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ID PMID Title PublicationDate abstract
15080082 Psychological distress and depressed mood in employees with asthma, chronic bronchitis or 2004 OBJECTIVES: To evaluate if employees with asthma, chronic bronchitis or emphysema can be characterized as a population of patients with a high prevalence of psychological distress and/or depressed mood. Above all, we wanted to examine the influence of smoking status on the relationship between chronic disease and psychological distress/depressed mood. METHODS: A postal survey was conducted among 12,103 employees participating in the Maastricht Cohort Study. RESULTS: Smoking employees, who reported having asthma, chronic bronchitis or emphysema were more likely to report suffering from depressed mood compared to smokers with no long-lasting disease (prevalence rate, PR: 29.3 and 9.0%, respectively; OR for depressed mood = 4.04; 95% CI: 2.56-6.39) and when compared to smoking employees with a history of heart disease, hypertension or myocardial infarction (PR: 18.1%; OR: 1.99; 95% CI: 1.07-3.68), or rheumatoid arthritis (PR: 20.1%; OR: 1.73; 95% CI: 0.96-3.11). CONCLUSION: These findings provide health care professionals with additional evidence regarding the importance for including the assessment of psychological distress and depressed mood in the routine evaluation of the patient with asthma, chronic bronchitis or emphysema, especially with regard to smoking cessation.
14746685 [Causes and diagnostic procedure of diffuse lung disease in 28 children]. 2003 Jul OBJECTIVE: Diffuse lung disease comprises a large, heterogeneous group of pulmonary interstitial and parenchymal disease. It is therefore difficult to some extent to make etiologic diagnosis. Little information on clinical spectrum and diagnostic evaluation of pediatric diffuse lung disease is available in our country. The purpose of this study was to explore the causes of and diagnostic approach to diffuse lung disease in children. METHODS: Twenty-eight children with diffuse lung disease aged 2 months to 14 years were studied retrospectively. Their history, physical examination, radiographic findings, final diagnosis and diagnostic processes were reviewed. RESULTS: Confirmed diagnosis was established in 25 cases and suggestive diagnosis in 3 cases. Confirmed diagnoses included: mycoplasma pneumonia in 1 case, Chlamydia trachomatis pneumonia in 2 cases, Epstein-Barr virus pneumonia in 1, CMV pneumonia in 2, hematogenous disseminated pulmonary tuberculosis in 3, pulmonary cryptococcosis in 1, invasive pulmonary aspergillosis in 2, Staphylococcus aureus sepsis in 1, diffuse bronchiectasis in 2, idiopathic pulmonary hemosiderosis in 1, idiopathic pulmonary fibrosis in 1, extrinsic allergic alveolitis in 1, HIV-related lymphocytic interstitial pneumonitis in 1, Wegner's granulomatosis in 1, Langerhan's cell histiocytosis in 2, and lymphoma in 3. Suggestive diagnoses included Nocardia pneumonia in 1, Pneumocystis carinii pneumonia in 1, and juvenile rheumatoid arthritis-associated pulmonary fibrosis in 1. The diagnostic directions of 26 patients were conducted by radiographic features. In 17 of 26 cases, the diagnostic range was confined by history. The diagnosis of 14 cases was made by noninvasive tests including antibody detection, bacterial culture, those of 8 cases by examination of biopsy material, and those of 2 cases by autopsy. CONCLUSIONS: The causes of pediatric diffuse lung disease included pulmonary infectious disease, idiopathic pulmonary disease and pulmonary lesion associated with systemic diseases. The diagnosis may be made by radiography, history, physical examination, noninvasive tests in most cases, while in some cases invasive procedures were necessary.
