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ID PMID Title PublicationDate abstract
28876734 2004 Oct This SBU report, "Chronic Periodontitis – Prevention, Diagnosis and Treatment", is based on a systematic and critical review of the scientific literature. A powered toothbrush is more effective than a manual toothbrush for reducing gingivitis (Evidence Grade 3). Dentifrices containing stannous fluoride, amine fluoride / stannous fluoride, chlorhexidine or triclosan / copolymer are more effective than conventional fluoridated dentifrices for reducing gingivitis (Evidence Grade 3). Mouth-rinsing with a chlorhexidine solution (0.12–0.2 percent) or essential oils as an adjunct to tooth brushing is more effective than tooth brushing alone for reducing gingivitis (Evidence Grade 3). Repeated instructions by dental professionals lead to increased knowledge about oral hygiene. The findings are contradictory as to whether increased knowledge and desired behavioral changes lead to reduction of gingivitis. Preventing Gingivitis Diagnosing Chronic Periodontitis: Bleeding following probing of the periodontal pocket is a sign of inflammation in the periodontal tissues (Evidence Grade 2). Probing pocket depth overestimates the actual depth when periodontitis is present and underestimates it when the periodontal tissues are healthy (Evidence Grade 2). The use of electronic pressure-sensitive probes does not improve the reproducibility of periodontal pocket measurements compared to that of manual probing (Evidence Grade 3). Radiographic measurements underestimate alveolar bone loss. The degree of underestimation depends on the extent of bone loss and its location in the dental arch (Evidence Grade 3). The accuracy of assessing alveolar bone loss from direct digital radiography is comparable to that obtained from film radiography (Evidence Grade 3). The number of periapical radiographs can be considerably reduced when a clinical examination, along with bitewing radiographs of the posterior teeth or a panoramic radiograph precedes a full-mouth radiographic examination (Evidence Grade 3). The accuracy of bitewing and periapical radiography is low for estimating small alveolar bone changes (less than 1 mm) over time (Evidence Grade 3). Thus, performing radiographic examinations at regular intervals for the purpose of assessing changes of the periodontal support over time is not justified. Predicting Disease Progression: The absence of “bleeding on probing” is a good predictor of periodontal stability (Evidence Grade 3). Scientific evidence is insufficient for assessing the value of pocket depth as a prognostic method. Treating Chronic Periodontitis: Mechanical infection control (scaling and root planing) reduces probing pocket depth and improves probing attachment level. Mechanical infection control combined with flap surgery eliminates 10–15 percent more pockets deeper than 4 mm than mechanical infection control alone (Evidence Grade 3). Local adjunctive therapy with 25 percent metronidazole gel does not result in improved probing pocket depth or probing attachment level compared to mechanical infection control alone (Evidence Grade 3). Scientific evidence is insufficient for determining the efficacy of other local antibiotics and antiseptics. Systemic antibiotic therapy as an adjunct to mechanical infection control does not improve probing pocket depth or probing attachment level compared to mechanical infection control alone (Evidence Grade 1). Scientific evidence for the benefit derived from using anti-inflammatory drugs is insufficient. Adjunctive therapy with guided tissue regeneration (GTR) or with enamel matrix derivative (EMD) in individual angular bone defects results in improved probing attachment level and bone level. An improvement in probing attachment level by more than 4 mm can be expected twice as often with GTR or EMD as with flap surgery alone (Evidence Grade 1). Adjunctive therapy with coralline calcium carbonate in individual angular bone defects improves bone level more effectively than flap surgery alone (Evidence Grade 3). The outcomes are contradictory regarding probing attachment level. Scientific evidence for the efficacy of using other filler materials is insufficient. Adjunctive therapy with GTR and EMD appears to result in less improvement in smokers than in non-smokers. Scientific evidence for assessing and designing programs of supportive periodontal therapy is insufficient. Economic Aspects: Scientific evidence is lacking for determining cost-effectiveness and patient-perceived quality with regard to the various methods of prevention, diagnosis and treatment of chronic periodontitis. The studies that were included are too limited regarding quantity and assessed quality. Chronic Periodontitis as a Risk for Other Diseases: Scientific evidence is contradictory as to whether individuals with chronic periodontitis are at increased risk of developing coronary heart disease or stroke. Scientific evidence is lacking as to whether individuals with chronic periodontitis are at increased risk of developing diabetes mellitus, chronic obstructive pulmonary disease or rheumatoid arthritis. Scientific evidence is insufficient and contradictory as to whether women with chronic periodontitis during pregnancy have an increased risk for preterm birth. Scientific evidence of a relationship between chronic periodontitis and low birth weight is also insufficient. Principles of Evidence Grading Quality refers to the scientific quality of a particular study and its ability to reliably answer a specific question. Evidence Grade refers to the total scientific evidence for a conclusion, i.e., how many high-quality studies support the conclusion. Evidence Grade 1 A conclusion assigned Evidence Grade 1 is supported by at least two studies with high quality among the total scientific evidence. If some studies are at variance with the conclusion, the evidence grade may be lower. Evidence Grade 2 A conclusion assigned Evidence Grade 2 is supported by at least one study with high quality and two studies with moderate quality among the total scientific evidence. If some studies are at variance with the conclusion, the evidence grade may be lower. Evidence Grade 3 A conclusion assigned Evidence Grade 3 is supported by at least two studies with moderate quality among the total scientific evidence. If some studies are at variance with the conclusion, the evidence grade may be lower.
