bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serotonin Syndrome with Elevated Paroxetine Concentrations
Authors: Velez Larissa I , Shepherd Greene , Roth Brett A , Benitez Fernando L 
Published: January 2004

OBJECTIVE To describe a case of serotonin syndrome due to paroxetine and ethanol. CASE SUMMARY A 57-year-old white man was brought to the emergency department one day after ingesting paroxetine 3600 mg and a pint of hard liquor. He denied the use of any other drug or herbal products and regular use of alcohol. Upon arrival to the hospital, vital signs were blood pressure 188/103 mm Hg, heart rate 114 beats/min, respiratory rate 28 breaths/min, temperature 36.8 °C, and O2 saturation 96% on room air. Findings on physical examination included dilated pupils, facial flushing, diaphoresis, shivering, myoclonic jerks, tremors, and hyperreflexia. A tentative diagnosis of serotonin syndrome was made. Initially, cyproheptadine 8 mg was administered orally with no observable effect. An additional 12 mg was given in 3 doses over 24 hours. Symptoms abated slowly over the next 6 days, during which a thorough evaluation failed to reveal any other potential causes for the patient's condition. Serum paroxetine concentrations at 27.5 and 40 hours after ingestion were 1800 and 1600 ng/mL, respectively (normal 20–200 ng/mL). DISCUSSION Serotonin syndrome is rarely reported in patients taking only one serotonergic medication. Although serum paroxetine concentrations have not been shown to correlate with efficacy or toxicity, our patient's serum paroxetine concentration was 9 times the upper end of the therapeutic range. Cyproheptadine, which has been suggested as a therapy, did not appear beneficial in this patient. Use of the Naranjo probability scale indicated a probable relationship between the serotonin syndrome and the overdose of paroxetine taken by this patient. CONCLUSIONS More studies are needed to better assess the role of cyproheptadine and other serotonin antagonists in the management of the serotonin syndrome. Regardless of the use of cyproheptadine or other agents, attention should be paid to fluid status, decontamination, and management of hyperthermia, agitation, and seizures.
Teriparatide for Severe Osteoporosis
Authors: Cappuzzo Kimberly A , Delafuente Jeffrey C 
Published: January 2004

OBJECTIVE To review the pharmacology, toxicology, pharmacokinetics, pharmacodynamics, efficacy, safety, therapeutic controversies, administration, patient counseling, and formulary recommendations for teriparatide (rDNA origin). DATA SOURCES A MEDLINE search (1966–May 2003) of articles using the key words parathyroid hormone and osteoporosis, parathyroid hormone and fracture, and teriparatide was conducted to identify relevant literature in the English language. Additional references were obtained from bibliographies of those articles. Some clinical trial data not yet published were obtained from the manufacturer. STUDY SELECTION AND DATA EXTRACTION All articles obtained from the data sources were reviewed; all data deemed relevant were included. DATA SYNTHESIS Teriparatide, recombinant human parathyroid hormone (1–34) [rhPTH (1–34)], is the first anabolic agent to treat postmenopausal women with osteoporosis and men with idiopathic or hypogonadal osteoporosis who are at high risk for osteoporotic fracture. Daily subcutaneous injections of teriparatide significantly increase both spine and hip bone-mineral density (BMD) while decreasing the incidence of fractures in both women and men. Common adverse effects noted with teriparatide use were nausea, headache, dizziness, and arthralgias. An increased incidence of osteosarcoma in rats during preclinical trials with teriparatide led to a black box warning for the drug. CONCLUSIONS Teriparatide substantially increases spine and hip BMD and may offer additional benefits to patients with severe osteoporosis. Clinical trials comparing teriparatide with other available agents to treat osteoporosis are needed to more clearly define its place in therapy. Long-term safety and efficacy are not known.
Effect of Atorvastatin on Cyclosporine Pharmacokinetics in Liver Transplant Recipients
Authors: Taylor Paul J , Kubler Paul A , Lynch Stephen V , Allen Joan , Butler Maree , Pillans Peter I 
Published: January 2004

