Antihypertensive Agents and Incident Alzheimer's Disease: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: Hypertension is a recognized risk factor for dementia. However, evidence for using antihypertensive agents to reduce the risk of Alzheimer's disease in people with hypertension is inconclusive. OBJECTIVE: To examine the association between antihypertensive agents and the incidence of Alzheimer's disease in adults with hypertension and normal cognition. DESIGN: We conducted a systemic review and performed meta-analyses using Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, Web of science and Scopus, from inception to 18th February 2022. SETTING: Cohort and case-control studies. PARTICIPANTS: Adults ≥ 40 years with hypertension and normal cognition. INTERVENTION: Antihypertensive agents. MEASUREMENTS: We performed two separate meta-analyses, pooling the adjusted relative risk (RR) of non-antihypertensive comparator and antihypertensive comparator study design. RESULTS: We included nine studies, totalling 1,527,410 individuals. Meta-analysis of non-antihypertensive user comparator studies found that the use of antihypertensive agents is associated with a reduced risk of incident Alzheimer's disease (RR= 0.94, 95% CI 0.90-0.99; p=0.01). Meta-analysis of antihypertensive comparator studies found evidence that angiotensin II receptor blocker users are associated with a reduction in the risk of Alzheimer's disease compared to other antihypertensive agents (RR= 0.78, 95% CI 0.68-0.88; p< 0.001). CONCLUSION: Our review provides evidence that the use of antihypertensive agents is associated with a lower incidence of Alzheimer's disease. The use of angiotensin II receptor blockers may provide the most benefit among antihypertensive agents. Lowering raised blood pressure may not be the only mechanism for cognitive protection and further investigation of the effects of angiotensin II on cognition is indicated.

The use of antipsychotic agents during pregnancy and the risk of gestational diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Previous studies have found contradicting results with regard to the use of antipsychotics during pregnancy and the risk of gestational diabetes mellitus (GDM). We aimed to evaluate the association between antipsychotic use in pregnancy and GDM. METHODS: A systematic literature search was conducted in PubMed, EMBASE, PsycINFO and Cochrane Library databases up to March 2019, for data from observational studies assessing the association between gestational antipsychotic use and GDM. Non-English studies, animal studies, case reports, conference abstracts, book chapters, reviews and summaries were excluded. The primary outcome was GDM. Estimates were pooled using a random effect model, with the I2 statistic used to estimate heterogeneity of results. Our study protocol was registered with PROSPERO number: CRD42018095014. RESULTS: In total 10 cohort studies met the inclusion criteria in our systematic review with 6642 exposed and 1 860 290 unexposed pregnancies. Six studies were included in the meta-analysis with a pooled adjusted relative risk of 1.24 overall [95% confidence interval (CI) 1.09-1.42]. The I2 result suggested low heterogeneity between studies (I2 = 6.7%, p = 0.373). CONCLUSION: We found that the use of antipsychotic medications during pregnancy is associated with an increased risk of GDM in mothers. However, the evidence is still insufficient, especially for specific drug classes. We recommend more studies to investigate this association for specific drug classes, dosages and comorbidities to help clinicians to manage the risk of GDM if initiation or continuation of antipsychotic prescriptions during pregnancy is needed.

Tumor suppression in mice lacking GABARAP, an Atg8/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death.

GABARAP belongs to an evolutionary highly conserved gene family that has a fundamental role in autophagy. There is ample evidence for a crosstalk between autophagy and apoptosis as well as the immune response. However, the molecular details for these interactions are not fully characterized. Here, we report that the ablation of murine GABARAP, a member of the Atg8/LC3 family that is central to autophagosome formation, suppresses the incidence of tumor formation mediated by the carcinogen DMBA and results in an enhancement of the immune response through increased secretion of IL-1ß, IL-6, IL-2 and IFN-γ from stimulated macrophages and lymphocytes. In contrast, TGF-ß1 was significantly reduced in the serum of these knockout mice. Further, DMBA treatment of these GABARAP knockout mice reduced the cellularity of the spleen and the growth of mammary glands through the induction of apoptosis. Gene expression profiling of mammary glands revealed significantly elevated levels of Xaf1, an apoptotic inducer and tumor-suppressor gene, in knockout mice. Furthermore, DMBA treatment triggered the upregulation of pro-apoptotic (Bid, Apaf1, Bax), cell death (Tnfrsf10b, Ripk1) and cell cycle inhibitor (Cdkn1a, Cdkn2c) genes in the mammary glands. Finally, tumor growth of B16 melanoma cells after subcutaneous inoculation was inhibited in GABARAP-deficient mice. Together, these data provide strong evidence for the involvement of GABARAP in tumorigenesis in vivo by delaying cell death and its associated immune-related response.

