might be associated with the tumour necrosis factor receptor-associated periodic syndrome (TRAPS). Moreover, the TNFRSF1A gene was examined in Japanese patients with autoimmune diseases, including SLE, rheumatoid arthritis (RA), mixed connective tissue disease (MCTD) and Behçet's disease, and in healthy Japanese controls. Enzyme-amplified sensitivity immunoassay (EASIA) analysis was used to assess serum levels of TNF, the 55-kDa TNF receptor (TNFRSF1A) and the 75-kDa TNF receptor (TNFRSF1B). Membrane TNFRSF1A expression was analysed on the surface of peripheral blood mononuclear cells by flow cytometry. RESULTS: A novel mutation, a heterozygous C to T transition in exon 3 which substitutes an isoleucine for a threonine at position 61 (T61I) was detected in the TNFRSF1A gene derived from the genomic DNA of a Japanese female TRAPS patient. Two nieces and one nephew, all with a similar clinical phenotype, also possessed the same TNFRSF1A mutation. We further demonstrated the same mutation in five of 60 SLE patients (8.3%) and in five of 120 healthy individuals (4.2%), with no significant differences. Although high titres of serum TNF and soluble TNFRSF1B protein were observed in this patient, low titres of soluble TNFRSF1A protein were detected. However, a defect in TNFRSF1A shedding in vitro was not observed in monocytes derived from this patient. CONCLUSION: This is the first report of a TRAPS patient associated with SLE with a novel TNFRSF1A mutation (T61I).
12194075 A comparative study to assess the clinical use of Fluorescein Meniscus Time (FMT) with Tea 2002 Sep INTRODUCTION: The clinical diagnosis of dry-eye is confirmed by a suitable test of tear production and the technique commonly used today to diagnose dry eye is the Schirmer's test (ST). Although the ST is easy to perform it gives variable results, poor reproducibility and low sensitivity for detecting dry eyes. Another test, the tear break up time (TBUT) is used to assess the stability of tears which if abnormal may also cause symptomatic dry-eye. We present the results of both these tests and a new test, which shows greater sensitivity than the ST in detecting aqueous tear deficiency. The fluorescein meniscus time (FMT) is a new test developed in conjunction with one of the authors (CL) and the Department of Ophthalmology at the University Hospital of Wales. The FMT is a measure of the rate at which a fluorescent tear meniscus is formed using 2% sodium fluorescein, a stopwatch and suitable illumination with a slit lamp. METHOD: An open controlled study in 62 patients and 51 controls was conducted to compare the ability of ST, FMT and TBUT to detect dry-eye in a group of patients diagnosed with rheumatoid arthritis and symptomatic dry eyes for a minimum period of 6 months. A separate control group of 15 subjects was tested on three separate occasions to assess the reproducibility of the FMT test. RESULTS: All three tests showed a statistically significant difference between the patient and control populations; Mann-Whitney P < 0.001. There was a correlation between the right and left eye for all three tests in the control group (ST r(2) = 0.77, FMT r(2) = 0.98, TBUT r(2) = 0.94). This correlation was markedly reduced for FMT and TBUT in the patient population and was in keeping with the symptoms reported as being worse on one side in a proportion of the patients (FMT r(2) = 0.52, TBUT r(2) = 0.54, ST r(2) = 0.75). A correlation with age was also observed for all the three tests in the control group (ST r(2) = 0.74, FMT r(2)= 0.92, TBUT r(2) = 0.51), but not in the patient population (ST r(2) = 0.06, FMT r(2) = 0.18, TBUT r(2) = 0.03). A significant correlation was observed between the ST and FMT in both the control (ST vs FMT r(2) = 0.65) and patient population (ST vs FMT r(2) = 0.44). There was no value greater than 200 seconds for FMT recorded in the control group. Using this value to define an abnormal FMT, 85% of the patients (72% of the eyes tested) had an abnormal result. This was in contrast to 35% of patients (26% of the eyes tested) with abnormal results detected by ST. Using ANOVA and Student's paired t-test, there were no significant differences between the three sets of values recorded serially over 3 months to assess the reproducibility of the FMT. The average standard error of the mean was 2.72% and the average co-efficient of variation 4.07%. CONCLUSION: Our study suggests that the FMT is a more sensitive test with good reproducibility compared to the Schirmer's test. The FMT correlates with the ST and suggests that both tests measure aqueous tear deficiency. The FMT therefore is a better alternative to ST currently being used to test aqueous tear deficiency.