BACKGROUND The development of hyperlipidemia after liver transplant is frequently treated with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) such as atorvastatin. As atorvastatin and the primary immunosuppressant drug, cyclosporine, are metabolized by the same pathway, there is the potential for an interaction. OBJECTIVE To determine the effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients. METHODS Six stable, long-term adult liver transplant recipients from a single center who developed posttransplant dyslipidemia were recruited to participate in a 14-day, open-label study of atorvastatin 10 mg/d coadministered with standard posttransplant immunosuppression using constant oral doses of cyclosporine and corticosteroids. A 10-point pharmacokinetic profile was performed prior to and on day 14 after commencement of atorvastatin therapy. Cyclosporine concentrations were measured by HPLC-electrospray-tandem mass spectrometry. The AUC was calculated by the linear trapezoidal rule, with other parameters determined by visual inspection. RESULTS Atorvastatin coadministration increased the cyclosporine AUC by 9% (range 0–20.6%; 3018 vs 3290 ng•h/mL; p = 0.04). No significant change was evident for other cyclosporine pharmacokinetic parameters. Total cholesterol and low-density lipoprotein cholesterol levels were significantly lower on day 14 than at baseline (p < 0.02). One patient developed a twofold increase in transaminases after 2 weeks of atorvastatin therapy, but no other clinical or biochemical adverse events were recorded. CONCLUSIONS Atorvastatin coadministration increases the cyclosporine AUC by approximately 10% in stable liver transplant recipients. This change in systemic exposure to cyclosporine is of questionable clinical significance. Atorvastatin is effective in reducing cholesterol levels in liver transplant recipients.
Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors
Authors: Kawaguchi Yasushi , Takagi Kae , Hara Masako , Fukasawa Chikako , Sugiura Tomoko , Nishimagi Emi , Harigai Masayoshi , Kamatani Naoyuki 
Published: January 2004

AbstractObjectiveTissue fibrosis in systemic sclerosis (SSc) is attributed to excessive deposition of extracellular matrix components produced by fibroblasts in skin lesions. Angiotensin II (Ang II), a vasoconstrictive peptide, is reported to have profibrotic activity as a result of induction of the extracellular matrix. The aim of the present study was to examine the expression of Ang II and its type 1 (AT1) and type 2 (AT2) receptors in affected skin and dermal fibroblasts from patients with SSc and to study the role of Ang II in collagen production by SSc dermal fibroblasts.MethodsLevels of Ang II in sera from SSc patients and normal subjects were measured by a solid‐phase immobilized‐epitope immunoassay. Expression of angiotensinogen (Angt) in the skin was evaluated by immunohistochemistry. Expression of Angt, AT1, and AT2 in cultured dermal fibroblasts was analyzed by reverse transcription–polymerase chain reaction and immunohistochemistry. Levels of type I procollagen produced by cultured dermal fibroblasts were measured by enzyme‐linked immunosorbent assay.ResultsSerum Ang II levels in patients with diffuse cutaneous SSc were significantly higher than those in patients with limited cutaneous SSc and in healthy donors. Immunohistochemical and immunoblotting analyses showed that Angt was present in skin from SSc patients, but not in normal skin. Angt messenger RNA (mRNA) was expressed in fibroblasts from patients with diffuse cutaneous SSc who had high levels of serum Ang II, but not in normal fibroblasts. AT1 mRNA expression was found in both SSc and normal fibroblasts, whereas AT2 mRNA was found only in SSc fibroblasts. Exogenous Ang II augmented the production of type I procollagen and transforming growth factor β1 by cultured fibroblasts via activation of AT1.ConclusionAberrant Ang II production may be involved in tissue fibrosis through excessive production of the extracellular matrix components in SSc dermal fibroblasts. This suggests that the use of AT1 receptor antagonists may be a novel strategy for the treatment of tissue fibrosis in SSc patients.
Analysis of single‐nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences
Authors: Kochi Yuta , Yamada Ryo , Kobayashi Kyoko , Takahashi Atsushi , Suzuki Akari , Sekine Akihiro , Mabuchi Akihiko , Akiyama Fumihiro , Tsunoda Tatsuhiko , Nakamura Yusuke , Yamamoto Kazuhiko 
Published: January 2004