MMP-19 deficiency causes aggravation of colitis due to defects in innate immune cell function.

Matrix metalloproteinases (MMPs) are potential biomarkers for disease activity in inflammatory bowel disease (IBD). However, clinical trials targeting MMPs have not succeeded, likely due to poor understanding of the biological functions of individual MMPs. Here, we explore the role of MMP-19 in IBD pathology. Using a DSS-induced model of colitis, we show evidence for increased susceptibility of Mmp-19-deficient (Mmp-19(-/-)) mice to colitis. Absence of MMP-19 leads to significant disease progression, with reduced survival rates, severe tissue destruction, and elevated levels of pro-inflammatory modulators in the colon and plasma, and failure to resolve inflammation. There was a striking delay in neutrophil infiltration into the colon of Mmp-19(-/-) mice during the acute colitis, leading to persistent inflammation and poor recovery; this was rescued by reconstitution of irradiated Mmp-19(-/-) mice with wild-type bone marrow. Additionally, Mmp-19-deficient macrophages exhibited decreased migration in vivo and in vitro and the mucosal barrier appeared compromised. Finally, chemokine fractalkine (CX3CL1) was identified as a novel substrate of MMP-19, suggesting a link between insufficient processing of CX3CL1 and cell recruitment in the Mmp-19(-/-) mice. MMP-19 proves to be a critical factor in balanced host response to colonic pathogens, and for orchestrating appropriate innate immune response in colitis.

Ascertainment of acute liver injury in two European primary care databases.

PURPOSE: The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. METHODS: The Clinical Practice Research Datalink (CPRD) in UK and the Spanish "Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria" (BIFAP) were used. Both are primary care databases from which we selected individuals of all ages registered between January 2004 and December 2009. We developed two case definitions of idiopathic ALI using computer algorithms: (i) restrictive definition (definite cases) and (ii) broad definition (definite and probable cases). Patients presenting prior liver conditions were excluded. Manual review of potential cases was performed to confirm diagnosis, in a sample in CPRD (21%) and all potential cases in BIFAP. Incidence rates of ALI by age, sex and calendar year were calculated. RESULTS: In BIFAP, all cases considered definite after manual review had been detected with the computer algorithm as potential cases, and none came from the non-cases group. The restrictive definition of ALI had a low sensitivity but a very high specificity (95% in BIFAP) and showed higher rates of agreement between computer search and manual review compared to the broad definition. Higher incidence rates of definite ALI in 2008 were observed in BIFAP (3.01 (95% confidence interval (CI) 2.13-4.25) per 100,000 person-years than CPRD (1.35 (95% CI 1.03-1.78)). CONCLUSIONS: This study shows that it is feasible to identify ALI cases if restrictive selection criteria are used and the possibility to review additional information to rule out differential diagnoses. Our results confirm that idiopathic ALI is a very rare disease in the general population. Finally, the construction of a standard definition with predefined criteria facilitates the timely comparison across databases.

[Objective structured clinical examination (OSCE) on completion of surgical block practical training--twelve months experience with a hands-on examination]. / Implementierung einer OSCE-Prüfung zur Benotung des Chirurgischen Blockpraktikums--Zwölf Monate Erfahrung mit einer praktischen Prüfungsmethode.