14626790 The combined oral contraceptive pill in women over age forty. 2003 Sep INTRODUCTION: By the age of 35 years, most women would have completed their families and contraception then becomes an important consideration. In the next one or two decades, other health concerns such as osteoporosis, dysfunctional uterine bleeding, ovarian, endometrial, colorectal and breast cancers and cardiovascular diseases will assume prominence in the lives of women. We review the role of the combined oral contraceptive (OC) pill in the older woman in the context of these important health concerns. METHODS: A Medline search was made for possible interaction between OC use and the above conditions. An important criteria for citation was publication in a high impact factor journal; furthermore to represent the wider context from which there issues derive we choose, whenever appropriate, general journal with wide readership including, but not limited to the Lancet or New England Journal of Medicine; we also choose studies published in journals of other medical disciplines instead of purely gynaecological journals to reflect the multidisciplinary impact of the combined OC pills. RESULTS: Combined OC retards bone demineralisation which could translate clinically to a reduction in postmenopausal osteoporotic fractures; it affords good menstrual cyclicity and alleviation of perimenopausal vasomotor symptoms; it offers chemoporophylaxis against epithelial ovarian cancers and endometrial cancers. There is evidence that it could be protective against colorectal cancers. The combined OC may attenuate the disease progression of rheumatoid arthritis and reduces the risk of ectopic pregnancy and pelvic inflammatory disease. In an older woman who does not smoke and is in good health, the excess risk of stroke, myocardial infarcts and venous thromboembolism is minimal, if at all, as is the risk of breast neoplasm. In women with proven human papilomavirus infection of the cervix who are using OCs, regular cervical screening is especially important. CONCLUSION: The non-contraceptive health benefits of the combined OCs justify its usage in the healthy older woman.
14514992 Further validation of a questionnaire to identify women likely to have low bone density. 2003 Fall A questionnaire instrument called the Simple Calculated Osteoporosis Risk Estimation (SCORE*) stratifies risk for osteoporosis, potentially reducing population-screening costs. SCORE is calculated using race, weight, age, history of estrogen use, fracture history, and presence/absence of rheumatoid arthritis. We tested SCORE in 912 postmenopausal women aged 45 yr or more using a Hologic QDR4500C densitometer for the total hip, femoral neck, and lumbar spine. National Health and Nutrition Examination Survey (NHANES III) norms were used to calculate hip T-scores. Low bone density (T-score < -2.0) was found in 29.6% of patients at the femoral neck, 17.7% at the total hip, 36.1% at the lumbar spine, and 46.1% at one or more sites. The sensitivity/specificity of the SCORE model (using a threshold of 6 points) was 0.97/0.36 for the femoral neck, 0.95/0.30 for the total hip, 0.86/0.35 for the spine, and 0.88/0.41 for any site (total hip, femoral neck, or spine). When used to detect low bone density at any site, SCORE would have deferred 27.6% of women referred for DXA scans, but 20.7% of these (5.7% of the entire population) would have been false-negatives, and thus inappropriately deferred. At a cutpoint of 3 instead of 6, sensitivity/specificity was 0.96/0.16. In those aged 50-60, the group with the greatest need for risk stratification, sensitivity/specificity for low density at any site was 0.72/0.54, and 46.1% would have been deferred, but 18.5% of this group would have been false-negatives. A cutpoint of 1 in this age group yielded sensitivity/specificity of 0.94/0.16. After age 65, few women would be deferred. CONCLUSION: When used to detect low bone density at any site with sufficient sensitivity for clinical practice, SCORE did not have sufficient discriminatory power to be broadly applicable.
14506910 A randomised, double-blind, clinical trial comparing the efficacy of nimesulide, celecoxib 2003 Joint pain is the main complaint in patients affected by osteoarthritis (OA), and NSAIDs are commonly used to treat pain associated with OA. Over the past few years, cyclo-oxygenase (COX)-2-selective inhibitors have been proved to have certain advantages over non-selective NSAIDs and have been increasingly used for pain management in patients with OA. OBJECTIVE: The main objective of this randomised, double-blind, within-patient study was to compare the analgesic efficacy of three COX-2 inhibitors in 30 patients affected by symptomatic OA of the knee. We evaluated the effects of oral nimesulide (100mg), celecoxib (200mg) and rofecoxib (25mg). Each drug was administered for 7 days. METHODS: Analgesic efficacy was determined using the patient's assessment of pain on a visual analogue scale (VAS) and by total pain relief over 3 hours (TOPAR3) on the first and last days of treatment. In addition, the overall analgesic efficacy and tolerability were determined by a global assessment by the patient at the end of each week of treatment, using 5-point categorical scales. At the end of the study, each patient was asked about which of the three forms of treatment they would choose as a continuation of the pain therapy. RESULTS: Taking all the results into consideration, nimesulide proved to be significantly more effective in providing symptomatic relief than did celecoxib and rofecoxib. Furthermore, nimesulide provided more rapid relief of pain associated with walking than did the other two drugs tested. Patients expressed similar preference for nimesulide and rofecoxib, but a lesser preference for celecoxib treatment. No patient withdrew from the study because of adverse events and the three different forms of treatment were generally safe and well tolerated. CONCLUSION: The present data confirm our previous observations in patients with rheumatoid arthritis, further suggesting that nimesulide represents an effective agent for the treatment of joint pain, with particular reference to the rapid onset of its analgesic effect.
