bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-Molecular-Weight Heparin–Induced Thrombocytopenia in a Child
Authors: Dager William E , White Richard H
Published: January 2004

OBJECTIVE

To report a case of probable acute venous thrombosis caused by heparin-induced thrombocytopenia (HIT) in a pediatric patient with a normal platelet count after prolonged enoxaparin therapy.

CASE SUMMARY

An 11-year-old African American female with Crohn's disease developed extensive vena cava thrombosis. Her deep vein thrombosis (DVT) was treated with intravenous unfractionated heparin followed by extended outpatient warfarin therapy. Four months later, the warfarin was stopped and subcutaneous enoxaparin 1.5 mg/kg once daily was substituted prior to an elective colonoscopy. She was readmitted 6 weeks later with acute DVT with a platelet count of 233 × 10 3 /mm 3 , significantly lower than the count of 550–700 × 10 3 /mm 3 5 months previously and the count of 433 × 10 3 /mm 3 3 months earlier. An enzyme-linked immunosorbent assay for heparin-platelet factor 4 antibodies was strongly positive and a d-dimer was elevated at 2.9 mg/L (normal <1.5). She was treated with lepirudin followed by warfarin when repeat d-dimer on day 3 was normal. An ultrasound at that time showed no clot extension, and the platelet count had risen to >300 × 10 3 /mm 3 . Over the next 4 months, there was no further thrombosis.

DISCUSSION

HIT appears to be rare in the pediatric population, and only a few cases treated with a direct thrombin inhibitor have been reported. This is the first case report to our knowledge of a pediatric patient developing HIT secondary to enoxaparin. An interesting feature of this case is the development of HIT in the face of a normal platelet count, which is rare but has been reported in adults.

CONCLUSIONS

Pediatric patients receiving low-molecular-weight heparin are still at risk for developing HIT. Treatment of HIT should involve the initial use of a direct thrombin inhibitor to manage thrombosis until the platelet count returns to higher values. Once the platelet count returns, warfarin can be used for long-term thrombosis management.
Herbals and Asthma: Usage Patterns Among a Border Population
Authors: Rivera José O , Hughes Harold W , Stuart Armando González
Published: January 2004

BACKGROUND

The use of herbal products (HP) is rising in the US. Higher rates of HP use have been documented in the US/Mexico border population, as well as increasing concerns about herbal-related adverse events.

OBJECTIVE

To evaluate the prevalence of HP use in adult asthmatic patients requiring hospitalization and the frequency of HP documentation in medical records.

METHODS

We conducted a retrospective chart review of admissions for asthma to determine the frequency of HP documentation. Additionally, during a 12-month period, a bilingual interviewer conducted prospective, semistructured interviews with patients with asthma exacerbations to record data on HPs used specifically for the treatment of asthma.

RESULTS

A total of 67 cases were chart-reviewed retrospectively; 60 patients were interviewed prospectively. We found no documentation of HP use by chart review, while prospective interviews showed that 42% of patients reported using HPs for the treatment of asthma. The most common HPs used were oregano 28%, chamomile 20%, garlic 16%, eucalyptus 12%, and lime 12%. Ten patients reported taking an HP that could potentially exacerbate their asthma and 18 patients reported using an HP that could interact with other medications or cause other types of adverse events.

CONCLUSIONS

An obvious lack of documentation for HP use was observed in the medical records reviewed. Because a number of HPs that are commonly used by residents along the border can interact with antiasthmatic agents and/or result in compromised asthma control, questions about HP use should be included in routine history taking.
Transfer of Risperidone and 9-Hydroxyrisperidone into Human Milk
Authors: Ilett Kenneth F , Hackett L Peter , Kristensen Judith H , Vaddadi Krishna S , Gardiner Sharon J , Begg Evan J
Published: January 2004

OBJECTIVE

To quantify the transfer of risperidone and its active metabolite 9-hydroxyrisperidone into breast milk, estimate the amount the infant receives, measure infant plasma concentrations, and clinically assess the safety of breast feeding during maternal risperidone administration.