BACKGROUND: According to the approval system for medical doctors, practical courses such as block practical training must be graded. The grading of the surgical block practical training at the Klinikum rechts der Isar, Technische Universität of Munich (TUM), was changed from single grades of each day to a final objective structured clinical examination (OSCE). We report about the experiences in the past 12 months with this relatively new form of examination. METHODS: An OSCE was established as a practical exam with seven stations about suture techniques, internal fixation, first-aid education, hygiene and sterility, clinical examination and perioperative management. The feasibility of a comprehensive OSCE with the necessary modifications was studied and the grades had been compared. RESULTS: In the past 12 months four surgical block placements for over three weeks had been organised with a total of 326 students. 309 students were admitted for the OSCE at the end of block practical training. The average score was 1.75. The medical student raters graded either equally or more stringently compared to the medical doctors. The transcript revealed in all OSCEs a normal distribution of grading with high validity. However, an adaptation of the evaluation forms and an extension of the stations with modified content was required to obtain the same test conditions for all students. The implementation of the OSCE on this scale is possible with adequate preparation time and sufficient financial support. The evaluation of the specimens after completion of the test were all positive. CONCLUSION: The new medical approval system calls for restructuring, not only in teaching but also in the form of examination of the courses. Through this practical test, those skills of a student will be assessed that cannot be tested by the IMPP exam. Moreover, this examination form provides an excellent preparation for the practical part of the oral state examination. This OSCE is even feasible with high numbers of students and offers with appropriate adaptation of the evaluation forms and test stations, a normal distribution of grading.

Effect of perioperative administration of a drug regimen on the primary function of human renal allografts.

Delayed graft function (DGF) has one of the greatest effects on short- and long-term outcomes of cadaveric renal allografts. Ischemia reperfusion injury in the context of cold ischemia time and acute calcineurin inhibitor (CNI) nephrotoxicity is a major factor predisposing to DGF. A drug regimen consisting of prostaglandin E(1) (PGE(1)) furosemide and dopamine has been used to reduce DGF after kidney transplantation. Prostaglandin E(1) has multiple anti-ischemic and tissue-protective abilities, furosemide improves diuresis, and dopamine augments renal blood flow and urinary volume. To evaluate a potential positive effect of this drug regimen on the primary function of cadaveric renal allografts, we performed a retrospective single-center study that compared 100 patients who received this regimen with a control group. The results showed no significant improvement in renal function. In contrast, plasma levels of creatinine and urea were increased in the drug regimen group. Thus, the effectiveness of PGE(1) in combination with high-dose furosemide and dopamine in diminishing DGF was not demonstrated in this trial.

The role of proinflammatory cytokines in the generation and maintenance of joint pain.

The proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) not only promote and maintain inflammation, they also contribute to the generation and maintenance of inflammatory pain by acting at nociceptive nerve cells. A large proportion of dorsal root ganglion (DRG) neurons express TNF receptors and receptor units for stimulation with IL-6. In the rat model of antigen-induced arthritis (AIA), neutralization of TNF-alpha by etanercept and infliximab reduced inflammation-evoked mechanical hyperalgesia at the inflamed knee joint. This treatment also attenuated the infiltration of macrophages into the DRGs usually observed during the acute phase of AIA. Intra-articular application of etanercept reduced the responses of C-fibers to mechanical stimulation of the inflamed joint but did not influence responses to stimulation of the normal joint. Finally, in cultured DRG neurons TNF-alpha increased the proportion of neurons that express the TRPV1 receptor and may thus contribute to the generation of inflammation-evoked thermal hyperalgesia.

Combination therapy with dexamethasone and osteoprotegerin protects against arthritis-induced bone alterations in antigen-induced arthritis of the rat.

OBJECTIVE: To investigate the influence of a combined therapy consisting of dexamethasone and osteoprotegerin (OPG) on bone alterations and disease activity in antigen-induced arthritis (AIA) in the rat. METHODS: AIA rats received dexamethasone (0.25 mg kg(-1) day(-1), i.p.), OPG (2.5 mg kg(-1) day(-1), i.p.), or a combination of both at regular intervals for 21 consecutive days. At the end of the treatment, bone structure was analyzed by histomorphometry. Primary spongiosa was measured using linear scanning. RESULTS: AIA led to significant periarticular and axial bone loss. Dexamethasone monotherapy substantially suppressed joint swelling without inhibiting bone loss of the secondary spongiosa, whereas OPG monotherapy showed no anti-inflammatory effect. Despite reduction of bone resorption, OPG did not inhibit AIA-induced bone loss. In contrast, the combination of dexamethasone and OPG not only produced an anti-inflammatory effect, but also resulted in inhibition of periarticular and axial bone loss. OPG increased trabecular number of the primary spongiosa whilst combination therapy led to an increase in both trabecular number and trabecular width. CONCLUSION: The principle of combining a glucocorticoid together with inhibition of the receptor activator of NF-kappaB ligand (RANKL) may be an effective bone-saving therapy in rheumatoid arthritis.

