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ID PMID Title PublicationDate abstract
11274068 Impaired neurotransmitter release from lacrimal and salivary gland nerves of a murine mode 2001 Apr PURPOSE: To determine whether lacrimal and salivary gland nerves of an animal model of Sjögren's syndrome, the MRL/lpr mouse, are able to release acetylcholine. The second purpose was to determine whether activation of the lacrimal gland nerves of the MRL/lpr mouse leads to protein secretion. METHODS: Total saliva was collected for 10 minutes from the oral cavity of male and female MRL/lpr and MRL/+ mice, after intraperitoneal stimulation with pilocarpine and isoproterenol. Lacrimal and salivary gland lobules prepared from 18-week-old MRL/lpr and MRL/+ mice were incubated in the presence of depolarizing KCl (75 mM) solution. Acetylcholine release and peroxidase secretion (a protein secreted by the lacrimal gland) were measured using a spectrofluorometric assay. RESULTS: Female, but not male, MRL/lpr mouse salivary glands were hyper-responsive to in vivo injection of secretagogues. These mice produced significantly higher amounts of saliva than did age-matched MRL/+ mice. Lacrimal and salivary gland nerves from 18-week-old MRL/+ mice released acetylcholine in response to a depolarizing KCl solution. In contrast, nerves in glands from 18-week-old MRL/lpr mice did not increase acetylcholine release in response to the depolarizing solution. Moreover, lacrimal glands from 18-week-old MRL/+ mice were able to secrete peroxidase in response to a depolarizing KCl solution, whereas those from 18-week-old MRL/lpr could not. This was not due to a defect in the secretory process, because addition of an exogenous secretagogue elicited peroxidase secretion from 18-week-old MRL/lpr as well as MRL/+ mice lacrimal glands. CONCLUSIONS: The results show that activation of nerves of lacrimal and salivary glands infiltrated with lymphocytes does not increase the release of neurotransmitters, which results in impaired secretion from these glands.
11141328 Characterization and V(H) sequences of human monoclonal anti-F(ab')(2) autoantibodies from 2001 Jan To investigate the genetic background of anti-F(ab')(2) autoantibodies and the mechanism behind their production we have analyzed 10 human monoclonal antibodies directed against IgG F(ab')(2) and IgG Fab. They were all derived from peripheral blood by the EBV/hybridoma technique. Eight were from three healthy individuals and two from two patients with primary Sjögren's syndrome (pSS). They react with epitopes on distinct regions of IgG, including epitopes present on or near the hinge of IgG, epitopes on the Fd gamma, and an antigenic determinant(s) present on lambda light chains. These determinants are either exposed on the intact IgG molecule or revealed following pepsin or papain digestion. The V(H) germline gene repertoire used is diverse and with considerable overlap with that used by rheumatoid factors (RF). The two IgG antibodies from normals are extensively mutated (13 and 24 mutations/V(H)), but with a replacement to silent mutation ratio in the CDR(H)1 + 2 of only 3.7. The IgM antibodies from normals are also heavily mutated (mean 10 mutations/V(H)). This suggests that anti-F(ab')(2) from normals are generated by an antigen-driven somatic hypermutation mechanism. In contrast, the two IgM antibodies from pSS are virtually unmutated in both V(H) and V(L). Together with published data of pSS RF and anti-Ro 52-kDa sequences (1-3), this suggests that there is an expanded population of naïve B cells with autoantibody specificities in the peripheral blood of pSS patients.