15164605 [A novel molecular marker for thrombus formation and life prognosis--clinical usefulness o 2004 Apr For a long time fibrinopeptide A(FPA), fibrinopeptide B(FPB), D-dimer, FM test, serum FDP, and thrombin anti-thrombin complex(TAT) are being used as molecular markers to for sure diagnose hypercoagulable state and thrombus formation. Indeed these molecular markers are very useful for diagnosing thrombus formation, disseminated intravascular coagulation(DIC), and the indicator of treatment of DIC. But these molecular parameters are not enough and difficult for prognosis of the disease or predicting the complication of patients as the most important subject for clinicians. The soluble fibrin monomer-fibrinogen complex (SF) is a complex coupling fibrin monomer and fibrinogen molecules to be formed in the early-activated state of blood coagulation. Thus such a molecular complex is expected to serve as a parameter for the diagnosis of thrombus formation and DIC, in particular its early stage. The aim of the present study is to evaluate a potential usefulness of a newly developed SF test utilizing an SF specific monoclonal antibody (IF-43). We measured SF together with established other parameters in 195 patients with DIC, subclinical DIC/hypercoagulable state, and non-DIC. The diagnosis of DIC was made based on a modified version of the criteria established by the Ministry of Health, Labor and Welfare of Japan. Underlying disease includes leukemia, malignant lymphoma, myelodysplastic syndrome (MDS), multiple injury, giant ovarian tumor, prostatic cancer with multiple bone metastasis, lung cancer, breast cancer with multiple lung and bone metastasis, severe pneumoniae, sepsis, hemophagocytic syndrome (HPS), and rheumatoid arthritis. The SF levels in DIC patients were significantly higher than those in the subclinical DIC/hypercoagulable state, and the non-DIC patients. Receiver operating characteristic (ROC) analysis shows that the specificity and sensitivity of the SF assay appears to be satisfactory. As the level of SF reflects the thrombin generation activity in plasma, it would serve as a strong tool to selectively kick up the state of thrombin generation. These results indicate that the SF could be a specific and reliable parameter for the diagnosis of DIC and contribute to legitimate managements of patients with DIC. The excessive life response to serious clinical insults, such as sepsis, severe pancreatitis, trauma and shock, is called systemic inflammatory response syndrome (SIRS). Once SIRS occurs, people may often die from serious complications such as adult respiratory distress syndrome (ARDS), acute lung injury (ALI), disseminated intravascular coagulation (DIC) and multiple organ failure (MOF). Especially, ALI followed by pneumoniae associated with SIRS could depend on patient's prognosis and life. That is to say, it seems to be urgent for clinicians to make differential diagnosis between Pneumoniae associated with SIRS and Coagulopathy (PASC) and Simple Pneumoniae (SP). Soluble fibrin monomer-fibrinogen complex(SF) is formed in the early-activated state of blood coagulation. Thus such a molecular complex is expected to serve as a parameter for the diagnosis of coagulopathy, in particular its early stage. The aim of the present study is to make differential diagnosis between Pneumoniae associated with SIRS and Coagulopathy (PASC) and Simple Pneumoniae(SP) by using a newly developed SF test utilizing an SF specific monoclonal antibody (IF-43). We measured SF together with established other parameters, hemogram, blood laboratory items in 7 patients with PASC and 17 patients with SP. The diagnosis of Pneumoniae was defined according to the criteria: clinical symptoms abnormal shadow in both Chest X-p and Chest CT, increased level of CRP, number of WBC. The diagnosis of SIRS was based on the criteria established by American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM) Consensus Conference held in August of 1991 in Northbrook, IL (USA). Underlying disease includes leukemias, malignant lymphoma, myelodysplastic syndrome (MDS), multiple myeloma, idiopathic thrombocytopenia purpura(ITP), multiple injury (bone fracture), cerebral hemorrhage, enterocolitis, Appendicitis, lung cancer, larynx cancer, bronchiolitis obliterans organizing pneumonia(BOOP), chronic obstructive pulmonary disease(COPD), sepsis. The SF levels in PASC patients are significantly higher than those in SP patients (p < 0.001). Otherwise, there is no significant difference of the CRP levels between in PASC group and SP group (p < ns). There is no co-relationship between SF level and D-dimer level. Receiver operating characteristic (ROC) analysis shows that the specificity and sensitivity of the SF assay appears to be quite satisfactory. As the level of SF reflects the thrombin generation activity in plasma, it would serve as a strong tool to selectively kick up the state of thrombin generation. These results indicate that the SF could be a specific and reliable parameter for the diagnosis of PASC and contribute to legitimate managements of patients with PASC.
23720861 Gadolinium-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-icosahedral closo 2004 Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally (1). Protons (hydrogen nuclei) are widely used in imaging because of their abundance in water molecules. Water comprises ~80% of most soft tissue. The contrast of proton MRI depends primarily on the density of the nucleus (proton spins), the relaxation times of the nuclear magnetization (T1, longitudinal, and T2, transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the development of contrast agents. Most contrast agents affect the T1 and T2 relaxation times of the surrounding nuclei, mainly the protons of water. T2* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field. Cross-linked iron oxide nanoparticles and other iron oxide formulations affect T2 primarily and lead to decreased signals. On the other hand, paramagnetic T1 agents, such as gadolinium (Gd(3+)) and manganese (Mn(2+)), accelerate T1 relaxation and lead to brighter contrast images (2). Gadolinium (Gd), a lanthanide metal ion with seven unpaired electrons, has been shown to be very effective in enhancing proton relaxation because of its high magnetic moment and water coordination (3, 4). Gd-Labeled diethylenetriamine pentaacetic acid (Gd-DTPA) was the first intravenous MRI contrast agent used clinically, and a number of similar Gd chelates have been developed in an effort to further improve clinical use. Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (5). 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 (6-10). 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 antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (8-12). Extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) contain a tripeptide sequence consisting of Arg-Gly-Asp (RGD), which binds to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for the imaging of tumors and tumor angiogenesis (13). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (14) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in xenografts in nude mice (15, 16). Several small molecular MRI Gd-based contrast agents conjugated with a cyclic RGD peptide have been studied (17). However, these low molecular weight Gd chelates have short blood and tissue retention times, which limit their use as imaging agents in the vasculature and cancer. Furthermore, these low molecular weight MRI contrast agents exhibit low r(1) relaxivity value (~4 mM(–1)s(–1) per Gd) and high toxicity (nephrogenic systemic fibrosis in patients with renal dysfunction) (18). In order to obtain sufficient contrast enhancement, a large number of Gd(3+) ions bound per target is needed. Li et al. (19) have developed polyhedral boranes as a scaffold for the targeted high payload delivery of drugs and imaging agents. A functionalizable monodisperse molecular borane scaffold, [closoB(12)(OH)(12)](2–), conjugated with twelve radial ethylene glycol (PEG)(3) arms with attachments of Gd-chelates (20). Goswami et al. (21) utilized [closoB(12)(OH)(12)](2–) as a high payload MRI contrast agent (CA-12) carrying eleven copies of Gd-DOTA chelates and one copy of Glu-Glu-{[cyclo(Arg-Gly-Asp-d-Phe-Lys)](2)}(2) (cRGD) via PEG linkers for use as a high-performance MRI contrast agent in nude mice bearing human breast cancer xenografts.