12950026 Infrequent somatic Fas mutations but no evidence of Bcl10 mutations or t(11;18) in primary 2003 Sep Genetic alterations that allow tumour cells to evade apoptosis have recently been identified as key features of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type (MALT-type lymphoma). The t(11;18), which produces the putative anti-apoptotic fusion protein API2-MALT1, has been identified in a large proportion of extracutaneous MALT-type lymphomas and a smaller fraction of tumours harbour mutations that inactivate the pro-apoptotic functions of Fas and Bcl10. The present study has examined the status of these genes in 19 primary cutaneous B-cell lymphomas (PCBCLs), 12 of which were MALT-type lymphomas according to the WHO classification. None of the 19 PCBCLs carried the t(11;18) and tumour-specific Bcl10 alterations were not identified at the genomic level or at the mRNA level. Somatic Fas mutations causing truncation of the Fas receptor were identified in two MALT-type lymphomas. Both patients with Fas mutant PCBCL exhibited benign conditions of dysregulated lymphoproliferation. One had autoimmune diabetes and rheumatoid arthritis and the other had a 25-year history of recurrent cutaneous pseudo-lymphomas. It is suggested that Fas mutation permits the survival and hence the accumulation of autoreactive B cells. This expansion of autoreactive B cells is analogous to the expansion of B cells chronically stimulated by exogenous antigens in the development of MALT-type lymphoma.
12892735 Linear epitopes of two different autoantigens-La/SSB and myelin basic protein--with a high 2003 Aug The region 147-154aa of La/SSB presents 83% sequence similarity with the 139-146aa region of the human myelin basic protein (MBP). The aim of this study was to investigate the prevalence and significance of antibodies against both epitopes in sera from patients with systemic autoimmune diseases, and to compare the humoral responses produced after rabbit immunization. Peptides 147-154aa of La/SSB and 139-146aa of the MBP were attached on tetrameric sequential oligopeptide carriers and used for immunizations of New Zealand White rabbits. Antibodies to immunizing peptides, as well as to the peptides corresponding to other previously defined La/SSB epitopes (289-308aa, 349-364aa), to the intact human MBP (hMBP) and to the recombinant human La/SSB (rechLa) proteins, were identified using specific ELISA assays. Sera from 45 patients with Sjogren's syndrome (pSS), 49 with Systemic Lupus Erythematosus (SLE), and 18 with Rheumatoid Arthritis (RA) were tested against the two peptides and the hMBP. Twenty-two per cent of sera from pSS patients, 27% of SLE patients, and none from RA sera reacted with the La epitope; 27% from pSS sera, 22% of SLE sera, and 17% of RA sera gave a positive reaction against the MBP peptide. Finally, 19% of pSS, 30% of SLE, and 38% of RA sera reacted with the hMBP. Thirty-five days after immunization of rabbits with the La epitope, antibodies were produced against all three La/SSB peptides, the MBP peptide, and the hMBP and rechLa proteins. Rabbits immunized with the MBP peptide produced antibodies against the immunizing peptide and the mimicking peptide of La shortly after immunization, whilst antibodies against the other La epitopes and the two intact proteins were produced later. Inhibition experiments in rabbit sera with high reactivity against hMBP, using the MBP peptide as inhibitor, revealed that 80% of serum reactivity was abolished. In conclusion, a significant proportion of human autoimmune sera reacted with both La and MBP derived peptides, as well as with hMBP. La 147-154aa peptide, when used for animal immunizations, induces a fast epitope spreading involving both La and MBP. In contrast, the mimicking MBP epitope induces a delayed response against the other La epitopes. Thus, despite the fact that these peptides present molecular similarity, they induce different immune responses.