11092531 Prolactin up-regulates cathepsin B and D expression in minor salivary glands of patients w 2000 Nov Various proteases are expressed in the minor salivary glands (MSG) of patients with Sjögren's syndrome (SS), and as we have already shown, prolactin is neosynthesized in the acinar cells of patients with SS. The present study aims to characterize the influence of PRL on the expression of cathepsin B and D in the MSG of patients with SS. Cathepsin B and D expression was investigated immunohistochemically in MSG of 30 patients with SS and 15 healthy volunteers. The presence of cathepsin B and D mRNAs was checked in three SS patients and three control subjects by means of reverse transcription-polymerase chain reaction (RT-PCR). The specificity of the anti-cathepsin B and D antibodies used for the immunohistochemistry was checked by means of western blotting analysis. The influence of prolactin on the immunohistochemical expression of cathepsin B and D was quantitatively assayed by computer-assisted microscopy at three different doses (5, 50, and 500 ng/ml) on eight MSGs (four control subjects and four patients with SS) maintained ex vivo under organotypic cultures. This influence was also investigated at the mRNA level. Whereas cathepsin B immunopositivity was absent from glandular epithelial cells of healthy subjects and only slightly present in SS patients, cathepsin D immunoreactivity was considerably greater (p < 0.0001) in both the acini and the ducts of patients with SS as compared with control subjects. Cathepsin B, but not D, was also expressed in about 20% of infiltrating mononuclear cells of SS patients. Treatment of both healthy and SS minor salivary glands with PRL significantly (p < 0.05 top < 0.0001) enhanced cathepsin B and D expression in acinar and ductal cells at both protein and mRNA levels. PRL produced locally in MSGs of SS patients, but not those of healthy subjects, could play a role in the pathogenesis of Sjogren's syndrome, if only through the activation of proteolytic activity on the part of cathepsins B and D.
11145040 Differential expression of matrix metalloproteinases in labial salivary glands of patients 2000 Dec OBJECTIVE: To determine the enzymatic activity and cellular localization of matrix metalloproteinases (MMPs) 2, 3, and 9 in labial salivary glands from patients with different degrees of severity of primary Sjogren's syndrome (primary SS). METHODS: Gelatinase activity was determined by zymography and quantified by densitometry. The specificity of MMPs was determined using protease inhibitors and chelators, as well as activators of the latent forms of these enzymes. The cellular localization of MMPs was carried out using monoclonal antibodies that recognize their latent and active forms. RESULTS: Labial glands from control subjects and patients showed gelatinase activity for MMP-2 and MMP-9. Activation studies revealed that both enzymes were predominantly present in their latent forms. The highest levels of MMP-9 activity were detected in patients with severe, active, primary SS (except for patients with severe clinical symptoms for extended periods) and correlated with structural and functional glandular changes. MMP-2 activity was almost the same in patients and controls. MMPs were detected by immunolocalization only in acinar and ductal cells and were homogeneously distributed throughout patients' glands. MMP-2 and MMP-9 expression paralleled their gelatinase activity. MMP-3, detectable only with immunologic methods, was absent in control subjects but abundantly expressed in patients. Importantly, MMP protein levels in acinar and ductal cells were independent of either the presence or the proximity of mononuclear infiltrate cells. CONCLUSION: MMP-3 and MMP-9 expression, as well as MMP-9 catalytic activity, were increased in tissue samples from SS patients in a manner that correlated with the severity of the disease. Most important, increased MMP activity stemmed from exocrine epithelial cells and was not due to infiltrating lymphocytes. Thus, changes in salivary glands as a consequence of proteolysis may lead to severe glandular destruction.
10699568 An instrument for the multiparameter assessment of speech. 1999 Nov This paper describes the development of SNORS+, a clinical, user-friendly instrument for measurement of the articulators during speech. The design criteria for the instrument were based upon a wide-ranging review of current practice and available techniques. SNORS+ allows objective assessment of the function and co-ordination of key articulators. Appropriate targeting of therapy is therefore possible. Visual feedback is provided, for therapy, and an objective measurement of outcome is easily obtained. Preliminary results are presented. These suggest that the instrument will prove extremely useful in the assessment and management of many speech disorders.