21755635 Poly(ethylene glycol)-coated gold nanocages bioconjugated with [Nle(4),d-Phe(7)]-α-melano 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets in small animals (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 background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have a wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low infrared background, 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 becoming a noninvasive alternative to radionuclide imaging in small animals (4, 5). Photoacoustic imaging (PAI) is an emerging hybrid biomedical imaging modality based on the photoacoustic effect. In PAI, non-ionizing optical pulses are delivered into biological tissues. Some of the delivered energy is absorbed and converted into heat, leading to transient thermoelastic expansion and thus ultrasonic emission. The generated ultrasonic waves are then detected by ultrasonic transducers to form images. It is known that optical absorption is closely associated with physiological properties, such as hemoglobin concentration and oxygen saturation. As a result, the magnitude of the ultrasonic emission (i.e., photoacoustic signal), which is proportional to the local energy deposition, reveals physiologically specific optical absorption contrast and tissue structures. However, exogenous NIR contrast agents are necessary to overcome the intrinsic low tissue- and hemoglobin- absorption and scattering of tissue. On the other hand, these small molecules exhibit fast clearance, small optical absorption cross section, and non-targeted specificity. Therefore, there is a need for contrast agents with long blood circulation and targeted specificity. Gold (Au) nanoparticles have been studied as molecular imaging agents because of their bright NIR fluorescence emission of 700–900 nm and low toxicity (6, 7). They can be tuned to emit in a range of wavelengths by changing their sizes, shapes, and composition, thus providing broad excitation profiles and high absorption coefficients. They can be coated and capped with hydrophilic materials for additional conjugation with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds for in vitro and in vivo studies. Au nanoparticles have been approved by the United States Food and Drug Administration for the treatment of patients with rheumatoid arthritis. Au nanoparticles have been studied as contrast agents in X-ray/computed tomography, NIR optical coherence tomography, PAI, and photoacoustic tomography (PAT) (8). NIR Au nanocages (AuNCs) are biocompatible, have low toxicity, and are tunable to strong NIR absorption (9). They have an outer edge of ~50 nm and an inner edge of ~42 nm, with a wall thickness of ~4 nm. Yang et al. (10) have performed PAT of the cerebral cortex of rats with poly(ethylene glycol)-coated AuNCs (PEG-AuNCs) as an optical contrast agent. The investigators observed an enhanced optical contrast in the vasculature in the cerebral cortex. Song et al. (11) demonstrated the use of Au nanocages as a PAI probe for detection of sentinel lymph nodes in rats. Malignant melanoma is the deadliest form of skin cancer (12). Early and accurate diagnosis is necessary for surgery and successful treatment (13). The melanocortin (MC) system is a neuropeptide network of the skin, and it is involved in pigmentation regulation, cortisol production, and many other physiological processes (14). Most cutaneous cell types express MC receptors, proopiomelanocortin (POMC), and prohormone convertases, and they also release MCs. However, these receptors have been found to be overexpressed in melanoma cells. There are five MC receptors (MC1R to MC5R), which belong to the G-protein−coupled receptor superfamily. Melanotropin-stimulating hormones (α-, β-, and γ-MSH) are derived from POMC by the proteolytic action of prohormone convertases. α-MSH (Ac-Ser(1)-Tyr(2)-Ser(3)-Met(4)-Glu(5)-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH(2)), produced by the brain and pituitary gland, is a tridecapeptide (13 amino acids) and is the most potent melanotropic peptide (15) in the regulation of skin pigmentation via MC1R. Radiolabeled α-MSH peptide analogs have been shown to specifically bind to MC1R, which is overexpressed on human and mouse melanoma cells (16-20). Kim et al. (21) have evaluated [Nle(4),d-Phe(7)]-α-MSH-PEG-AuNCs for in vivo PAT imaging of melanomas in mice.