CASE SUMMARIES

The transfer of risperidone and 9-hydroxyrisperidone into milk was studied in 2 breast-feeding women and one woman with risperidone-induced galactorrhea. Plasma samples were available from 2 of the women and from both breast-fed infants. The milk/plasma concentration ratio determined in 2 women was <0.5 for both compounds. The calculated relative infant “doses” were 2.3%, 2.8%, and 4.7% (as risperidone equivalents) of the maternal weight-adjusted doses. Risperidone and 9-hydroxyrisperidone were not detected in the plasma of the 2 breast-fed infants studied, and no adverse effects were noted.

DISCUSSION

Risperidone therapy is sometimes necessary in breast-feeding women, raising the issue of safety in the exposed infants. Our study shows that the relative infant dose is lower than the arbitrary 10% level of concern. The data provide clear guidance on infant exposure for the cases presented.

CONCLUSIONS

Maternal risperidone therapy is unlikely to be a significant hazard for the breast-fed infant in the short term. Nevertheless, decisions on whether a woman may breast-feed should be made as an individual risk-benefit analysis.
Recurrent Ibuprofen-Induced Aseptic Meningitis
Authors: Nguyen Huy TV , Juurlink David N
Published: January 2004

OBJECTIVE

To report a case of recurrent aseptic meningitis temporally associated with the use of ibuprofen.

CASE SUMMARY

A previously well 51-year-old white man presented with acute confusion and aphasia 7 days after taking a variety of nonprescription medications, including ibuprofen. Imaging of the brain was unremarkable, and lumbar puncture revealed lymphocytic pleocytosis with an elevated protein level. The symptoms improved shortly after admission, and no infectious cause was identified. Two weeks later, the patient was readmitted with similar symptoms beginning immediately after resumption of ibuprofen. His symptoms resolved promptly after ibuprofen was discontinued.

DISCUSSION

Drug-induced aseptic meningitis is an unusual complication of drug therapy. Nonsteroidal antiinflammatory drugs (NSAIDs), particularly ibuprofen, are among the most commonly implicated agents, but rechallenge with the suspected agent is uncommon. Use of an objective causality tool indicated a probable relationship between ibuprofen and development of aseptic meningitis in our patient.

CONCLUSION

Clinicians should consider NSAIDs as potential causes of aseptic meningitis, especially in patients with recurrent illness and no obvious infectious cause. A detailed drug history is invaluable in the assessment of such patients, with particular attention to nonprescription medications such as ibuprofen.
Possible Gatifloxacin-Induced Seizure
Authors: Quigley Carrie A , Lederman Janet R
Published: January 2004

OBJECTIVE

To report a case of seizure activity following gatifloxacin administration during treatment of urosepsis in an intensive care unit.

CASE SUMMARY

An 86-year-old African American male nursing home resident with a history of hypertension and cerebrovascular accident with aphasia was initiated on gatifloxacin therapy for treatment of urosepsis. After 2 intravenous doses (400 mg followed 24 h later with 200 mg), he developed 2 generalized seizures lasting <2 minutes each. Gatifloxacin was discontinued, and the patient was switched to ceftazidime. Phenytoin was initiated, and no recurrent seizures were witnessed.

DISCUSSION

Fluoroquinolones have been shown to induce seizures or decrease seizure threshold. The majority of reports include older-generation fluoroquinolones such as ofloxacin. The incidence of seizures associated with fluoroquinolones varies among the individual agents and is relatively rare. Risk factors include increased age, compromised renal function, history of seizures, and coadministration with theophylline or nonsteroidal antiinflammatory drugs. Application of an objective causality scale indicates the seizures in our patient were possibly associated with gatifloxacin.

CONCLUSIONS

This case of gatifloxacin-induced seizures may reflect a class-effect phenomenon versus an effect caused by an individual fluoroquinolone. Caution is warranted when using these agents in patients at risk for drug-induced seizures.
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

Objective

Tissue 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.

Methods

Levels 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.

Results

Serum 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.

Conclusion

Aberrant 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

Objective

To 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.

Methods

The 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.

Results

HLA–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).

Conclusion

These 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

Objective

To investigate the mechanisms whereby tumor necrosis factor α (TNFα) increases osteoclastogenesis in vivo.