12509998 Cloning, overexpression, and purification of functional human purine nucleoside phosphoryl 2003 Jan Purine nucleoside phosphorylase (PNP) catalyzes the phosphorolysis of the N-ribosidic bonds of purine nucleosides and deoxynucleosides. A genetic deficiency due to mutations in the gene encoding for human PNP causes T-cell deficiency as the major physiological defect. Inappropriate activation of T-cells has been implicated in several clinically relevant human conditions such as transplant tissue rejection, psoriasis, rheumatoid arthritis, lupus, and T-cell lymphomas. Human PNP is therefore a target for inhibitor development aiming at T-cell immune response modulation. In addition, bacterial PNP has been used as reactant in a fast and sensitive spectrophotometric method that allows both quantitation of inorganic phosphate (P(i)) and continuous assay of reactions that generate P(i) such as those catalyzed by ATPases and GTPases. Human PNP may therefore be an important biotechnological tool for P(i) detection. However, low expression of human PNP in bacterial hosts, protein purification protocols involving many steps, and low protein yields represent technical obstacles to be overcome if human PNP is to be used in either high-throughput drug screening or as a reagent in an affordable P(i) detection method. Here, we describe PCR amplification of human PNP from a liver cDNA library, cloning, expression in Escherichia coli host, purification, and activity measurement of homogeneous enzyme. Human PNP represented approximately 42% of total soluble cell proteins with no induction being necessary to express the target protein. Enzyme activity measurements demonstrated a 707-fold increase in specific activity of cloned human PNP as compared to control. Purification of cloned human PNP was achieved by a two-step purification protocol, yielding 48 mg homogeneous enzyme from 1L cell culture, with a specific activity value of 80 Umg(-1).
12476949 Clinical evaluation of a new automated anti-dsDNA fluorescent immunoassay. 2002 Oct The measurement of anti-double-stranded DNA (anti-dsDNA) antibodies is a useful tool for the diagnosis and the follow-up of systemic lupus erythematosus (SLE). Anti-dsDNA antibodies are involved in the pathogenesis of lupus nephritis and they are, specially the high-avidity antibodies, the most specific antibodies associated with SLE nephritis and active SLE. The aim of the present study was to assess the clinical utility of an enzyme-linked immunosorbent assay (EUSA) that utilizes a circular double-stranded plasmid DNA as a nucleic acid source, adapted to an automated fluorescence immunoassay (EliA dsDNA, Pharmacia, Freiburg, Germany). Also, we compared this method with other immunoassays used in clinical laboratories. We have measured anti-dsDNA antibodies in the serum of 179 patients with a positive result for antinuclear antibodies (ANA). Seventy six sera were from SLE patients (14 men and 62 women), and the other 103 sera (from 20 men and 83 women) constituted the control group. This latter group includes nine Sjogren's syndrome patients, six patients with rheumatoid arthritis and 88 with various other diseases, including connective tissue diseases (n=34), hepatopathies (n= 17; 11 primary biliary cirrhosis and 6 autoimmune hepatitis), and 37 patients with nonautoimmune diseases (viral hepatitis, renal disease, diabetes, exanthema and hypertension). Methods used were "EliA dsDNA" (Pharmacia, Germany), "Varelisa dsDNA" (Pharmacia, Germany), Farr (Amersham, UK) and Chritidia luciliae immunofluorescence test (Vitro-Immun, Germany). We assessed sensitivity, specificity, positive predictive value and negative predictive value in the clinical study, and kappa index and scatter plots in the comparative study. The results show a low concordance between methods (kappa < 0.6). The evaluated EliA method shows a very good specificity for SLE (93.2%) and a good sensitivity for active SLE (70.8%).