[Quality and quality assurance of teaching in surgery - recommendations from a workshop of the surgical cooperative for quality assurance]. / Qualität und Qualitätssicherung der Lehre in der Chirurgie - Empfehlungen aus einem Workshop der Chirurgischen Arbeitsgemeinschaft für Qualitätssicherung.

The shortage of surgeons in the operative disciplines field has in recent years further increased. The training of a surgeon and the required lifestyle combined with the work-life balance of the surgeons are perceived as being less attractive, so that young doctors after finishing medical school rarely decide for surgical careers. Changes in the social environment outside of our clinics has resulted in a decline of the social prestige. The modified structural preconditions require a rethinking of the training processes for studying and working conditions in surgery. The quality of surgical education is therefore a cornerstone for the future development of our subject and is directly linked to the training and junior development. The CAQ meeting in Greifswald in February 2009, has focused on the teaching in surgery and developed together with medical students of different faculties solutions for the three major problem factors: teaching, training and junior development. The students are demanding clear guidelines regarding the required theoretical and practical knowledge in the form of catalogues or learning logs. The absence of intrinsic commitment to an excellent teaching and role model is due to the ongoing conflict between patient care and teaching. Because in teaching usually neither the quantity nor the quality will be systematically registered and no sanctions promote the lesson, so that the training is always considered as a last resort. One approach could be a scoring system for teaching that reflect the quantity and quality of teaching in points. The practical year needs to be reformed, since over 25% of the students spend their surgery part abroad, because they are afraid to be considered as cheap labour. Especially at this point, the lecturer is asked to reform the education of students during the practical year and to strengthen the role model for young academic teachers.

Liver transplantation in the rat: single-center experience with technique, long-term survival, and functional and histologic findings.

OBJECTIVE: Orthotopic liver transplantation (OLT) in rats is frequently used as an experimental model. Numerous surgical techniques have been developed that enable the investigator to conduct clinically relevant studies. The objective of this study was to develop a rat model of acute and chronic rejection, to explicitly study technical modifications of vascular anastomoses with precision, and to examine histopathologic and functional changes in the graft. MATERIALS AND METHODS: With DA-(RT1av1) rats as donors and Lewis-(RT1) rats as recipients, arterialized OLT was performed using a combined suture, cuff, and splint method. Recipients were divided into 5 groups: syngeneic control rats (group 1), allogeneic control rats (group 2), allogeneic OLT rats with low-dose tacrolimus (FK506) immunosuppression (group 3), allogeneic OLT rats with high-dose tacrolimus immunosuppression (group 4), and allogeneic OLT rats with high-dose tacrolimus immunosuppression and retrograde reperfusion via the infrahepatic caval vein (group 5). After OLT, serum parameters were determined and hepatic biopsy specimens were sampled. We examined the effects of acute rejection with or without immunosuppression therapy at histopathologic evaluation. RESULTS: Liver grafts in syngeneic and allogeneic rats (groups 1, 2, 4, and 5) demonstrated normal serum parameters and histopathologic findings at 10 days after OLT, and 93% survival at 3 months. The simplified technique using 1 suture and 2 cuff anastomoses provided the best short- and long-term survival after OLT in all groups. Retrograde perfusion via the infrahepatic caval vein resulted in lower postoperative liver enzyme values. CONCLUSION: The present model is feasible, enabling comprehensive preclinical experimental research on liver transplantation. Furthermore, we provide helpful instructions for learning this surgical technique.

[Paradoxical role of interferon-gamma in arthritis]. / Paradoxe Rolle von Interferon-gamma bei Arthritis.

In T cell-mediated autoimmune diseases such as rheumatoid arthritis, Th1 cells and their cytokines, especially interferon-gamma (IFN-gamma), are responsible for the induction and persistence of chronic inflammation and tissue destruction. But emerging evidence from experimental models has demonstrated that IFN-gamma also possesses unexpected anti inflammatory properties. The recent data discussed in this article indicate that beside the well-known proinflammatory efficacy, IFN-gamma may function as a master regulator of inflammation and immune responses. Such self-regulatory processes seem to play an important role in the inhibition of excessive responses and to maintain or reestablish homeostasis of the immune system.