Methods

TNFα‐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.

Results

OCP 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.

Conclusion

Systemic 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

Objective

To 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.

Methods

In 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.

Results

Both 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.

Conclusion

We 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

Objective

To investigate in vivo and in vitro whether macrophages have an intermediate role in transforming growth factor β (TGFβ)–induced osteophyte formation.

Methods

In 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.

Results

Triple 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.

Conclusion

These 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

Objective

To 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).

Methods

Frozen 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.

Results

Expression 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.

Conclusion

In 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

Objective

To 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).

Methods

We 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.

Results

Immature 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.

Conclusion

The 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

Objective

To 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.

Methods

Immunohistochemistry 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.

Results

Apoptosis 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.

Conclusion

In 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.
Voiding dysfunction in women with systemic lupus erythematosus
Authors: Yu Hong‐Jeng , Lee Wei‐Chia , Lee Kuang‐Lun , Chen Mao‐Yuan , Chen Cheng‐Yuan , Chen Jun
Published: January 2004

Objective

We sought to explore bladder dysfunction in a cohort of women with systemic lupus erythematosus (SLE).

Methods

We conducted a prospective study of 152 female patients with SLE during a 15‐month period. The clinical status of SLE was determined according to the SLE Disease Activity Index (SLEDAI), and bladder function was evaluated by lower urinary tract symptoms and urodynamic studies. We adapted the American Urological Association (AUA) index questionnaire to assess lower urinary tract symptoms in patients, which were compared with those in 227 age‐matched healthy women.

Results

The proportion of individuals reporting urinary frequency, urgency, weak urinary stream, and incomplete emptying, as well as severe lower urinary tract symptoms (AUA index score ≥20), was significantly higher in the SLE group when compared with the control group. The AUA index score showed a modest correlation with the SLEDAI score (r = 0.35, P < 0.001) but not with patient age or disease duration. There was a significant relationship between central nervous system involvement and the AUA index score. The most common urodynamic finding was a small cystometric bladder capacity (<150 ml; n = 7 patients), followed by a subnormal urinary flow rate (<12 ml/second; n = 6 patients). In 3 of 7 patients with small cystometric bladder capacities, imaging studies documented a contracted bladder with marked hydroureteronephrosis.

Conclusion

Patients with SLE experience an increased prevalence of voiding dysfunction compared with healthy individuals. Voiding dysfunction can be attributable to either direct bladder involvement or other disease‐related factors.
Expression profiling of metalloproteinases and their inhibitors in cartilage
Authors: Kevorkian Lara , Young David A. , Darrah Clare , Donell Simon T. , Shepstone Lee , Porter Sarah , Brockbank Sarah M. V. , Edwards Dylan R. , Parker Andrew E. , Clark Ian M.
Published: January 2004

Objective

To profile the expression of all known members of the matrix metalloproteinase (MMP), ADAMTS, and tissue inhibitor of metalloproteinases (TIMP) gene families in normal cartilage and cartilage from patients with osteoarthritis (OA).

Methods

Human cartilage was obtained from femoral heads at joint replacement for OA or following fracture to the femoral neck. Total RNA was purified, and gene expression was assayed using quantitative real‐time polymerase chain reaction.

Results

Several members of the above gene families were regulated in OA. Genes that showed increased expression in OA were MMP13, MMP28, and ADAMTS16 (all at P < 0.001), MMP9, MMP16, ADAMTS2, and ADAMTS14 (all at P < 0.01), and MMP2, TIMP3, and ADAMTS12 (all at P < 0.05). Genes with decreased expression in OA were MMP1, MMP3, and ADAMTS1 (all at P < 0.001), MMP10, TIMP1, and ADAMTS9 (all at P < 0.01), and TIMP4, ADAMTS5, and ADAMTS15 (all at P < 0.05). Correlation analysis revealed that groups of genes across the gene families were coexpressed in cartilage.