10446878 DNA typing of maternal HLA in congenital complete heart block: comparison with systemic lu 1999 Aug OBJECTIVE: To investigate which maternal HLA allele or haplotype is primarily associated with isolated congenital complete heart block (CCHB) in offspring. METHODS: HLA class II typings were assessed by line probe assay and polymerase chain reaction-sequence-specific oligonucleotide probe methods, and HLA class I by the microlymphocytotoxicity test, in 13 Italian anti-Ro-positive mothers of children with CCHB and 41 anti-Ro-positive mothers with healthy children (20 mothers with systemic lupus erythematosus [SLE] and 21 with Sjögren's syndrome [SS]). Anti-Ro antibodies were studied by immunoblot. RESULTS: HLA-DRB1*03011 and DRB1*03011; DQA1*0501;DQB1*0201 were more frequent in mothers of infants with CCHB than in mothers who had SLE, but not in mothers who had SS and whose children were healthy. Mothers of infants with CCHB were either HLA-B5/35, B17, or B44 positive and had a higher prevalence of B44;DRB11;DQA1*0501;DQB1*0301 and isolated anti-52-kd antibodies, which were absent in SS and SLE controls. CONCLUSION: Mothers of infants with CCHB presented a strong genetic similarity to mothers who had SS, except for HLA class I phenotype. HLA-DRB1*03011;DQA1*0501;DQB1*0201 seemed not to be primary CCHB-associated genes, but were involved in an SS-like anti-Ro/La response. The combined presence of HLA-DRB1*03011 and anti-52-kd SSA/Ro antibodies conveyed the highest risk of giving birth to an affected child.
9855214 Low copy numbers of human T-cell lymphotropic virus type I (HTLV-I) tax-like DNA detected 1998 To evaluate the hypothesis, proposed in previous reports from HTLV-I non-endemic areas, that HTLV-I is involved in a significant proportion, about a quarter, of Sjögren's syndrome patients who lack serum antibodies to the virus, we examined for the presence or absence of HTLV-I in DNA samples isolated from salivary gland tissues of 17 seronegative as well as 7 seropositive patients with Sjögren's syndrome in Nagasaki, Japan, where the virus is highly endemic. The nested two-step polymerase chain reaction (PCR), with a sensitivity capable of detecting a single DNA molecule, failed to amplify the HTLV-I tax sequence from DNA of 14 of the 17 seronegative patients. The tax was only amplifiable from the tissue DNA of the remaining three seronegative patients. The detection rate, 3/17 (18%), was, unexpectedly, less than those previously reported from the HTLV-I non-endemic areas. Moreover, in contrast to high viral loads (10(-1) to 10(-3) per cell) in the salivary gland of the seropositive patients, a semiquantitative PCR revealed that the copy number of the HTLV-I tax in the gland tissue of these seronegative patients was very low, 10(-5) per cell. This level is unlikely to be sufficient to promote an inflammatory reaction in the tissue. Our findings might argue against the involvement of "prototype" HTLV-I in the pathogenesis of Sjögren's syndrome in seronegative patients.
9125242 T cell receptor alpha-chain and beta-chain junctional region homology in clonal CD3+, CD8+ 1997 Apr OBJECTIVE: Up to 42% of patients with Felty's syndrome (FS) have peripheral blood expansions of CD3+,CD8+ large granular lymphocytes (LGLs). The aim of this study was to determine whether the T cell receptor (TCR) alpha- and beta-chain sequences of these expansions from different patients have features in common that would support the hypothesis of an antigen-driven process. METHODS: Extraction of RNA from peripheral blood lymphocytes followed by synthesis of complementary DNA, inverse polymerase chain reaction (PCR) with TCR-specific primers, bacteriophage transformation, and sequencing of PCR products. RESULTS: Structural analysis of TCR beta-chain usage in such patients demonstrated a junctional region motif comprising the amino acids -LG- or -RG- in 7 of 14 clonal sequences and the motif -GXG- in 8 of 14. A biased alpha-chain junctional region usage of a hydrophobic and/or basic amino acid at position 2 was seen in 5 of 8 expanded sequences. These features differed significantly from control sequences. CONCLUSION: Given current models of TCR-peptide-major histocompatibility complex interaction, these observations are consistent with an antigen-driven, rather than a superantigen-driven, process in at least a subgroup of patients with FS.