AbstractObjectiveTo examine the entire HLA region for loci (other than the DRB1 locus) associated with rheumatoid arthritis (RA) susceptibility, by typing HLA–DRB1 alleles and multiple single‐nucleotide polymorphisms (SNPs) in the Japanese population.MethodsThe HLA–DRB1 alleles and 88 SNPs distributed over the HLA gene complex were genotyped, for 828 patients with RA and 1,032 control subjects. The data were evaluated for linkage disequilibrium, and case–control associations were analyzed in 2 ways, in the presence or absence of the disease‐susceptibility DRB1 allele, to detect loci independent of the DRB1 allele.ResultsHLA–DRB1 alleles *0405, *0401, *0901, *0101, *1401, *1602, *0403, and *1405 were significantly associated with RA in the Japanese population. The smallest P value (P = 1.4 × 10−27) was observed in association with an intronic SNP of the NOTCH4 gene, which was due to strong linkage disequilibrium with the HLA–DRB1 allele. A strong association that was independent of HLA–DRB1 shared epitope alleles was observed in 2 SNPs: one in the intron of the MICA gene, the other in the intron of the HLA–DQB2 gene. Their association with RA, independent of HLA–DRB1 shared epitope alleles, was suggestive (P = 0.0024 [corrected P (Pcorr) = 0.068, and P = 0.00037 [Pcorr = 0.012], respectively).ConclusionThese findings suggest that 1 or more other loci besides the HLA–DRB1 or other DRB1 (non–shared epitope, non‐*0901) alleles are involved in RA susceptibility/protection.
Systemic tumor necrosis factor α mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor α–transgenic mice
Authors: Li Ping , Schwarz Edward M. , O'Keefe Regis J. , Ma Lin , Looney R. John , Ritchlin Christopher T. , Boyce Brendan F. , Xing Lianping 
Published: January 2004

AbstractObjectiveTo investigate the mechanisms whereby tumor necrosis factor α (TNFα) increases osteoclastogenesis in vivo.MethodsTNFα‐transgenic (TNF‐Tg) and wild‐type mice injected with TNFα were studied. In vitro osteoclastogenesis assays, monocyte colony‐forming assays, and fluorescence‐activated cell sorting were performed using splenocytes, peripheral blood mononuclear cells (PBMCs), and bone marrow cells to quantify and characterize osteoclast precursors (OCPs). Etanercept, a TNFα antagonist, was used to block TNFα activity in vivo. The effects of TNFα on proliferation, apoptosis, and differentiation of OCPs were assessed using 5‐bromo‐2′‐deoxyuridine labeling, annexin V staining, and reverse transcriptase–polymerase chain reaction.ResultsOCP numbers were increased 4–7‐fold in PBMCs and spleen, but not in bone marrow of TNF‐Tg mice. The OCPs in spleen were in the CD11bhigh population and contained both c‐Fms− and c‐Fms+ cells. The increased number of OCPs correlated with the initiation of detectable TNFα in serum and the onset of inflammatory arthritis in TNF‐Tg mice. Etanercept eliminated the increase in peripheral OCPs. TNFα did not affect proliferation, survival, or differentiation of CD11bhigh splenocytes in vivo or in vitro, but caused a rapid increase in CD11b+ cells in blood within 4 hours of a single injection and an accumulation of CD11bhigh OCPs in spleen after 3 days of multiple injections.ConclusionSystemic TNFα induces a marked increase in circulating OCPs that is reversible by anti‐TNF therapy and may result from their mobilization from bone marrow. Our findings provide a new mechanism whereby TNFα stimulates osteoclastogenesis in patients with inflammatory arthritis, suggesting that CD11b+ PBMCs could be used to evaluate a patient's potential for erosive disease and the efficacy of anti‐TNF therapy.
Effects of different molecular weight elastoviscous hyaluronan solutions on articular nociceptive afferents
Authors: Gomis Ana , Pawlak Matthias , Balazs Endre A. , Schmidt Robert F. , Belmonte Carlos 
Published: January 2004