Conclusion

This is the first comprehensive expression profile of all known MMP, ADAMTS, and TIMP genes in cartilage. Elucidation of patterns of expression provides a foundation with which to understand mechanisms of gene regulation in OA and potentially to refine the specificity of antiproteolytic therapies.
Ovarian vein thrombosis in the antiphospholipid syndrome
Authors: André Marc , Delèvaux Isabelle , Amoura Zahir , Corbi Pierre , Courthaliac Christophe , Aumaître Olivier , Piette Jean‐Charles
Published: January 2004

Ovarian vein thrombosis (OVT) is an unusual condition mainly observed during the postpartum period. It has not been reported to date in the antiphospholipid syndrome. Two female patients with definite antiphospholipid syndrome, ages 33 years and 73 years, were diagnosed as having OVT by computed tomography (CT) scan, according to the radiologic criteria described by Zerhouni et al. In 1 of the women, the left vein was affected by OVT, while in the other woman, the right vein was affected. One of the patients had a pulmonary embolism; the diagnosis of OVT was established after she underwent a cesarean section and a right atrium thrombectomy. The other patient had no vascular manifestations. OVT was asymptomatic in both patients. Searches for associated thrombophilic states yielded negative results. With the continuation of anticoagulation therapy, the 2 patients have remained in good condition. Resolution of the OVT was observed in the patient who underwent a CT scan during followup. To our knowledge, this is the first report of OVT occurring in the antiphospholipid syndrome. Given that it may develop in the absence of pelvic clinical manifestations, this complication may be underdiagnosed.
Complex segregation and linkage analysis of familial gout in Taiwanese aborigines
Authors: Wang Wen Hsin , Chang Shun Jen , Wang Tsu Nai , Cheng Li Shu‐Chuan , Feng Yu Ping , Chen Chung Jen , Huang Chun Hsiung , Ko Ying Chin
Published: January 2004

Objective

The prevalence of gout and hyperuricemia in Taiwanese aborigines is remarkably high. Although previous studies have failed to find evidence of a major gene responsible for gout, the disease is thought to involve genetic predisposition. We sought to determine whether genetic factors for familial gout exist among Taiwanese aborigines, and, if so, their chromosomal location.

Methods

We first performed complex segregation analysis. The study sample comprised 945 relatives distributed in 64 pedigrees; among them, 261 affected members (including probands) were found. In all of the aboriginal probands with gout, the disease was diagnosed and confirmed by rheumatologists. Blood specimens were then collected from 127 individuals living in one community that was used in the segregation analysis (from 25 pedigrees, 36 nuclear families, and 112 full sibpairs), and sibpair linkage analysis and a combined transmission disequilibrium test (TDT) method were used to test the genetic components.

Results

In segregation analysis, after adjusting for sex and age, an autosomal‐arbitrary major gene model was found to fit the data best, with disease allelic frequency of 0.31 and susceptibility of 0.92. In sibpair analysis, there was a clustering of many flanking markers showing significant linkage, including D1S498 (regression coefficient −0.52), D1S2635 (regression coefficient −0.47), and D1S196 (regression coefficient −0.51), in the 1q21 region of chromosome 1 (all P < 0.005). Results of the combined TDT showed that the marker D1S484 was significantly associated (had linkage) with allele 1 and was transmitted more frequently than other markers to the affected offspring (P < 0.005).

Conclusion

Results of this study provide evidence of a genetic basis for familial gout in the aboriginal Taiwanese population and suggest that a susceptibility locus may be located in the 1q21 region of chromosome 1.
Prognostic markers of radiographic progression in early rheumatoid arthritis
Authors: Goronzy Jörg J. , Matteson Eric L. , Fulbright James W. , Warrington Kenneth J. , Chang‐Miller April , Hunder Gene G. , Mason Thomas G. , Nelson Audrey M. , Valente Robert M. , Crowson Cynthia S. , Erlich Henry A. , Reynolds Rebecca L. , Swee Ronald G. , O'Fallon W. Michael , Weyand Cornelia M.
Published: January 2004

Objective

To identify prognostic markers that are predictive of progressive erosive disease in patients with early rheumatoid arthritis (RA).