15563237 Gadofosveset: MS 325, MS 32520, Vasovist, ZK 236018. 2004 Gadofosveset [MS 325, MS 32520, Vasovist, ZK 236018], a gadolinium-based chelate, is an injectable angiography imaging agent for use in magnetic resonance imaging (MRI) scans. The agent is being developed by EPIX Medical (formerly Metasyn) for diagnostic imaging of blood vessels of the cardiovascular system. Gadofosveset has potential as an alternative to the range of x-ray, invasive, catheter-based angiograms and thallium stress tests currently used in the diagnosis of coronary artery disease. The agent may also have applications in the diagnosis of peripheral vascular disease, thrombosis and breast cancer. Unlike conventional MRI contrast agents, gadofosveset binds to serum albumin in the blood and moves with the blood through the arteries and veins for an extended period of time before being excreted by the kidneys. The MRI with gadofosveset allows 3D images of the whole body to be accessed in one imaging session. Moreover, it makes it possible to view vessel structures.EPIX Medical has acquired an exclusive licence from the Massachusetts General Hospital to a certain technology, including patents and patent applications, that relates to the company's product candidates such as gadofosveset.EPIX Medical, Mallinckrodt (Tyco International) and Schering AG signed several agreements to develop, manufacture and market gadofosveset (formerly known as Mallinckrodt's AngioMARK). Initially, in June 2000 Schering AG acquired worldwide exclusive rights (except for Japan) from EPIX Medical to develop and market gadofosveset. Under the terms of the agreement, EPIX Medical is responsible for the completion of clinical trials and filing for approval in the US, while Schering AG undertakes responsibility for clinical investigation of gadofosveset outside the US. Mallinckrodt is responsible and will undertake a long-term supply contract for gadofosveset for clinical development and sales. Schering's subsidiary Berlex will market the product in the US after the approval via its 100 sales representatives. In January 2001, EPIX Medical reacquired the Japanese rights for gadofosveset from Daiichi Radioisotope Laboratories and exclusively licensed them to Schering AG. With this agreement, Schering AG has worldwide rights for gadofosveset. The financial terms of the Japanese rights agreement included a US$3 million upfront fee, and additional milestone payments from Schering AG to EPIX Medical. On 16 December 2003, EPIX announced that it submitted an NDA to the US FDA for gadofosveset for vascular imaging using magnetic resonance angio-graphy (MRA). This is the first NDA filed for approval with the FDA for a MR contrast agent for the primary indication of MRA. The NDA is based on the results of 18 clinical trials in 1438 patients who received gadofosveset. In February 2004, EPIX Medical announced that the NDA for gadofosveset was accepted for filing by the FDA and would proceed through a standard review cycle. The approval for gadofosveset is expected at the end of 2004. In January 2004, Schering reported at the JP Morgan Healthcare Conference that it plans a product launch in the US sometime in 2005.EPIX and Schering have completed four phase III studies in patients with suspected atherosclerotic disease in the aortoilliac, pedal and renal arteries for inclusion in the NDA submission. These trials were conducted at 86 clinical sites and involved 782 patients. The blinded reading of almost 4000 vessels showed that gadofosveset improved diagnostic accuracy of MRA compared with non-contrast MRA. The diagnostic efficacy of gadofosveset-enhanced MRA was comparable to that of x-ray angiography. These trials were initiated in accordance with the recommendations of the FDA to expand gadofosveset's target indication of aortoiliac occlusive disease to a broader peripheral vascular disease indication. In July 2004, EPIX Medical initiated a multicentre, post-NDA trial with gadofosveset for use in high-resolution vessel imaging for the characterisation of vascular wall structures and vulnerable plaque. The trial will investigate whether gadofosveset has an extended imaging window above and beyond that which was demonstrated in phase III studies. In June 2004, Schering submitted gadofosveset for approval in Europe for use as a conrast agent for MRA. The launch in Europe is projected for 2006 (Schering, Annual Report 2003). Schering has initiated its first feasibility, multicentre (Europe, US), phase III clinical trial with gadofosveset for the imaging of coronary artery disease in approximately 50 patients. This trial follows a successful completion of phase II feasibility studies with gadofosveset in the imaging of coronary artery disease and breast tumour imaging. In July 2004, EPIX announced that it initiated a multicentre phase IIa feasibility clinical trial with gadofosveset in the imaging of both the coronary arteries and myocardial perfusion.EPIX Medical is conducting preclinical investigation with gadofosveset for myocardial perfusion and rheumatoid arthritis.EPIX Medical, Mallinckrodt and Pfizer have announced a collaboration to investigate MRI imaging with gadofosveset in the diagnosis and monitoring of female sexual arousal dysfunction (FSAG). EPIX Medical completed enrolment in a phase II clinical feasibility trial using gadofosveset for this indication. It is estimated that more than 10 million women in the US suffer from FSAD.EPIX Medical was granted a US patent No. 6,676,929 covering composition-of-matter claims for the chemical structure of gadofosveset. The patent is entitled "Diagnostic Imaging Contrast Agents With Extended Blood Retention". Its expiry date is August 2015. However, under provision of the Hatch-Waxman Act, the terms of the patent may be extended following FDA approval. In its 2002 Annual Report, Schering predicted that gadofosveset has the potential to reach peak sales of EUR100 million, 3 years after launch - at the time, launch in the US was anticipated in 2005. Earlier, at an analyst presentation in Berlin in March 2002, the company stated that launch in the US was planned for 2004.
12369790 Basic fibroblast growth factor stimulates osteoclast recruitment, development, and bone pi 2002 Oct Increased local osteoclast (OC)-mediated bone resorption coincides with angiogenesis in normal bone development and fracture repair, as well as in pathological disorders such as tumor-associated osteolysis and inflammatory-related rheumatoid arthritis or periodontal disease. Angiogenic stimulation causes recruitment, activation, adhesion, transmigration, and differentiation of hematopoietic cells which may therefore enable greater numbers of pre-OC to emigrate from the circulation and develop into bone-resorptive OCs. A chick chorioallantoic membrane (CAM) model, involving coimplantation of a stimulus in an agarose plug directly adjacent to a bone chip was used to investigate if a potent angiogenic stimulator, basic fibroblast growth factor (bFGF), could promote OC recruitment, differentiation, and resorption in vivo. Angiogenesis elicited by bFGF on the CAM was accompanied by increased OC formation and bone pit resorption (both overall and on a per OC basis) on the bone implants in vivo. In complementary in vitro assays, bFGF did not directly stimulate avian OC development from bone marrow mononuclear cell precursors, consistent with their low mRNA expression of the four avian signaling FGF receptors (FGFR)-1, FGFR-2, FGFR-3, and FGFR-like embryonic kinase (FREK). In contrast, bFGF activated isolated avian OC bone pit resorption via mechanisms inhibited by a selective cyclo-oxygenase (COX)-2 prostaglandin inhibitor (NS-398) or p42/p44 MAPK activation inhibitor (PD98059), consistent with a relatively high expression of FGFR-1 by differentiated avian OCs. Thus, bFGF may sensitively regulate local bone resorption and remodeling through direct and indirect mechanisms that promote angiogenesis and OC recruitment, formation, differentiation, and activated bone pit resorption. The potential for bFGF to coinduce angiogenesis and OC bone remodeling may find clinical applications in reconstructive surgery, fracture repair, or the treatment of avascular necrosis. Alternatively, inhibiting such bFGF-dependent processes may aid in the treatment of inflammatory-related or metastatic bone loss.