11361180 Microflora in oral ecosystems in primary Sjögren's syndrome. 2001 May OBJECTIVE: Knowledge of the effect of primary Sjögren's syndrome (pSS) on the microbial flora in the different predilection sites for oral disorders is needed for planning preventive treatment. We carried out microbial analysis of samples from the dorsum of the tongue, smooth mucosa, supragingival tooth surfaces, and the gingival crevice region of 20 patients with pSS. METHODS: A clinical oral examination was performed and whole unstimulated and stimulated secretion rates were measured. RESULTS: Compared with healthy controls, subjects with pSS harbored higher numbers and frequencies of Streptococcus mutans, Lactobacillus spp., and Candida albicans in the supragingival plaque. On the smooth mucosa and tongue, the pSS subjects displayed an increased frequency of C. albicans, Staphylococcus aureus, enterics, and enterococci. C. albicans was detected about twice as frequently in the supragingival plaque as it was on the tongue. In the gingival crevice region, the pSS group harbored slightly lower proportions of Fusobacterium nucleatum and Prevotella intermedia/Prevotella nigrescens than controls. The clinical and microbial differences were mainly due to the pSS subjects with a stimulated secretion rate of < 0.5 ml/min. Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were not detected in any subject with pSS. CONCLUSION: The microbial flora in the different ecosystems reflected the status of oral disorders in the subjects with pSS. Specific site sampling and analysis in subjects with pSS revealed further differences compared with controls, and is therefore preferable to saliva sampling for oral treatment planning and for the evaluation of the effect of oral treatment and of preventive measures implemented in individuals with pSS.
10087183 Abundance of NKT cells in the salivary glands but absence thereof in the liver and thymus 1999 Mar 15 It is known that ALY/Nsc Jcl-aly/aly (aly/aly) mice that congenitally lack lymph nodes fall victim to Sjögren syndrome as a function of age. We investigated how TCRint cells of extrathymic origin and TCRhigh cells of thymic origin are distributed in various organs of these mice. Although the distribution of T-cell subsets was not different between control aly/+ and aly/aly mice in youth in any of the tested organs, the proportion of TCRint cells in the liver and spleen of aly/aly mice increased with aging. Usually, TCRint cells in the liver comprise a half-and-half mixture of a NK1. 1(+) subset (i.e., NKT cells) and a NK1.1(-) subset. In constrast, almost all expanding TCRint cells in various immune organs of aly/aly mice were found to be NK1.1(-). A large proportion of lymphocytes, including NK cells and TCRint cells, were also present in the salivary glands of aly/aly mice. Interestingly, these TCRint cells in the salivary glands contained an NK1.1(+) subset (i.e., NKT cells) that used an invariant chain of Valpha14Jalpha281 for TCRalphabeta (>50%). Moreover, gammadeltaT cells that used Vgamma 1, 2, 4/Vdelta 1, 4, 6 mRNAs, different from those of gammadeltaT cells in the liver and intestine, were abundant. Possibly reflecting the in situ generation of these T cells in the salivary glands, the expression of RAG-2 mRNA was evident by the RT-RCR method. These results suggest that (i) inflammatory lymphocytes that evoke Sjögren syndrome in aly/aly mice are NK cells or TCRint cells (both NK1.1(+) and NK1.1(-) subsets) and (ii) TCRint cells in the salivary glands might be generated in situ.
9814662 Hughes' syndrome: the antiphospholipid syndrome. A historical view. 1998 In the 15 years since our description of the antiphospholipid syndrome, it has become recognised as an important disease, not only in the world of lupus but in the broader areas of obstetrics, neurology and vascular disease. Although advances have been made in the understanding of the interactions of antibodies, protein co-factors, clotting molecules, endothelium and platelets, much still needs to be learnt about management where strokes, in particular, continue to cause significant morbidity.
9377848 [Hepatitis C and systemic diseases]. 1997 Apr In 1989 HCV was demonstrated to be the leading cause of non-A, non-B hepatitis. Not only HCV is able to determine chronic hepatitis in most patients, often leading to hepatocellular carcinoma, but it has also been shown to be strictly associated with a number of immunologically-mediated diseases. This review focuses on the reported associations between HCV and other diseases and the role that HCV might play in their pathogenesis.