12417102 Stable expression of human tartrate-resistant acid phosphatase isoforms by CHO cells. 2002 Dec OBJECTIVE: In human serum, type-5 tartrate-resistant acid phosphatase (TRACP) exists as two closely related isoforms: 5a and 5b. Serum isoform 5b is an osteoclast product that reflects bone resorption rate and is frequently increased in diseases of increased bone turnover. Isoform 5a protein is often increased in rheumatoid arthritis (RA) sera and may be a product of inflammatory macrophages. Our objective was to compare the biochemical characteristics of TRACP 5a and 5b. METHODS: We transfected the human ACP 5 gene into CHO cells and cloned a stable cell line (CHO/TRACP 8F5) that expresses high levels of TRACP activity both intracellularly and as a secreted product. Both enzyme preparations were purified on an anti-TRACP antibody column. Their biochemical properties were compared to the natural serum isoforms using colorimetric assays for activity and total protein. Their structural properties were compared to natural serum isoforms using denaturing and nondenaturing polyacrylamide gel electrophoresis. RESULTS: Both enzyme preparations were heterogeneous. The combined secreted recombinant TRACPs (rTRACP(ex)) had all the characteristics of natural serum TRACP 5a. There were seven uncleaved glycoproteins with a pH optimum of 5.2, relatively low specific activity (278 U/mg) and differentially sialylated. The combined intracellular TRACPs (rTRACP(in)) had all the characteristics of natural serum TRACP 5b. They consisted of two proteins, one of which was a processed heterodimer, with a pH optimum of 5.8, a relatively high specific activity (887 U/mg) and lacked sialic acid. CONCLUSION: This cell line provides an avenue for the simultaneous study of the regulation, function and intracellular trafficking of separate TRACP isoforms and the identification of their physiologic substrates in a single uniform cell source.
12375327 Clues to pathogenesis of spondyloarthropathy derived from synovial fluid mononuclear cell 2002 Oct OBJECTIVE: To use gene expression profiles of spondyloarthropathy (SpA) synovial fluid mononuclear cells (SFMC) to determine if there are transcripts that support the unfolded protein response (UPR) hypothesis, and to identify which cytokines/chemokines are being expressed and which cell fractions are involved. METHODS: Gene expression profiles were generated by microarray screening of SFMC of 5 patients with SpA, 5 patients with rheumatoid arthritis (RA), and peripheral blood mononuclear cells (PBMC) of 6 controls. Results were validated by reverse transcription polymerase chain reaction using samples from a larger panel of subjects. RESULTS: The repertoires of proinflammatory cytokines/chemokines expressed by SpA and RA SFMC were very similar: monocyte chemotractant protein 1 (MCP-1), interleukin 8 (IL-8), IL-1beta, endothelial-monocyte activating polypeptide II, interferon-gamma, and tumor necrosis factor-alpha. MCP-1 was highly expressed in SpA SFMC. There was enhanced expression of immunoglobulin heavy chain binding protein (BiP) in SpA, which is compatible with the UPR hypothesis. BiP was most highly expressed in the adherent fraction of SpA SFMC. CONCLUSION: Previous data postulating UPR in SpA are based on in vitro experiments with transfected cell lines. Our patient derived data suggest that it also occurs in vivo in the macrophages of SpA joints.
12223450 Critical role of NF-kappaB and stress-activated protein kinases in steroid unresponsivenes 2002 Nov Glucocorticoid resistance is a serious clinical problem in chronic inflammatory diseases, because many patients with rheumatoid arthritis, asthma, or Crohn's disease fail to respond to steroid treatment. The molecular mechanisms underlying this unresponsiveness, however, are completely unknown. The effects of steroids are largely mediated by the interference of the glucocorticoid receptor (GR) with proinflammatory transcription factors. In the present study, we therefore investigated the activation of the transcription factors nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and the upstream kinases p38 and c-Jun N-terminal kinase (JNK) in steroid-sensitive and steroid-resistant patients with Crohn's disease. We demonstrated that steroid-sensitive and steroid-resistant patients reveal a remarkably different cellular activation pattern of these proinflammatory mediators. In steroid-sensitive patients, activation of NF-kappaB, AP-1, p38, and JNK was mainly found in lamina propria macrophages. In contrast, steroid-resistant patients revealed activation of all these mediators mostly in epithelial cells. The functional interference of the proinflammatory mediators with the glucocorticoid response was supported by reporter gene assays. Expression of NF-kappaB and, interestingly, also JNK1 and p38 inhibited the activity of the GR. Thus, our results suggest that steroid resistance is associated with increased epithelial activation of stress-activated protein kinases and NF-kappaB, which might inhibit the anti-inflammatory action of a limited number of GRs.