Relative contribution of matrix metalloprotease and cysteine protease activities to cytokine-stimulated articular cartilage degradation.

OBJECTIVE: Both matrix metalloprotease (MMP) activity and cathepsin K (CK) activity have been implicated in cartilage turnover. We investigated the relative contribution of MMP activity and CK activity in cartilage degradation using ex vivo and in vivo models. METHODS: Bovine articular cartilage explants were stimulated with oncostatin M (OSM) 10 ng/ml and tumor necrosis factor-alpha (TNF-alpha) 20 ng/ml in the presence or absence of the broad-spectrum MMP inhibitor GM6001 and the cysteine protease inhibitor, E64. Cartilage degradation was evaluated in the conditioned medium by glycosaminoglycans (GAG), hydroxyproline, and cross-linked C-telopeptide fragments of type II collagen (CTX-II), which were compared to immunohistochemical evaluations of proteoglycans and CTX-II. We assessed MMP expression by gelatine zymography and CK expression by immunohistochemistry. In vivo, CTX-II release was measured from CK-deficient mice. RESULTS: OSM and TNF-alpha combined induced significant (P<0.01) increase in cartilage degradation products measured by hydroxyproline and CTX-II compared to vehicle control. The cytokines potently induced MMP expression, assessed by zymography, and CK expression investigated by immunohistochemistry. Inhibition of MMP activity completely abrogated hydroxyproline and CTX-II release (P<0.01) and GAG release (P<0.05). In contrast, E64 resulted in increased CTX-II release by 100% (P<0.05) and inhibited GAG release by 30%. Up-regulation of CTX-II fragments was confirmed in vivo in CK null mice. CONCLUSION: Inhibition of MMP activity reduced both proteoglycan loss and type II collagen degradation. In contrast, inhibition of cysteine proteases resulted in an increase rather than a decrease in MMP derived fragments of collagen type II degradation, CTX-II, suggesting altered collagen metabolism.

Osteoprotegerin reduces the loss of periarticular bone mass in primary and secondary spongiosa but does not influence inflammation in rat antigen-induced arthritis.

OBJECTIVE: To assess the effect of osteoprotegerin (OPG) on joint swelling, synovial inflammation and cartilage destruction, periarticular and axial bone volume, and bone turnover in rat antigen-induced arthritis (AIA). DESIGN: Rats were treated with OPG (3 mg/kg/day) at regular intervals from day 1 to day 20 of AIA. Disease activity was evaluated by measurement of joint swelling as well as, joint inflammation and destruction by histology. Bone volume and cellular turnover parameters of secondary spongiosa of the right tibia head and the third lumbar vertebra were evaluated by histomorphometry. Periarticular bone volume of the primary spongiosa at the right tibia head was measured by linear scanning. The findings were compared with those of PBS-treated AIA and healthy animals. RESULT: OPG treatment did not reduce joint swelling or histological signs of inflammation. Cartilage destruction was reduced. However, this effect did not reach statistical significance . In the secondary spongiosa OPG treatment reduced the loss of periarticular bone volume. However, the latter did not reach the level of healthy controls. OPG treatment significantly reduced parameters of bone formation and bone resorption. In the primary spongiosa, OPG-treatment led to a higher amount of mineralized tissue and a greater number of trabeculae compared to PBS-treated animals with AIA or healthy controls. In the axial skeleton, OPG treatment reduced bone formation and bone resorption parameters compared to healthy animals. This treatment had no influence on bone volume. CONCLUSIONS: In periarticular bone of AIA rats, OPG treatment reduced the loss of bone volume and decreased the bone turnover, thus preventing periarticular bone destruction. OPG treatment had no influence on inflammatory process or on cartilage destruction.

Anti-CD4 monoclonal antibody treatment in acute and early chronic antigen induced arthritis: influence on macrophage activation.