11683959 A carbohydrate neoepitope that is up-regulated on human mononuclear leucocytes by neuramin 2001 Oct The expression of cell-surface antigens can delineate specific leucocyte developmental or functional stages. For example, certain membrane glycoproteins are expressed selectively on leucocyte subsets only after activation. Leucocyte activation can also induce changes in carbohydrate epitopes expressed on surface antigens. In the present studies, we report on a novel monoclonal immunoglobulin M antibody (mAb 13.22) that recognizes a unique carbohydrate epitope expressed on human leucocyte membrane proteins. Characterization of mAb 13.22 specificity by immunoblotting showed that it recognized proteins of MW approximately 95 000 and 150 000, including both CD18 and CD11b. The mAb 13.22 epitope was removed by N-glycosidase F but not by endoglycosidase H or fucosidase, demonstrating that it is an N-linked carbohydrate antigen. Interestingly, immunoblot staining was enhanced after neuraminidase treatment, suggesting that the antibody epitope might also be partially masked by sialic acid. In resting leucocytes, the mAb 13.22 antigen was expressed strongly on neutrophils, while dull staining was present on monocytes, and no lymphocyte staining was observed. In marked contrast, treatment of leucocytes with neuraminidase resulted in exposure of a mAb 13.22 neoepitope on a subset of lymphocytes (primarily T lymphocytes and natural killer cells) as well as up-regulated staining more than 18-fold on monocytes. Activation of lymphocytes in culture with phytohaemagglutinin or concanavalin A also unmasked the mAb 13.22 neoepitope on approximately 37% of the CD45RO+ lymphocytes. Furthermore, analysis of leucocytes collected from the synovial fluid of patients with rheumatoid arthritis showed that approximately 18% of the lymphocytes present expressed the mAb 13.22 neoepitope. Taken together, our results suggest that the mAb 13.22 carbohydrate neoepitope could represent a physiologically relevant marker that is up-regulated on leucocyte subsets during the inflammatory response.
11557301 TH1 cytokine response of CD57+ T-cell subsets in healthy controls and patients with alcoho 2001 Jul Patients with chronic inflammatory diseases, including Crohn's disease and rheumatoid arthritis, as well as those with certain viral infections, and patients who are transplant recipients or who have certain hematologic malignancies have been observed to have CD57+ T cell expansion in both CD4+ and CD8+ subsets. We have reported previously that alcoholic patients also have CD57+ T cell expansion. Because many alcoholics become seriously deficient in cell-mediated immunity, it is of interest to determine whether the expanded CD57+ subsets can respond to stimulation with normal T helper cell subtype 1 (TH1) cytokine production. We report evaluation of the CD57 T-cell subsets of patients with alcoholic liver disease (ALD) with the use of cytoplasmic staining after stimulation through the T-cell receptor (TCR). The CD57+ subsets of the T cells of both healthy individuals and patients with ALD express significantly higher amounts of cytoplasmic tumor necrosis factor-alpha (TNF-) and interferon-gamma (IFN-) after 6 h of stimulation than do the CD57- subsets. This increased production can persist up to 46 h of continuous stimulation. Under these assay conditions, very little cytoplasmic interleukin (IL)-4 is observed in the T cells of either healthy control subjects or patients with ALD. Measurement of cytokine secretion by sort-purified CD57 T-cell subsets with the use of enzyme-linked immunosorbent assay (ELISA) shows that the CD57+ T-cell subset produces 18- to 30-fold more TNF- and IFN-, respectively, than does the CD57- subset in the first 12 h of stimulation. This response requires only stimulation through the TCR for the CD57+ subset, whereas significant secretion by the CD57- subset requires added IL-2 or anti-CD28 antibody. These results are consistent with the concept of the CD57+ T-cell subset as a differentiated effector cell and demonstrate that patients with ALD who are not drinking at the time of evaluation have normal or increased immediate TH1 T-cell responses.