12167567 Disposition of a specific cyclooxygenase-2 inhibitor, valdecoxib, in human. 2002 Sep Valdecoxib is a potent and specific inhibitor of cyclooxygenase-2, which is used for the treatment of rheumatoid arthritis, osteoarthritis, and the dysmenorrhea pain. Eight male human subjects each received a single 50-mg oral dose of [(14)C]valdecoxib. Urine, feces, and blood samples were collected after administration of the radioactive dose. Most of the radioactivity in plasma was associated with valdecoxib and the hydroxylated metabolite of valdecoxib (M1). The estimated terminal half-life for valdecoxib was about 7 h. About 76.1% of the radioactive dose was recovered in urine and 18% of the radioactive dose was recovered in feces. Valdecoxib was extensively metabolized in human, and nine phase I metabolites were identified. The primary oxidative metabolic pathways of valdecoxib involved hydroxylation at either the methyl group to form M1 or N-hydroxylation at the sulfonamide moiety to form M2. Further oxidation of M1 led to the formation of several other phase I metabolites. Oxidative breakdown of the N-hydroxy sulfonamide function group in M2 led to the formation of corresponding sulfinic acid and sulfonic acid metabolites. The O-glucuronide conjugate of M1 and N-glucuronide conjugate of valdecoxib were the major urinary metabolites, which accounted for 23.3 and 19.5% of the total administered dose, respectively. The remaining urinary metabolites were glucuronide conjugates of other phase I metabolites. Only 3% of the administered dose was recovered in urine as unchanged parent, suggesting that renal clearance is insignificant for valdecoxib. Absorption of valdecoxib was excellent since the recovery of unchanged valdecoxib in feces was <1% of the administered dose.
12139459 Synthesis of potent leukotriene A(4) hydrolase inhibitors. Identification of 3-[methyl[3-[ 2002 Aug 1 Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention in these disease states, since the action of this enzyme is the rate-limiting step in the production of LTB(4). Our previous efforts focused on the exploration of a series of analogues related to screening hit SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) and resulted in the identification of potent, orally active inhibitors such as 2. Additional structure-activity relationship studies around this structural class resulted in the identification of a series of alpha-, beta-, and gamma-amino acid analogues that are potent inhibitors of the LTA(4) hydrolase enzyme and demonstrated good oral activity in a mouse ex vivo whole blood LTB(4) production assay. The efforts leading to the identification of clinical candidate SC-57461A (8d, 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described.
12023572 Reactive angioendotheliomatosis: a study of 15 cases demonstrating a wide clinicopathologi 2002 Jun Reactive angioendotheliomatosis (RAE) is a rare condition characterized by cutaneous vascular proliferation that usually occurs in patients with diverse types of coexistent systemic disease. Although intravascular proliferation of endothelial cells has been considered to be the key histologic feature in RAE, other patterns of vascular proliferation have also been described. We reviewed the clinicopathologic features in 15 cases of RAE. The study group comprised eight males and seven females with an age range of 47-88 years (median 65 years). Eleven patients had coexistent systemic disease: renal disease (six patients, including three post renal transplantation); valvular cardiac disease (two patients); one patient each had alcoholic cirrhosis, glioblastoma multiforme (on chemotherapy), and rheumatoid arthritis/polymyalgia rheumatica. Six patients were iatrogenically immunosuppressed at the onset of the skin lesions. The clinical appearance included multiple erythematous macules, plaques, tumors, and ulcerated lesions, with a wide distribution but a propensity to involve limbs. Lesions had been present for 1 month to 4 years (median 4 months). Lesions resolved in four cases, improved in two cases, remained static in one case, and progressed in four cases. Two cases were recent and follow-up was not available in two other cases. Three patients died of their coexistent systemic disease with resolution, improvement, and progression of lesions, respectively. All lesions were characterized histologically by a proliferation of capillaries in the dermis, with variably diffuse (seven cases), lobular (six cases), or mixed lobular and diffuse patterns (two cases). There was marked intercase and intracase heterogeneity in histologic features. Common features included fibrin microthrombi (nine cases), reactive (fasciitis-like) dermal alterations (seven cases), and foci of epithelioid endothelium (four cases). Four of 10 cases tested showed positive immunohistochemical staining for HHV-8 latent nuclear antigen in lesional endothelial cell nuclei. This study suggests that RAE has a broader clinicopathologic spectrum than previously described. The pathogenesis of this rare disorder is unknown, but it is likely that immunologic factors play a role.