OBJECTIVE: To investigate the indirect effects of anti-CD4 treatment on the functions of macrophages (CD4(-) in mice) in the acute and early chronic phase of mouse antigen induced arthritis (AIA). METHODS: C57BL/6 mice with AIA were treated intraperitoneally with the anti-CD4 mAb GK1.5 or control rat IgG on days -1, 0, 1, 3, 5, and 7. Proinflammatory cytokines (IL1 beta, IL6, and TNF alpha) were quantified by sandwich ELISA in joint extracts, serum, and supernatants of ex vivo stimulated spleen/lymph node cells or peritoneal macrophages (+LPS/IFN gamma). Nitric oxide (NO) levels in supernatants of ex vivo stimulated peritoneal macrophages were measured by the Griess reaction. Proteolytic activity in joint homogenates was analysed by gelatin, casein, and elastin zymography, and substrate assays. RESULTS: Anti-CD4 treatment significantly reduced joint swelling in acute (days 3, 5) and early chronic AIA (day 7) and diminished inflammation and destruction scores in late chronic AIA (day 21). On day 3, anti-CD4 treatment significantly reduced IL6 levels in all compartments. IL1 beta was reduced in joint extracts, unaffected in serum or cells from lymphoid organs, and increased in stimulated peritoneal macrophages. TNF alpha was significantly increased in the joints, decreased in serum, and otherwise unchanged. NO production by stimulated peritoneal macrophages was significantly reduced by anti-CD4 treatment. Lower activity of matrix metalloproteinases and neutrophil elastase was seen in joint extracts of anti-CD4 treated animals than in IgG treated AIA controls. CONCLUSION: CD4(+) T cell directed treatment had strong local and systemic effects on macrophages. These indirect effects may contribute to the reduction of destructive mediators/joint destruction in AIA.

The expression and localization of somatostatin receptors in dorsal root ganglion neurons of normal and monoarthritic rats.

Somatostatin has antinociceptive effects by acting on somatostatin (sst) receptors in primary afferent neurons. Five sst receptor subtypes (sst(1-5)) have been identified. In the present study we assessed the expression and localization of the sst receptor subtypes in lumbar dorsal root ganglia of normal rats and of rats with unilateral antigen-induced arthritis (AIA) in the knee joint. We used polymerase chain reaction (PCR) of material from dorsal root ganglia and immunohistochemistry in dorsal root ganglion paraffin sections. PCR data show that sst(1), sst(2(a)), sst(2(b)), sst(3), and sst(4) receptors are expressed in lumbar dorsal root ganglia of the rat. The sst(5) receptor was expressed in a few samples. Available antibodies revealed sst(2(a)) and sst(2(b)) receptor-like immunoreactivity in the vast majority of neurons, and sst(4) receptor-like immunoreactivity in about 40% of the dorsal root ganglion neurons and in some satellite cells. Real time PCR at 3, 10 and 21 days after induction of AIA did not reveal changes in receptor expression. Immunohistochemistry showed that a similar high proportion of neuronal profiles expressed sst(2(b)) receptor-like IR in control and AIA rats, but the proportion of neuronal profiles with sst(2(a)) receptor-like IR was significantly lower in acute and chronic AIA rats than in control rats. Although the proportion of neuronal profiles with sst(4) receptor-like IR was significantly higher at 21 days than at 3 days values at 3 or at 21 days were not significantly different from control. These data show that the majority of dorsal root ganglion neurons exhibit somatostatin receptor-like IR thus suggesting a high potential for inhibition by somatostatin. The reduction in the proportion of neuronal profiles with sst(2(a)) immunoreactivity suggests that inhibition of neuronal activity by somatostatin is reduced during painful arthritis.

Amelioration of murine antigen-induced arthritis by dehydroepiandrosterone (DHEA).