Methods

The study involved an inception cohort of 111 consecutive patients with RA and a disease duration of <1 year. Patients were treated according to an algorithm designed to avoid overtreatment of mild disease and to accelerate treatment in patients who had continuous disease activity. Patients were evaluated for the presence of clinical and laboratory disease activity markers. We determined the frequency of CD4+,CD28null T cells by flow cytometry, HLA–DRB1 gene polymorphisms by polymerase chain reaction (PCR)/sequencing, and 26 single‐nucleotide polymorphisms in 19 candidate genes by multiplex PCR and hybridization to an immobilized probe array. Data were analyzed using proportional odds models to identify prognostic markers predictive of erosive progression over 2 years on serial hand/wrist radiographs.

Results

After 2 years, disease activity in 52% of the cohort was controlled by treatment with hydroxychloroquine and nonsteroidal agents. Forty‐eight percent of the patients did not develop erosions. Older age, presence of erosions at baseline, presence of rheumatoid factor, rheumatoid factor titer, and HLA–DRB1*04 alleles, particularly homozygosity for HLA–DRB1*04, were univariate predictors of radiographic progression. Promising novel markers were the frequency of CD4+,CD28null T cells as an immunosenescence indicator, and a polymorphism in the uteroglobin gene.

Conclusion

Clinical disease activity in patients with early RA can frequently be controlled with nonaggressive treatment, but this is not always sufficient to prevent new erosions. Rheumatoid factor titer, HLA–DRB1 polymorphisms, age, and immunosenescence markers are predictors of poor radiographic outcome. A polymorphism in the uteroglobin gene may identify patients who have a low risk of erosive disease.
Emergence of lyme arthritis after autologous chondrocyte transplantation
Authors: Marlovits Stefan , Khanakah Gelas , Striessnig Gabriele , Vécsei Vilmos , Stanek Gerold
Published: January 2004

We report herein the first known incidence of the emergence of borrelial arthritis following autologous chondrocyte transplantation for repair of a cartilage defect. The patient had no recent manifestation of Lyme borreliosis, but 15 years earlier had had an expanding erythematous lesion after a tick bite. The current infection resulted in massive joint swelling, elevated body temperature, dissemination of the graft, and transplant failure. Results of routine bacteriologic studies were negative. A diagnosis of Lyme arthritis was first considered following the detection of Borrelia‐specific serum antibodies. Additional evidence was provided when borrelial DNA sequences were detected in the synovial fluid through polymerase chain reaction. The diagnosis was confirmed by culture of Borrelia burgdorferi from the synovial fluid. The possibility of a dormant borrelial infection should be considered in patients who undergo repair of cartilage defects with autologous chondrocyte transplantation. We recommend that synovial fluid and joint tissue be screened for the presence of viable Borrelia before transplantation of an autologous graft.
Failure of in vitro–differentiated mesenchymal stem cells from the synovial membrane to form ectopic stable cartilage in vivo
Authors: De Bari Cosimo , Dell'Accio Francesco , Luyten Frank P.
Published: January 2004

Objective

We previously reported the identification in a nude mouse assay of molecular markers predictive of the capacity of articular cartilage–derived cells (ACDCs) to form ectopic stable cartilage that is resistant to vascular invasion and endochondral ossification. In the present study, we investigated whether in vitro–differentiated mesenchymal stem cells (MSCs) from the synovial membrane (SM) express the stable‐chondrocyte markers and form ectopic stable cartilage in vivo.

Methods

Chondrogenesis was induced in micromass culture with the addition of transforming growth factor β1 (TGFβ1). After acquisition of the cartilage phenotype, micromasses were implanted subcutaneously into nude mice. Alternatively, cells were released enzymatically and either replated in monolayer or injected intramuscularly into nude mice. Marker analysis was performed by quantitative reverse transcription–polymerase chain reaction. Cell death was detected with TUNEL assay.

Results

Cartilage‐like micromasses and released cells expressed the stable‐chondrocyte markers at levels comparable with those expressed by stable ACDCs. The released cells lost chondrocyte marker expression by 24 hours in monolayer and failed to form cartilage when injected intramuscularly into nude mice. Instead, myogenic differentiation was detected. When intact TGFβ1‐treated micromasses were implanted subcutaneously, they partially lost their cartilage phenotype and underwent cell death and neoangiogenesis within 1 week. At later time points (15–40 days), we retrieved neither cartilage nor bone, and human cells were not detectable.