11953973 The modulation of matrix metalloproteinase and ADAM gene expression in human chondrocytes 2002 Apr OBJECTIVE: Previous studies have reported elevated levels of interleukin-1 (IL-1) and oncostatin M (OSM) in rheumatoid joints, as well as the synergistic degradation of human articular cartilage by this cytokine combination. The present study was undertaken to investigate the ability of IL-1 and OSM to modulate gene expression of matrix metalloproteinase (MMP), ADAM, and ADAM-TS (ADAM with thrombospondin motifs) family members in human chondrocytes. METHODS: T/C28a4 human chondrocytes were stimulated for 2-48 hours with IL-1 and/or OSM. Total RNA was harvested, reverse transcribed, and assessed by real-time polymerase chain reaction for the expression of various MMP, ADAM, and ADAM-TS messenger RNAs (mRNA). Results were normalized to 18S ribosomal RNA. RESULTS: IL-1 and OSM synergized to markedly induce the expression of the collagenases MMP-1, MMP-8, and MMP-13 as well as MMP-3, an activator of proMMPs. Expression of mRNA for MMPs 1, 3, and 13 was induced early, whereas that of MMP-8 mRNA occurred late. Gene expression of MMP-14, an MMP that degrades collagen and activates proMMP-13, was elevated by this combination. IL-1 and OSM also synergized to induce gene expression of the aggrecanase ADAM-TS4, but not ADAM-TS5. CONCLUSION: These data indicate that the potent cartilage-degrading properties of the combination of IL-1 and OSM are potentially mediated by a synergistic induction of the aggrecan-degrading enzyme ADAM-TS4 and the collagen-degrading enzymes MMP-1, MMP-8, MMP-13, and MMP-14, although differences in the magnitude of response and in the time course of induction were observed. A role for MMPs 3 and 14 in the activation of proMMPs may also be implicated.
12764648 Performance of a flat-panel detector in the detection of artificial erosive changes: compa 2003 Jun The purpose of this study was to compare a large-area, direct-readout, flat-panel detector system with a conventional screen-film system, a storage-phosphor system, and a mammography screen-film system with regard to the detection of artificial bone erosions simulating rheumatoid disease, and to assess its diagnostic performance with decreasing exposure dose. Six hundred forty regions were defined in 160 metacarpophalangeal and proximal interphalangeal joint specimens from 20 monkey paws (4 regions per joint). Artificial bone erosions were created in 320 of these 640 regions. Specimens were enclosed in containers filled with water to obtain absorption and scatter radiation conditions similar to those of a human hand. Imaging was performed using a flat-panel system, a speed class 200 screen-film system, a mammography screen-film system, and a storage-phosphor system under exactly matched conditions. Different exposure doses equivalent to speed classes of S=100, 200, 400, 800, 1600, and 3200 were used. In all images the presence or absence of a lesion was assessed by three radiologists using a five-level confidence scale. Receiver operating characteristic (ROC) analysis was performed for a total of 21,120 observations (1920 for each imaging modality and exposure level) and diagnostic performance estimated by the area under the ROC curve (A(z)). The significance of differences in diagnostic performance was tested with analysis of variance. The ROC analysis showed A(z) values of 0.809 (S=200), 0.768 (S=400), 0.737 (S=800), 0.710 (S=1600), and 0.685 (S=3200) for the flat-panel system, 0.770 for the speed class 200 screen-film system, 0.781 (S=200), 0.739 (S=400), 0.724 (S=800), 0.680 (S=1600) for the storage-phosphor system, and 0.798 for the mammography screen-film system. Analysis of variance showed significant differences between different combinations of imaging modalities and exposure doses ( p<0.05). The diagnostic performance of the flat-panel detector system is superior to that of a screen-film system and a storage-phosphor system for the detection of erosive lesions at clinical exposure settings (S=200). Using the flat-panel system the exposure dose can be reduced by 50% to obtain a diagnostic performance comparable to a speed class 200 screen-film system.
15294004 Zinc ion dependent B-cell epitope, associated with primary Sjogren's syndrome, resides wit 2004 Aug 12 The Ro/La ribonucleoprotein (RNP) complex is composed of the proteins Ro60kD, Ro52kD, and La48kD that are in association with one small cytoplasmic RNA (YRNA). Specific protein-RNA and protein-protein interactions are thought to occur through the RNP and zinc-finger secondary structure elements of the Ro60kD protein. The aim of our study was to investigate the antigenic properties of the zinc finger domain of the Ro60KD autoantigen and its contribution to the formation of Ro/La RNP complex. It was found that the peptide VSLVCEKLCNEKLLKKARIHPFHILIA (Zif-1), which corresponds to the natural sequence of the zinc finger domain (301-327), and the peptide C(Acm)NEKLLKKARIC(Acm), analogous to the intermediate loop 310-319 (Zif-3) of the same domain of Ro60KD, are recognized by the majority of anti-Ro/SSA and anti-La/SSB positive sera (82.6% and 77.1%, respectively) in the absence of zinc ions. The same sera failed to react with Zif-1 peptide in the presence of Zn2+. In contrast, the addition of zinc ions was necessary for the binding of Zif-1 to recombinant Ro52KD as shown by direct binding experiments of the recombinant protein with synthetic peptides. Our data suggest the zinc finger domain of Ro60kD contains a B-cell epitope with high specificity for primary Sjogren's syndrome. Furthermore, depending on the presence of zinc ions, the zinc finger domain of the Ro60KD protein can exist in two different conformational states favoring either an interaction with the Ro52KD protein or binding with autoantibodies.
11817592 Candidate T cell epitopes of the human La/SSB autoantigen. 2002 Jan OBJECTIVE: To identify T cell epitopes of the human La autoantigen involved in the generation of anti-Ro/La autoantibodies. METHODS: Molecular techniques were used for HLA typing of 219 white patients with systemic lupus erythematosus and 125 white patients with primary Sjögren's syndrome. Anti-Ro/La antibody levels were measured by enzyme-linked immunosorbent assay. Peripheral blood mononuclear cell responses to an overlapping series of synthetic 15-mer peptides spanning the entire La sequence were examined in pools or individually in conventional 7-day proliferation assays. RESULTS: HLA typing confirmed that the HLA-DR3/DQ2 haplotype is closely associated with the occurrence of anti-Ro/La antibodies, and that the frequency of HLA-DR1 and DR4 haplotypes is reduced among antibody-positive patients. We identified 3 regions of the La sequence likely to contain T cell epitopes and 1 peptide, La 49-63, that generated a low-level but clear-cut T cell proliferative response. The HLA restrictions of these responses mirrored the HLA association data from the cohort study. Among individuals who were HLA-DR3 positive, there was no difference between patients and controls in the proliferative response to the La 49-63 peptide. CONCLUSION: Our data suggest that these are naive T cell responses, and that the identification of T cell epitopes involved in the generation of anti-Ro/La autoantibodies should focus on alternative candidate antigens.