11474314 The effects on gastroduodenal mucosa of a new nonsteroidal anti-inflammatory drug, amtolme 2001 Jul AIM: Amtolmetin-guacyl (AMG) (2-[2[1-methyl-5-(4-methylbenzoyl) pyrrol-2-yl] acetamido] acetic acid 2-methoxyphenyl ester) is a recent drug that, in preliminary studies, has shown effective anti-inflammatory properties with improved gastrointestinal safety. Our study was designed to investigate the effects of AMG and piroxicam on gastroduodenal mucosa in healthy volunteers. MATERIALS AND METHODS: Forty-two healthy volunteers aged 18--45 years were randomized in a double-blind manner to AMG 1200 mg for 2 days and 600 mg for 12 days, or piroxicam 40 mg for 2 days and 20 mg for 12 days. Endoscopic evaluation and laboratory tests were performed at baseline and at the end of the treatment. The mucosa was evaluated by endoscopy using a predefined scale: the score could range from 0 to 4. Only volunteers with endoscopy grade 0-1 entered the trial. RESULTS: The median post-treatment endoscopy gastric injury scores were 1 (range 0--4) in the AMG-treated volunteers and 3 (range 0--4) in the piroxicam-treated volunteers (P = 0.04). There were two cases with an endoscopic gastric score of 4 in the AMG group, and seven in the piroxicam group (P = 0.1). The corresponding values in the duodenum were 1/21 volunteers in the AMG group and 1/21 in the piroxicam group. Eight out of 11 subjects with an endoscopic score of 4 were Helicobacter pylori negative, and 3/11 were infected by the micro-organism. Different adverse reactions were reported by 15/21 volunteers (71%) in the AMG group and by 12/21 (57%) in the piroxicam group. None of these events resulted in interruption of the study. CONCLUSIONS: AMG is a new anti-inflammatory drug with limited gastric toxicity. If these findings are confirmed on a wider scale in long-term trials, then the drug might become a valid alternative to current treatments, especially for patients such as those with rheumatoid arthritis who need steroids and second-line drugs simultaneously.
11259363 A short peptide domain of platelet factor 4 blocks angiogenic key events induced by FGF-2. 2001 Mar Platelet factor 4 (PF-4) is a CXC-chemokine with strong anti-angiogenic properties. We have shown previously that PF-4 inhibits angiogenesis by associating directly with fibroblast growth factor 2 (FGF-2), inhibiting its dimerization, and blocking FGF-2 binding to endothelial cells. We now have characterized a small peptide domain (PF-447-70) derived from the C-terminus of PF-4, which conserves anti-angiogenic effects of the parent protein. PF-447-70 inhibited internalization of 125I-FGF-2 by endothelial cells in a time-dependent manner. The peptide reduced FGF-2-stimulated cell migration to control levels in wounded monolayers of bovine capillary endothelial cells. PF-447-70 also reduced FGF-2 induced phosphorylation of MAP kinases ERK-1 and ERK-2, which are essential for migration and survival of endothelial cells. In a serum-free ex vivo angiogenesis assay, the peptide blocked microvessel outgrowth by 89%. A single amino acid substitution within PF-447-70 abolished all inhibitory activities. To simulate a real anti-angiogenic treatment situation, we administered PF-447-70 systemically to mice implanted subcutaneously with FGF-2 containing gelatin sponges with the result of sparse, scattered, and immature vessel growth. The small peptide fragment derived from the angio-inhibitory CXC-chemokine PF-4 might be used as a starting point to develop anti-angiogenic designer drugs for angiogenesis-dependent pathologies such as cancer, diabetic retinopathy, and rheumatoid arthritis.