AbstractObjectiveTo compare 3 different hyaluronan (HA) preparations used as therapeutic agents for osteoarthritis pain in humans in order to establish the degree to which a single application affects the sensitivity of nociceptors in both the normal and the acutely inflamed rat joint.MethodsIn anesthetized rats, single‐unit recordings were performed from the medial articular nerve of the right knee joint under normal conditions and during an acute experimental arthritis. Fifty fine afferent units (conduction velocities 0.8–15.3 meters/second) responded to passive movements of the knee joint. They were exposed to a torque meter–controlled, standardized stimulus protocol consisting of innocuous and noxious inward and outward rotations of the joint. This stimulus protocol of 50 seconds' duration was repeated every 5 minutes for 2–3 hours. Three commercially available HA preparations and a buffer solution, the solvent of these preparations, were injected intraarticularly after discharges resulting from 6 stimulus protocols were averaged and used as controls.ResultsBoth in normal and in inflamed joints, the injection of Hyalgan did not reduce nerve impulse frequency of the evoked discharges. The injections of Orthovisc had no effect in normal joints, but produced a transient frequency reduction of the evoked discharge in inflamed joints. Synvisc significantly reduced (by an average of 50%) the impulse discharge in both normal and inflamed joints 50 minutes after injection, and this level of impulse discharge continued until the end of the recording period (120–130 minutes after injection). The buffer, which had elastoviscous properties substantially different from those of Hyalgan, Orthovisc, and Synvisc, had no such effect.ConclusionWe conclude that the elastoviscous properties of HA solutions are determining factors in reducing pain‐eliciting nerve activity both in normal and in inflamed rat joints.
Crucial role of synovial lining macrophages in the promotion of transforming growth factor β–mediated osteophyte formation
Authors: Van Lent P. L. E. M. , Blom A. B. , Van Der Kraan P. , Holthuysen A. E. M. , Vitters E. , Van Rooijen N. , Smeets R. L. , Nabbe K. C. A. M. , Van Den Berg W. B. 
Published: January 2004

AbstractObjectiveTo investigate in vivo and in vitro whether macrophages have an intermediate role in transforming growth factor β (TGFβ)–induced osteophyte formation.MethodsIn vivo, synovial lining macrophages were selectively depleted by injection of clodronate‐laden liposomes 7 days prior to injection of 20 ng or 200 ng of TGFβ into murine knee joints 3 times, on alternate days. Total knee joint sections were obtained on day 7 after the last injection and stained with Safranin O. Production of bone morphogenetic protein 2 (BMP‐2) and BMP‐4 was determined by immunolocalization. The interaction between murine macrophages and mesenchymal cells (precursors with chondrogenic potential) was studied in vitro using a Transwell system in which RAW macrophages were cocultured with C3H10T1/2 mesenchymal cells. Spheroid neocartilage formation was quantified microscopically after staining with May‐Grünwald–Giemsa.ResultsTriple injections of 20 ng or 200 ng of TGFβ into normal murine knee joints induced significant osteophyte formation at the lateral and medial sites of the patella and femur on day 7 after the last injection. Strikingly, removal of synovial lining macrophages prior to TGFβ injection resulted in a drastic reduction of osteophyte formation (by 70% and 64% after injection of 20 ng and 200 ng of TGFβ, respectively). Synovial lining cells produced BMP‐2 and BMP‐4 after TGFβ stimulation, whereas BMP‐2 and BMP‐4 were absent in the synovial tissue after macrophage depletion. In vitro, clustering and spheroid formation of C3H10T1/2 was induced by TGFβ concentrations of >1 ng/ml. However, in the Transwell system, in the presence of murine macrophages, 0.5 ng/ml of TGFβ was very effective in generating large spheroids, suggestive of macrophage‐derived (co)factors. In coculture supernatants, TGFβ concentrations were not elevated in the presence of macrophages, indicating generation of other growth factors involved in spheroid formation.ConclusionThese findings indicate that macrophages are crucial intermediate factors in osteophyte formation induced by TGFβ, probably by inducing other chondrogenic signals.
Continuous enhanced expression of Hsc70 but not Hsp70 in rheumatoid arthritis synovial tissue
Authors: Schick Christoph , Arbogast Martin , Lowka Klaus , Rzepka Rita , Melchers Inga 
Published: January 2004

AbstractObjectiveTo investigate the expression of constitutive and inducible members of the Hsp70 protein family in synovial tissue of patients with rheumatoid arthritis (RA) or osteoarthritis (OA).MethodsFrozen sections of synovial tissue and isolated synovial adherent cells obtained from 17 RA patients, 5 OA patients, and 1 patient with carpal tunnel syndrome (CTS) were analyzed with specific monoclonal antibodies, by immunohistochemistry, immunocytochemistry, and immunoblotting.ResultsExpression of the constitutive chaperone Hsc70 was increased in synovial tissue from 9 of 9 patients with RA, but was faint or undetectable in 3 of 3 samples from patients with OA. In RA samples, cells mainly of the synovial lining stained intensely for Hsc70 as well as for HLA–DR, CD14, and CD68. Also, in vitro–cultured synovial adherent cells from 8 of 9 RA patients overexpressed Hsc70 (specimens from 1 RA patient were used in both the immunochemistry and the in vitro culture studies). On immunoblots of protein extracts, the synovial and HeLa cell molecules appeared identical in size. The inducible chaperone Hsp70 was not detected in samples from any of the same 17 RA patients, except for rare, isolated cells in 3. Samples from 4 of 5 OA patients also were negative for the inducible chaperone Hsp70, and the fifth was very weakly positive. In addition, tissue from 1 patient with CTS was analyzed 10 months before diagnosis of RA. Synovial tissue from this patient showed extreme overexpression of both Hsc70 and Hsp70.ConclusionIn RA, synovial lining cells continuously overexpress Hsc70 but not Hsp70. Hsc70 may be up‐regulated due to the high activity of these cells in several respects, including antigen processing and presentation.
Anatomic localization of immature and mature dendritic cell subsets in dermatomyositis and polymyositis: Interaction with chemokines and Th1 cytokine–producing cells
Authors: Page Guillaume , Chevrel Guillaume , Miossec Pierre 
Published: January 2004