14634099 Tolerance through indifference: autoreactive B cells to the nuclear antigen La show no evi 2003 Dec 1 Systemic autoimmune diseases are characterized by the production of high titer autoantibodies specific for ubiquitous nuclear self-Ags such as DNA, Sm, and La (SS-B), so the normal mechanisms of B cell tolerance to disease-associated nuclear Ags have been of great interest. Mechanisms of B cell tolerance include deletion, anergy, developmental arrest, receptor editing, and B cell differentiation to the B-1 subtype. However, recent studies in our laboratory have suggested that B cell tolerance to the nuclear autoantigen La is limited in normal mice, and tolerance may reside primarily in the T cell compartment. To test this hypothesis, we created Ig transgenic mice expressing the IgM H chain from an mAb specific for a xenogeneic epitope within human La (hLa). These mice were bred with hLa-transgenic mice that constitutively express hLa in a manner comparable to endogenous mouse La. Between 5-15% of transgenic B cells developing in the absence of hLa were specific for hLa, and these cells were neither depleted nor developmentally arrested in the presence of endogenous hLa expression. Instead, these autoreactive B cells matured normally and differentiated into Ab-forming cells, capable of secreting high titer autoantibody. Additionally, the life span of autoreactive hLa-specific B cells was not reduced, and they were phenotypically and functionally indistinguishable from naive nonautoreactive hLa-specific B cells developing in the absence of hLa. Together these data suggest a lack of intrinsic B cell tolerance involving any known mechanisms indicating that these autoreactive B cells are indifferent to their autoantigen.
20301357 WAS-Related Disorders. 1993 CLINICAL CHARACTERISTICS: The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities. DIAGNOSIS/TESTING: The diagnosis of a WAS-related disorder is established in a male proband with both congenital thrombocytopenia (<70,000 platelets/mm(3)) and small platelets, in addition to at least one of the following features: eczema, recurrent bacterial or viral infections, autoimmune disease(s), malignancy, reduced WASP expression in a fresh blood sample, abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins, or positive maternal family history of a WAS-related disorder. Identification of a hemizygous WAS pathogenic variant on molecular genetic testing is necessary to confirm the diagnosis. MANAGEMENT: Treatment of manifestations: Treatment options depend on an individual's predicted disease burden; hematopoietic cell transplantation (HCT) is the only known curative treatment. Topical steroids for eczema; antibiotics for infected eczema; judicious use of immunosuppressants for autoimmune disease; granulocyte colony stimulating factor (G-CSF) and appropriate antibiotics for neutropenia. Prevention of primary manifestations: Pneumocystis jiroveci (formerly known as Pneumocystis carinii pneumonia, or PCP) prophylaxis with Bactrim(®) (trimethoprim-sulfamethoxazole) or pentamidine, intravenous immunoglobulin (IVIgG) replacement therapy, routine childhood "non-live" immunizations; judicious use of platelet transfusions for significant bleeding and surgical procedures. Surveillance: Routine monitoring of blood counts and adequacy of IVIgG replacement therapy. Agents/circumstances to avoid: Circumcision of at-risk newborn males who have thrombocytopenia; use of medications that interfere with platelet function. Defer elective procedures until after HCT. Evaluation of relatives at risk: Evaluation of at-risk newborn males so that morbidity and mortality can be reduced by early diagnosis and treatment. GENETIC COUNSELING: WAS-related disorders are inherited in an X-linked manner. If the mother is a carrier of a WAS pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Males will pass the pathogenic variant to all of their daughters and none of their sons. Female carriers of a WAS pathogenic variant are usually asymptomatic and have no immunologic or biochemical markers of the disorder. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant has been identified in the family.
23700638 Polyethylene glycol–coated gold nanoshells conjugated with anti-VCAM-1 antibody. 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets in small animals (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–650 nm) are used. Near-infrared (NIR) fluorescence (650–1,000 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have a wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low infrared background, 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 becoming a noninvasive alternative to radionuclide imaging in small animals (4, 5). Photoacoustic imaging (PAI) is an emerging hybrid biomedical imaging modality based on photoacoustic effects (6-9). In PAI, non-ionizing optical pulses are delivered into biological tissues. Some of the delivered energy is absorbed and converted into heat, leading to transient thermoelastic expansion and thus ultrasonic emission. The generated ultrasonic waves are then detected by ultrasonic transducers to form images. It is known that optical absorption is closely associated with physiological properties, such as hemoglobin concentration and oxygen saturation. As a result, the magnitude of the ultrasonic emission (i.e., photoacoustic signal), which is proportional to the local energy deposition, reveals physiologically specific optical absorption contrast and tissue structures. However, exogenous NIR contrast agents are necessary to overcome the intrinsic low tissue and hemoglobin absorption and the scattering of signal in tissue. On the other hand, these small molecules exhibit fast clearance, small optical absorption cross section, and non-targeted specificity. Therefore, there is a need for contrast agents with long blood circulation and targeted specificity. Gold (Au) nanoparticles have been studied as molecular imaging agents because of their bright NIR fluorescence emission of 700–900 nm and low toxicity (10). They can be tuned to emit in a range of wavelengths by changing their sizes, shapes, and composition, thus providing broad excitation profiles and high absorption coefficients. They can be coated and capped with hydrophilic materials for additional conjugation with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds for in vitro and in vivo studies. Use of Au nanoparticles has been approved by the United States Food and Drug Administration for the treatment of patients with rheumatoid arthritis. Au nanoparticles have been studied as contrast agents in X-ray/computed tomography, NIR optical coherence tomography, PAI, and photoacoustic tomography (PAT) (3). NIR Au nanocages (AuNCs) are biocompatible, have low toxicity, and are tunable to strong NIR absorption (11). They have an outer edge of ~50 nm and an inner