11950256 Effects of TNFalpha-antagonists on nitric oxide production in human cartilage. 2002 Apr OBJECTIVE: Nitric oxide (NO) produced by cartilage and synovial membrane is implicated in the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA). In inflamed joints NO is synthesized in response to proinflammatory cytokines and it is involved in the joint destruction. The aim of the present study was to investigate the effects of TNFalpha-antagonists infliximab and etanercept on NO production in human cartilage. DESIGN: Cartilage specimen obtained from OA patients undergoing knee replacement surgery were studied for iNOS expression and NO production in organ culture to allow intact chondrocyte-matrix interactions. TNFalpha and soluble TNFalpha receptor release was measured by ELISA. RESULTS: Osteoarthritic cartilage produced NO spontaneously and its production was enhanced by proinflammatory cytokines TNFalpha (tumor necrosis factor alpha), IL-1beta (interleukin-1beta), IL-17 (interleukin-17) and by bacterial lipopolysaccharide (LPS). TNFalpha-antagonists infliximab and etanercept inhibited TNFalpha-induced NO production in a dose dependent manner but they had no effect on IL-1beta-, IL-17- and LPS-stimulated NO synthesis. TNFalpha and soluble TNFalpha receptors (sTNFRI and sTNFRII) were produced by human osteoarthritic cartilage. A neutralizing antibody against soluble TNFRI enhanced spontaneous NO production whereas an antibody against soluble TNFRII had no effect. CONCLUSIONS: TNFalpha-antagonists infliximab and etanercept suppressed TNFalpha-induced NO production. This effect was not seen on IL-1-, IL-17- or LPS-induced NO production suggesting that TNFalpha is not an autacoid mediator in these processes. The studies with neutralizing antibodies against soluble TNFRI suggest that endogenous cartilage-derived TNFalpha-antagonists modulate NO production in osteoarthritic cartilage.
20641243 (99m)Tc(CO)(3)-Pyrazolyl-cyclo(Arg-Gly-Asp-D-Tyr-Lys). 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces and 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 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 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 (10). Most 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) (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 tumors in nude mice (12). The ready availability and low cost of (99m)Tc led to the development of (99m)Tc-RGD peptides to target α(v)β(3) integrins in tumor angiogenesis. (99m)Tc(CO)(3)-Pyrazolyl-cyclo-(Arg-Gly-Asp-D-Tyr-Lys) ((99m)Tc(CO)(3)-PZ-c(RGDyK)) has been prepared as a single-photon emission computed tomography (SPECT) tracer for imaging α(v)β(3) integrins in tumors (13).
15313415 Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections. Multi-purpose nutraceuti 2004 Sep 15 Interleukin-6 is a pleiotropic cytokine which plays a crucial role in immune physiology and is tightly controlled by hormonal feedback mechanisms. After menopause or andropause, loss of the normally inhibiting sex steroids (estrogen, testosterone) results in elevated IL6 levels that are further progressively increasing with age. Interestingly, excessive IL6 production promotes tumorigenesis (breast, prostate, lung, colon, ovarian), and accounts for several disease-associated pathologies and phenotypical changes of advanced age, such as osteoporosis, rheumatoid arthritis, multiple myeloma, neurodegenerative diseases and frailty. In this respect, pharmacological modulation of IL6 gene expression levels may have therapeutical benefit in preventing cancer progression, ageing discomforts and restoring immune homeostasis. Although "plant extracts" are used in folk medicine within living memory, it is only since the 20th century that numerous scientific investigations have been performed to discover potential health-protective food compounds or "nutraceuticals" which might prevent cancer and ageing diseases. About 2000 years ago, Hippocrates already highlighted "Let food be your medicine and medicine be your food". Various nutrients in the diet play a crucial role in maintaining an "optimal" immune response, such that deficient or excessive intakes can have negative consequences on the organism's immune status and susceptibility to a variety of pathologies. Over the last few decades, various immune-modulating nutrients have been identified, which interfere with IL6 gene expression. Currently, a broad range of phyto-pharmaceuticals with a claimed hormonal activity, called "phyto-estrogens", is recommended for prevention of various diseases related to a disturbed hormonal balance (i.e. menopausal ailments and/or prostate/breast cancer). In this respect, there is a renewed interest in soy isoflavones (genistein, daidzein, biochanin) as potential superior alternatives to the synthetic selective estrogen receptor modulators (SERMs), which are currently applied in hormone replacement therapy (HRT). As phyto-chemicals integrate hormonal ligand activities and interference with signaling cascades, therapeutic use may not be restricted to hormonal ailments only, but may have applications in cancer chemoprevention and/or NF-kappaB-related inflammatory disorders as well.