Conclusion

The chondrocyte‐like phenotype of human SM MSCs, induced in vitro under specific conditions, appears to be unstable and is not sufficient to obtain ectopic formation of stable cartilage in vivo. Studies in animal models of joint surface defect repair are necessary to evaluate the stability of the SM MSC chondrocyte‐like phenotype within the joint environment.
High insulin levels and increased low‐density lipoprotein oxidizability in pediatric patients with systemic lupus erythematosus
Authors: Posadas‐Romero Carlos , Torres‐Tamayo Margarita , Zamora‐González José , Aguilar‐Herrera Blanca Estela , Posadas‐Sánchez Rosalinda , Cardoso‐Saldaña Guillermo , de Guevara Guadalupe Ladrón , Solis‐Vallejo Eunice , Hafidi Mohammed El
Published: January 2004

Objective

To examine low‐density lipoprotein (LDL) size, LDL susceptibility to oxidation, and plasma insulin levels in children with systemic lupus erythematosus (SLE).

Methods

Fifty‐nine SLE patients and 59 healthy, age‐matched control subjects were studied. LDL size was determined by gradient gel electrophoresis. LDL oxidizability was assessed by lag time for conjugated diene formation during copper incubation. Plasma levels of fasting insulin, glucose, lipids, lipoproteins, apolipoproteins B and A‐I, and fatty acids were also measured.

Results

Compared with control subjects, SLE patients showed significantly higher plasma insulin levels and increased susceptibility of LDLs to oxidation. Patients with active disease were more likely than patients with inactive disease or control subjects to have the following lipid characteristics: small, dense LDL subclass, elevated total cholesterol levels, elevated LDL cholesterol levels, elevated triglyceride levels, and low levels of high‐density lipoprotein cholesterol (HDL‐C). Statistically significant direct correlations were observed between disease activity and triglyceride levels and between disease activity and lag time, whereas significant inverse correlations were found between disease activity and HDL‐C levels and between disease activity and LDL size. Prednisone dosage explained only 15.6% of the variance in insulin levels.

Conclusion

SLE patients have higher plasma insulin levels and increased LDL oxidizability compared with healthy control subjects. These abnormalities may contribute to the accelerated atherosclerosis observed in patients with SLE.
The transcription factors hypoxia‐inducible factor 1α and Ets‐1 colocalize in the hypoxic synovium of inflamed joints in adjuvant‐induced arthritis
Authors: Peters C. L. , Morris C. J. , Mapp P. I. , Blake D. R. , Lewis C. E. , Winrow V. R.
Published: January 2004

Objective

To determine the relationship between hypoxia and the expression of Ets‐1 and hypoxia‐inducible factor 1α (HIF‐1α) in both normal and inflamed joints. Adjuvant‐induced arthritis (AIA) was used as the model system, since it mirrors many aspects of the pathology of rheumatoid arthritis.

Methods

Adjuvant arthritis was induced in a group of 10 female Lewis rats. A second group of 10 uninjected female Lewis rats served as naive controls. When a maximum clinical joint score was achieved in the AIA group, all 20 rats were injected with the specific hypoxic cell marker Hypoxyprobe‐1 and subsequently killed. Hypoxyprobe‐1 adducts, Ets‐1, and HIF‐1α were localized in the joints of the hind feet from these groups using immunohistochemistry.

Results

Compared with the joints from control rats, inflamed joints contained markedly more cells with Hypoxyprobe‐1 adduct immunoreactivity, Ets‐1–immunoreactive nuclei, and nuclear immunoreactivity for both Ets‐1 and HIF‐1α.

Conclusion

Our results demonstrate the presence of hypoxia in inflamed joints in this experimental model of arthritis. The colocalization of Ets‐1 and HIF‐1α in these hypoxic areas suggests that hypoxia may induce Ets‐1 and HIF‐1α expression during joint inflammation.