11054608 Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. 2000 Oct The cachexia-anorexia syndrome occurs in chronic pathophysiologic processes including cancer, infection with human immunodeficiency virus, bacterial and parasitic diseases, inflammatory bowel disease, liver disease, obstructive pulmonary disease, cardiovascular disease, and rheumatoid arthritis. Cachexia makes an organism susceptible to secondary pathologies and can result in death. Cachexia-anorexia may result from pain, depression or anxiety, hypogeusia and hyposmia, taste and food aversions, chronic nausea, vomiting, early satiety, malfunction of the gastrointestinal system (delayed digestion, malabsorption, gastric stasis and associated delayed emptying, and/or atrophic changes of the mucosa), metabolic shifts, cytokine action, production of substances by tumor cells, and/or iatrogenic causes such as chemotherapy and radiotherapy. The cachexia-anorexia syndrome also involves metabolic and immune changes (mediated by either the pathophysiologic process, i.e., tumor, or host-derived chemical factors, e.g., peptides, neurotransmitters, cytokines, and lipid-mobilizing factors) and is associated with hypertriacylglycerolemia, lipolysis, and acceleration of protein turnover. These changes result in the loss of fat mass and body protein. Increased resting energy expenditure in weight-losing cachectic patients can occur despite the reduced dietary intake, indicating a systemic dysregulation of host metabolism. During cachexia, the organism is maintained in a constant negative energy balance. This can rarely be explained by the actual energy and substrate demands by tumors in patients with cancer. Overall, the cachectic profile is significantly different than that observed during starvation. Cachexia may result not only from anorexia and a decreased caloric intake but also from malabsorption and losses from the body (ulcers, hemorrhage, effusions). In any case, the major deficit of a cachectic organism is a negative energy balance. Cytokines are proposed to participate in the development and/or progression of cachexia-anorexia; interleukin-1, interleukin-6 (and its subfamily members such as ciliary neurotrophic factor and leukemia inhibitory factor), interferon-gamma, tumor necrosis factor-alpha, and brain-derived neurotrophic factor have been associated with various cachectic conditions. Controversy has focused on the requirement of increased cytokine concentrations in the circulation or other body fluids (e.g., cerebrospinal fluid) to demonstrate cytokine involvement in cachexia-anorexia. Cytokines, however, also act in paracrine, autocrine, and intracrine manners, activities that cannot be detected in the circulation. In fact, paracrine interactions represent a predominant cytokine mode of action within organs, including the brain. Data show that cytokines may be involved in cachectic-anorectic processes by being produced and by acting locally in specific brain regions. Brain synthesis of cytokines has been shown in peripheral models of cancer, peripheral inflammation, and during peripheral cytokine administration; these data support a role for brain cytokines as mediators of neurologic and neuropsychiatric manifestations of disease and in the brain-to-peripheral communication (e.g., through the autonomic nervous system). Brain mechanisms that merit significant attention in the cachexia-anorexia syndrome are those that result from interactions among cytokines, peptides/neuropeptides, and neurotransmitters. These interactions could result in additive, synergistic, or antagonistic activities and can involve modifications of transducing molecules and intracellular mediators. Thus, the data show that the cachexia-anorexia syndrome is multifactorial, and understanding the interactions between peripheral and brain mechanisms is pivotal to characterizing the underlying integrative pathophysiology of this disorder.
10884437 Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated 2000 Jul 5 The antimycotic clotrimazole, a potent inhibitor of the intermediate-conductance calcium-activated K(+) channel, IKCa1, is in clinical trials for the treatment of sickle cell disease and diarrhea and is effective in ameliorating the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by clotrimazole limits its therapeutic value. We have used a rational design strategy to develop a clotrimazole analog that selectively inhibits IKCa1 without blocking cytochrome P450 enzymes. A screen of 83 triarylmethanes revealed the pharmacophore for channel block to be different from that required for cytochrome P450 inhibition. The "IKCa1-pharmacophore" consists of a (2-halogenophenyl)diphenylmethane moiety substituted by an unsubstituted polar pi-electron-rich heterocycle (pyrazole or tetrazole) or a -C≡N group, whereas cytochrome P450 inhibition absolutely requires the imidazole ring. A series of pyrazoles, acetonitriles, and tetrazoles were synthesized and found to selectively block IKCa1. TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole) inhibits the cloned and the native IKCa1 channel in human T lymphocytes with a K(d) of 20-25 nM and is 200- to 1,500-fold selective over other ion channels. Using TRAM-34, we show that blocking IKCa1 in human lymphocytes, in the absence of P450-inhibition, results in suppression of mitogen-stimulated [(3)H]thymidine incorporation of preactivated lymphocytes with EC(50)-values of 100 nM-1 microM depending on the donor. Combinations of TRAM-34 and cyclosporin A are more effective in suppressing lymphocyte mitogenesis than either compound alone. Our studies suggest that TRAM-34 and related compounds may hold therapeutic promise as immunosuppressants.