edge of ~42 nm, with a wall thickness of ~4 nm. Yang et al. (12) performed PAT of the cerebral cortex of rats with polyethylene glycol–coated AuNCs (PEG-AuNCs) as an optical contrast agent. The investigators observed an enhanced optical contrast in the vasculature in the cerebral cortex. Song et al. (13) demonstrated the use of Au nanocages as a PAI probe for detection of sentinel lymph nodes in rats. Endothelial cells are important cells in inflammatory responses (14, 15). Bacterial lipopolysaccharide, virus, inflammation, and tissue injury increase tumor necrosis factor α (TNFα), interleukin-1 (IL-1), and other cytokine and chemokine secretion. Emigration of leukocytes from blood is dependent on their ability to adhere to endothelial cell surfaces. Inflammatory mediators and cytokines induce chemokine secretion from endothelial cells and other vascular cells and increase their expression of cell surface adhesion molecules, such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), integrins, and selectins. Chemokines are chemotactic toward leukocytes and toward sites of inflammation and tissue injury. The movement of leukocytes through endothelial junctions into the extravascular space are highly orchestrated through various interactions with different adhesion molecules on endothelial cells (16). VCAM-1 is found in very low levels on the cell surface of resting endothelial cells and other vascular cells, such as smooth muscle cells and fibroblasts (16-20). VCAM-1 binds to the very late antigen-4 (VLA-4) integrin on the cell surface of leukocytes. IL-1 and TNFα increase expression of VCAM-1 and other cell adhesion molecules on the vascular endothelial cells, which leads to leukocyte adhesion to the activated endothelium. Furthermore, VCAM-1 expression is also induced by oxidized low-density lipoproteins under atherogenic conditions (21). Overexpression of VCAM-1 by atherosclerotic lesions plays an important role in their progression to vulnerable plaques, which may erode and rupture. Rouleau et al. (22) developed gold nanoshells coated with polyethylene glycol (PEG) and anti-VCAM-1 antibody (AuNS-PEG-VCAM-1Ab) for use with in vivo PAT imaging of atherosclerotic plaques in mice.
15383579 CpG DNA induces IgG class switch DNA recombination by activating human B cells through an 2004 Oct 1 TLRs are pattern recognition receptors that initiate innate immune responses. TLR9 detects microbial DNA with hypomethylated CpG motifs and in humans is preferentially expressed by IFN-alpha-producing plasmacytoid dendritic cells and B cells. In addition to favoring IFN-alpha release, TLR9 signals B cell activation, proliferation, and IgM production. Recent findings suggest that CpG DNA-TLR9 interaction plays a key role in systemic lupus erythematosus and rheumatoid arthritis, two autoimmune disorders characterized by dysregulated production of DNA-reactive IgG. We show that CpG DNA initiates germline C(gamma)1, C(gamma)2, and C(gamma)3 gene transcription by activating B cells through a TLR9-mediated NF-kappaB-Rel-dependent innate pathway that cooperates with IL-10 through STAT proteins and IFN-responsive factors. This pathway is inhibited by chloroquine, a drug that attenuates the clinical manifestations of IgG-mediated autoimmune disorders. Germline C(gamma) gene transcription is associated with up-regulation of activation-induced cytidine deaminase, a key element of the B cell class switch-inducing machinery, and is followed by class switch DNA recombination from C(micro) to C(gamma)1, C(gamma)2, and C(gamma)3. Subsequent IgG production requires additional signals from BCR and a B cell-activating factor of the TNF family (BAFF), produced by dendritic cells upon exposure to IFN-alpha. Our findings suggest that CpG DNA-TLR9 interaction may be important to initiate or amplify early T cell-independent IgG responses against pathogens. This implies that CpG DNA released during infections may exacerbate autoimmunity by stimulating autoreactive B cells to switch from an IgM to a more pathogenic IgG isotype.
15265936 Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation thr 2004 Aug 1 The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-kappa B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-kappa B. In the present study, we investigated the effect of this drug on the activation of NF-kappa B by a wide variety of agents. We found that celecoxib suppressed NF-kappa B activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1 beta. Celecoxib inhibited TNF-induced I kappa B alpha kinase activation, leading to suppression of I kappa B alpha phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-kappa B without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-kappa B activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with I kappa B alpha kinase (IKK). Celecoxib abrogated the NF-kappa B-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-kappa B-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-kappa B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-kappa B, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-kappa B activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.
15008973 T cell help is required to induce idiotypic-anti-idiotypic autoantibody network after immu 2004 Mar Immunotherapies against autoimmune diseases have been of limited success. Preventive vaccines could be developed on the basis to abrogate unwanted immune responses to defined autodeterminants. In this study it is shown that immunization of BALB/c mice with two linear T and B cell epitopes of the human La/SSB autoantigen (spanning the regions 289-308aa and 349-364aa) and their complementary forms specified by the complementary mRNA, results in characteristic B and T cell responses. Mice immunized with the 289-308aa epitope or its complementary peptide elicited specific antibodies against both epitopes. In contrast, mice immunized with the 349-364aa epitope or its complementary peptide mounted antibody titres against the immunizing peptide only. According to these data, the 289-308aa epitope and its complementary form were capable to generate an idiotypic-anti-idiotypic response, which were cross-regulated. Peptide-specific T cell proliferation and cytokine production in vitro revealed the induction of a two-stage T helper response (Th1-->Th2 type) after immunization with either the epitope 289-308 or its complementary peptide. IgG1 was the predominant subclass after immunization with the two forms of epitopes 289-308 and 349-364, while a response of the IgG2b > IgG2a was obtained after the immunization with the complementary form of 349-364 epitope reflecting the TH2/TH1 polarization, respectively. Our data suggest that the complementary peptides of two immunodominant epitopes of human LaSSB can mimic the autoantibodies against these epitopes and establish an active idiotypic-anti-idiotypic network.