OBJECTIVE AND DESIGN: Sex hormones have immunomodulatory properties and may play an important role in the pathogenesis of autoimmune diseases like rheumatoid arthritis (RA). This study sought to examine the effects of the natural weak androgen dehydroepiandrosterone (DHEA) and its metabolite androstenediol (AED) on the development of murine antigen-induced arthritis (AIA). METHODS: DHEA and AED were administered orally, approximately 10 mg/day, from the time of AIA induction (i.e., 3 weeks after start of immunization) in young male as well as young and old female C57BL/6 mice. The effects were assessed in terms of joint swelling, histological changes, and cell-mediated and humoral immunity. RESULTS: Compared to untreated AIA animals, continuous administration of DHEA decreased knee joint swelling during acute and chronic AIA, as well as histological signs of inflammation and joint destruction during chronic AIA. These effects were age- and gender-independent. Delayed-type hypersensitivity (DTH) to the specific antigen methylated bovine serum albumin (mBSA) was significantly reduced, but there were no changes in the balance of the T helper (Th) cell subsets Th1/Th2, as tested by the ratio of IgG isotypes in the sera. Whereas serum levels of IgG antibodies to mBSA were not influenced, the formation of IgG autoantibodies to the matrix constituents collagen type I, collagen type II, and cartilage proteoglycans was significantly inhibited. In all experiments, the effects of AED were not significantly stronger than those of DHEA. CONCLUSIONS: Administration of exogenous DHEA ameliorates the severity of acute and chronic AIA, presumably by suppressing cell-mediated immunity against mBSA (the inducing antigen) and formation of autoantibodies. However, because of the fundamentally different DHEA physiology in rodents, the role of such a replacement therapy in human RA deserves further elucidation.

Anti-CD4 monoclonal antibody treatment in acute and early chronic antigen-induced arthritis: influence on T helper cell activation.

To examine the effects of anti-CD4 mAb treatment in acute and chronic antigen-induced arthritis (AIA), C57BL/6 mice were treated intraperitoneally either with the depleting anti-CD4 mAb GK1.5 or with rat-IgG (control) on Days -1, 0, 1, 3, 5, and 7. Arthritis was monitored by assessment of joint swelling and histological evaluation in the acute (Day 3) and the chronic phase (Day 21) of AIA. To determine the effects on cellular immune responses, in vivo T-cell reactivity (delayed type hypersensitivity; DTH) was measured, as well as protein levels of TH1- (IL-2, IFN-gamma) and TH2-cytokines (IL-4, IL-10) in joint extracts and supernatants of ex vivo stimulated spleen and lymph node cells. The humoral immune response was analysed by measuring serum antibodies against methylated bovine serum albumine (mBSA) and extracellular matrix proteins. Treatment with GK1.5 reduced swelling, inflammation, and destruction of the arthritic joint. Unexpectedly, the effects were even more pronounced in the acute than in the chronic phase. The anti-inflammatory effect was accompanied by a diminished DTH against the arthritogen mBSA and a decrease of TH1-cytokine production in spleen and pooled body lymph nodes, whereas the TH2-cytokine production in these organs was unchanged and the humoral immune response was only moderately reduced. There was a failure of depleting CD4+ T-cells in the joint, reflected also by unchanged local cytokine levels. Therefore, systemic rather than local effects on the TH1/TH2 balance appear to underlie the therapeutic efficacy of anti-CD4 treatment in AIA.

Expression of fibronectin splice variants and oncofetal glycosylated fibronectin in the synovial membranes of patients with rheumatoid arthritis and osteoarthritis.

OBJECTIVE: The aim of this study was to define and compare the expression of fibronectin (Fn) isoforms in synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Using monoclonal antibodies specific for total Fn, extra domain (ED)-A Fn, ED-B Fn, and oncofetal glycosylated Fn, we studied the expression of the Fn isoforms in synovium. Furthermore, in situ hybridization for the detection of ED-B Fn mRNA including a double labeling technique for the detection of cell type was applied. RESULTS: Strong expression of total Fn, ED-A Fn, oncofetal glycosylated Fn and, to a lesser extent, ED-B Fn could be demonstrated in the synovial lining layer in both RA and OA. Stromal and vessel expression of Fn isoforms was more prominent in RA tissue. Pannus tissue showed strong labeling with ED-B Fn. CONCLUSION: The expression of alternatively spliced isoforms of Fn is associated with tissue remodeling and, as a partial process of this phenomenon, with neovascularization rather than underlying disease, X-ray status, or parameters of acute inflammation. In the lining layer, Fn expression correlates with hyperplasia associated with cell recruitment but not with proliferative status. Most remarkably, the expression of ED-B Fn in pannus tissue seems to be associated with the invasive phenotype described in RA tissue.