20641497 [(18)F]-5-(2-fluoroethyl)2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxyl 2004 Adenosine is an important signaling molecule that is involved in several pathophysiological conditions such as asthma, inflammation, and neurodegeneration. It is known to mediate its effects through four G-protein–coupled receptors, A(1), A(2) (with sub types A(2A) and A(2B)), and A(3) (the receptors are also designated as A1AR, A2AR, and A3AR, respectively) in the mammalian system. These receptors have been identified in several human tissues and, because they play a role in different pathologies, are targeted for the clinical development of a variety of drugs (2, 3). Much information is available regarding the function and tissue distribution of the A(1) and A(2A) receptors; however, because of a lack of proper agonists and antagonists to study the A(2B) and A(3) receptors, the exact role of the latter two receptors in mammalian physiology is not clear (4). In addition to its possible involvement in the development of rheumatoid arthritis and brain, lung, and cardiac ischemia, the A(3) receptor was shown to be overexpressed and had a proliferative effect in certain cancer tissues and cell lines (5-7). Although this receptor is known to be involved in a number of diseases, little is known about its expression and distribution in the different regions and tissue of the body (4). In an attempt to study the ligand binding properties of the A(3) receptor, investigators developed antagonistic pyridine analogs that showed high affinity and specificity for the receptor (8, 9). Among these pyridine compounds, a fluoroethyl ester derivative, 5-(2-fluoroethyl)2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY), was determined to have a high affinity and selectivity for the A(3) receptor (9). Recently, Wadsak et al. developed a suitable precursor for the synthesis of FE@SUPPY and labeled the A(3) ligand with radioactive fluorine ((18)F) to obtain [(18)F]FE@SUPPY (4). The labeled compound was subsequently studied for its biodistribution in rats and its specificity was determined by autoradiography. The metabolic properties of [(18)F]FE@SUPPY were compared to those of its analogue, [(18)F]FE@SUPPY:2 (5-ethyl-2,4-diethyl-3-((2-[(18)F]fluoroethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate), in rodents by Haeusler et. al. (1). To compare the structures of [(18)F]FE@SUPPY and [(18)F]FE@SUPPY:2 see (1).
20641699 (99m)Tc-labeled anti-tumor necrosis factor-alpha monoclonal antibody. 2004 The tumor necrosis factor alpha (TNF-α) is synthesized as a 26-kDa membrane-bound protein on certain cell types, e.g., T cells. The membrane-bound protein is cleaved to release a 17-kDa soluble form that exists as a homotrimer. It has been implicated in the pathogenesis of different diseases including cancer and inflammatory diseases such as rheumatoid arthritis (RA), Crohn’s disease (CD), and ulcerative colitis (1, 2). The stimulation of TNF-α induction is known to activate several pro-inflammatory cytokines, chemokines, matrix metalloproteinases, and endothelial adhesion molecules that attract cells known to promote inflammation (3). Because of its role in the pathogenesis of different inflammatory diseases, a variety of anti–TNF-α agents have been developed and investigated for the treatment of these conditions (4). Several anti–TNF-α antibodies such as infliximab, adalimumab, and certolizumab are now available for the treatment of TNF-α–mediated inflammatory diseases (2). Infliximab is an anti–TNF-α, chimeric mouse-human IgG1 monoclonal antibody (mAb) that is commercially available and is approved by the United States Food and Drug Administration for the treatment of a variety of inflammatory diseases (2, 4). This mAb is known to bind TNF-α in the serum or on the cell membranes and to inhibit its biological activity mediated through the TNF-α receptor. To evaluate its in vivo use for the detection of TNF-α in the various inflammatory diseases, infliximab was labeled with radioactive meta-stable technetium ((99m)Tc) and used as detailed below (2, 5-7).