12102760 Intracellular trafficking and surface expression of SS-A (Ro), SS-B (La), poly(ADP-ribose) 2002 Jun Autoantibodies directed against nucleic acid and protein complexes present in cell nuclei characterize autoimmune diseases and are employed in diagnosis. The mechanisms by which these autoantigens escape immunological tolerance are largely unknown, but a number of recent observations suggest that modified self-protein generated during apoptosis my play an important part in the development of autoimmunity. To investigate the possibility that autoantibodies in patients with Sjögren's syndrome are induced by apoptosis and presented on the surface of the cell, the internal distribution of autoantigens in apoptotic human salivary gland cells was studied in vitro. Salivary gland cells were treated with tumour necrosis factor-alpha, an apoptosis inducer. At increasing times after induction, cells were homogenized and cytoplasmic, cell surface membrane and nuclear compartments were fractionated using a sucrose density-gradient system. Autoantigens alpha-fodrin, SS-A (Ro), SS-B (La), and the enzyme poly(ADP-ribose) polymerase, were detected by conventional immunofluorescence and confirmed by Western immunoblotting. At increasing times after apoptosis, nuclear proteins SS-A (Ro) and SS-B (La), but not poly(ADP-ribose) polymerase were relocated from the cell nucleus to the cell surface membrane. Fodrin, a cytoplasmic protein, was also translocated to the cell membrane after cleavage of alpha-fodrin. These results show that autoantigens fodrin, SS-A (Ro) and SS-B (La) in human salivary gland cells undergo a striking redistribution during apoptosis and relocate to the cell membrane of apoptotic cells. The appearance of autoantigens on the surface of induced cells could form the basis of a mechanism for autoantigen presentation, processing and autoantibody induction.
15545270 Autoimmunity against a tissue kallikrein in IQI/Jic Mice: a model for Sjogren's syndrome. 2005 Feb 4 We have recently characterized IQI/Jic mice as a model for Sjogren's syndrome (SS), a chronic autoimmune disease in humans. In SS, local lymphocytic infiltrations into salivary and lacrimal glands frequently develop to the involvement of systemic exocrine and nonexocrine organs, and the mechanism for progression of this disease remains obscure. Herein, we report identification of an autoantigen shared by various target organs in IQI/Jic mice. Polypeptides identified based on immunorecognition by autoantibodies in sera from IQI/Jic mice affected with autoimmune disease (>12 weeks of age) were tissue kallikrein (Klk)-1 and -13 and were cross-reactive to the autoantibodies. Interestingly, Klk-13, but not Klk-1, caused a proliferative response of splenic T cells from IQI/Jic mice from the age of 4 weeks onward. In addition, remarkably enhanced expression of Klk-13 was observed in the salivary glands of the mice in accordance with the development of inflammatory lesions. These results indicate that Klk-13 acts as an autoantigen and may increase T cells responsive to organs commonly expressing Klk-13, playing a pivotal role in the etiology of progression of disease in IQI/Jic mice. Our findings provide insights into the contributions of autoantigens shared by multiple organs in the progress of SS from an organ-specific to a systemic disorder.
12784401 Sex steroid hormones in primary Sjögren's syndrome. 2003 Jun OBJECTIVE: To investigate the relationships between concentrations of sex hormones and measures of disease activity in patients with primary Sjögren's Syndrome (pSS). METHODS: Fifty-four women were evaluated: 39 patients (age, Q1,Q3: 57.0 yrs; 46, 66) diagnosed with pSS and 15 patients (49.0 yrs; 45, 60) who did not meet diagnostic criteria for pSS. The following measures of disease activity were assessed: serological data [antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum immunoglobulin levels (IgG, IgA, IgM), serum protein, anti-SSA, and anti-SSB], labial minor salivary gland focus score, salivary flow rates, and objective measures of eye dryness (fluorescein corneal staining and unstimulated Schirmer's I test). Spearman correlations were calculated between these indices of disease activity and serum levels of sex hormones: dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, testosterone, dihydrotestosterone (DHT), estrone, estradiol, and sex hormone binding globulin (SHBG). RESULTS: Numerous differences were noted between cases and controls with disease activity measures. All median values of sex steroid hormones were within the range of normal for pSS cases. Positive correlations were noted between testosterone and ESR (r = 0.36, p = 0.03), testosterone and serum protein (r = 0.37, p = 0.05), and testosterone and focus score (r = 0.44, p = 0.007). Negative correlations were present between SHBG and anti-SSA (r = -0.33, p = 0.05), SHBG and anti-SSB (r = -0.43, p = 0.009), and DHT and CRP (r = -0.41, p = 0.05). No correlations were noted between estrogens and measures of pSS disease activity. CONCLUSION: Higher levels of disease activity (ESR, serum protein, and focus score) were associated with higher concentrations of testosterone. No correlation between disease activity and estrogens was found.
15187246 Combined therapy with rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone ( 2004 Aug OBJECTIVE: To determine the safety and therapeutic response of a regimen consisting of cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) plus rituximab in patients with Sjögren's syndrome (SS) and aggressive non-Hodgkin's lymphoma (NHL). METHODS: Four SS patients with aggressive marginal zone NHL were enrolled in this trial. All patients were classified according to the newly proposed revised European-American classification of lymphoid neoplasms. Three out of four patients also had mixed cryoglobulinaemia (MC) of type II. They were treated every 3 weeks for eight cycles of CHOP. Patients also received rituximab, at a dose of 375 mg per square metre, on day 1 of each of the eight cycles of CHOP. Four weeks after completion of the eighth course of CHOP plus rituximab and every 6 months thereafter, patients were re-evaluated for response. RESULTS: Complete remission of lymphoma was achieved in all four patients. The lymphoma patients remained in remission for a period of 23, 15, 12 and 10 months respectively, while certain signs and symptoms of MC type II (purpura, peripheral neuropathy and arthralgias) significantly improved with treatment. In addition, the titres of circulating cryoglobulins and RF decreased, while C4 levels returned to normal. CONCLUSION: CHOP plus rituximab was well tolerated and proved effective in SS patients with aggressive NHL. Our observations may warrant a larger controlled trial to assess the effectiveness of this regimen in such patients.