10685811 Occupational lifting is associated with hip osteoarthritis: a Japanese case-control study. 2000 Feb OBJECTIVE: Hip osteoarthritis (OA) is a frequent cause of pain and disability in Western countries, but the disorder is less common in Japan. A case-control study in Britain found obesity, hip injury, and occupational lifting to be associated with hip OA among men and women. However, there are few epidemiological studies concerning factors associated with hip OA in Japan. We performed a comparable case-control study of the disorder in Japan, and contrasted the findings with those from Britain. METHODS: The study was carried out in 2 health districts in Wakayama Prefecture, Japan. Cases were men and women aged > or = 45 years listed for total hip arthroplasty due to OA over one year, and who did not have an established cause of secondary OA (e.g., rheumatoid arthritis, ankylosing spondylitis). For each case, a control was selected randomly from the general population and was individually matched to the case for age, sex, and district of residence. Cases and controls were interviewed with a structured questionnaire about medical history, physical activity, socioeconomic factors, and occupation. Measurements were made of height and weight. RESULTS: One hundred fourteen cases (103 women, 11 men) were compared with 114 controls. We found no relationship between obesity and hip OA (OR = 1.0, 95% CI 0.5-1.9; highest vs lowest thirds of distribution of body mass index). There was, however, a statistically significant association between occupational lifting and hip OA, such that regular lifting of 25 kg in the individual's first job (OR = 3.6, 95% CI 1.3-9.7) or of 50 kg in their main job (OR = 4.0, 95% CI 1.1-14.2) was associated with increased risk of hip OA. These associations remained after adjustment for potential confounding variables. In contrast, those subjects who spent > 2 h each day sitting during their first job were significantly less likely to have the disorder (crude OR = 0.5, 95% CI 0.3-0.9). This association also remained statistically significant after adjustment for potential risk factors. CONCLUSION: Our findings support the hypothesis that occupational physical activity, particularly the lifting of very heavy loads in the workplace at regular intervals, predisposes to hip OA in both Britain and Japan. The lack of association between obesity or hand involvement and hip OA in Japan suggests that the contribution of constitutional and mechanical risk factors to this disorder might differ in different populations. However, attention to manual handling in the workplace would appear an important aspect of preventive strategies against hip OA in Western and Oriental populations.
10614883 Clinical experience with a proximally porous-coated second-generation cementless total hip 1999 Dec This study reports the minimum 5-year follow-up of our experience with the Porous-Coated Anatomic E (PCA-E) series femoral stem and the modular acetabular cup. A total of 115 consecutive total hip replacements using PCA-E series (Howmedica, Rutherford, NJ) were performed in 108 patients. Six patients whose hips were performing well clinically died before 5-year follow-up and were excluded from the final evaluation. The remaining 109 hips (102 patients) were assessed at a mean follow-up of 72 months (range, 60-84 months). The hip diagnoses were osteoarthritis in 73, osteonecrosis in 31, rheumatoid arthritis in 2, and hip dysplasia in 3. The mean age was 56 years (range, 24-83 years). Three hips were revised: 1 because of late hematogenous infection, 1 because of aseptic loosening of the femoral component, and 1 because of postoperative loosening of an acetabular component. The Harris hip scores improved from a mean of 50 points (range, 20-66 points) preoperatively to a mean of 92 points (range, 64-100 points) at final follow-up. The score differed in each Charnley functional class, with a mean of 93 points (range, 72-100 points) in 57 hips of class A (no other joint involvement); 90 points (range, 58-100 points) in 26 hips of class B (opposite hip involvement); and 85 points (range, 37-100 points) in 26 hips of class C (multiple joint involvement or severe systemic disease). Out of 106 hips that had a full radiographic evaluation performed, 103 femoral components revealed stable bony ingrowth, 2 revealed stable fibrous ingrowth, and 1 showed migration with progressive loosening. This patient with radiographic loosening has minimal symptoms and has not required or been offered further surgery (Harris hip score of 86 points). The low aseptic loosening rate (2%) at minimum 5-year follow-up compares favorably with any cemented or cementless series. The osteolysis that was seen was focal and localized. The short follow-up does not allow determination of progression. There were no cases of distal osteolysis. We attribute the improved results from reported first-generation experience to multiple factors, including increased number of sizes (9 vs 6), increased proportional metaphyseal size, improved polyethylene manufacture (ram extruded vs machined), improved acetabular locking mechanism, and change to 26-mm from 32-mm femoral heads.