AbstractObjectiveTo clarify the involvement of dendritic cells (DCs), chemokines, and proinflammatory Th1 cytokines in the pathogenesis of the chronic muscle diseases dermatomyositis (DM) and polymyositis (PM).MethodsWe characterized by immunohistochemistry the DC subsets and their interaction with cells producing chemokines and the Th1 cytokines interleukin‐17 (IL‐17) and interferon‐γ (IFNγ). Immature and mature DCs were defined by the expression of CD1a and DC‐LAMP/CD83, respectively.ResultsImmature DCs were mainly detected in lymphocytic infiltrates in DM and PM muscle tissue samples. Mature DCs were detected in perivascular infiltrates and surrounded muscle fibers. IL‐17–positive and IFNγ‐positive cells were also observed in perivascular infiltrates in both cases. We then focused on the expression of the CCL20/CCR6 chemokine/receptor complex, which controls immature DC migration, and on the expression of the CCL19/CCR7 and CCL21/CCR7 chemokine/receptor complexes, which control mature DC migration. CCL20 and CCR6 colocalized in lymphocytic infiltrates in DM and PM samples. CCL21 was rarely observed in DM samples and never observed in PM samples. CCL19‐ and CCR7‐expressing cells were absent in both tissues.ConclusionThe close association between CCL20/CCR6 and immature DCs suggests the contribution of CCL20 to CCR6+ immature DC homing. Detection of mature DCs in DM and PM muscle tissue samples despite the lack of CCL19 and CCR7 is evidence for a local maturation of DCs in inflammatory muscle tissue without lymphoid organ organization.
Immunohistologic evidence supports apoptosis, IgG deposition, and novel macrophage/fibroblast crosstalk in the pathologic cascade leading to congenital heart block
Authors: Clancy Robert M. , Kapur Raj P. , Molad Yair , Askanase Anca Dinu , Buyon Jill P. 
Published: January 2004

AbstractObjectiveTo assess in vivo the pathologic cascade leading to fibrosis in congenital heart block (CHB). In vitro studies suggest that CHB is initiated via apoptosis, resulting in translocation of SSA/Ro and SSB/La antigens and surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors inducing fibrosis.MethodsImmunohistochemistry analysis was performed on formalin‐fixed sections of 4 fetal hearts identified in utero as having CHB or isolated myocarditis; mothers had anti‐SSA/Ro and anti‐SSB/La antibodies.ResultsApoptosis was most extensive in fetuses dying early and most pronounced in regions containing conduction tissue. Deposition of IgG was observed in hearts from fetuses with CHB/myocarditis, but not in 3 control hearts, and was colocalized with apoptotic cells. Giant cells and macrophages (frequently seen proximal to IgG and apoptotic cells) were present in septal and thickened fibrous subendocardial regions, most apparent in the youngest fetuses. Septal tissue also revealed extensive areas of fibrosis and microcalcification in which a predominant smooth muscle actin (SMA)–positive infiltrate (myofibroblast scarring phenotype) was observed. In contrast, there were no macrophages or SMA‐positive cells (other than those lining blood vessels) in septal tissue from control hearts, although rare macrophages were seen in the working myocardium.ConclusionIn summary, findings in this unique autopsy material paralleled those in in vitro studies. These data support the notion of exaggerated apoptosis, probably due to ongoing inflammation caused by IgG binding and ingestion by macrophages. Transdifferentiation of cardiac fibroblasts to a scarring phenotype may be a pathologic process initiated by maternal antibodies, and persistence of this phenotype even after birth may relate to the progression of block seen in some infants postpartum.