Methotrexate specifically modulates cytokine production by T cells and macrophages in murine collagen-induced arthritis (CIA): a mechanism for methotrexate-mediated immunosuppression

Immunosuppressive therapy with methotrexate (MTX) has been established as effective treatment for patients with rheumatoid arthritis. To analyse the therapeutic potential and mechanisms of action of MTX, we determined serum cytokine levels and cytokine production by splenic T cells and macrophages in untreated and MTX-treated mice. Furthermore, we assessed the role of MTX in a murine model of experimental arthritis induced by collagen type II (CIA). MTX reduced spontaneous and IL-15-induced tumour necrosis factor (TNF) production by splenic T cells but not by macrophages from healthy mice in vitro in a dose-dependent manner. In contrast, interferon-gamma (IFN-γ) production was less strikingly reduced and IL-4 production was virtually unaffected. In addition, treatment of healthy mice with MTX in vivo led to reduced TNF serum levels and diminished TNF production by splenic T cells and macrophages. Intraperitoneal administration of MTX prior to the onset of arthritis completely prevented clinical and pathological signs of CIA. This was associated with a striking reduction of TNF production by spleen cells from MTX-treated mice. The role of TNF in MTX-mediated effects on cytokine production was further underlined by the finding that MTX effects on IFN-γ production were augmented in TNF-transgenic mice but abrogated in mice in which the TNF-α gene had been inactivated by homologous recombination. Thus, MTX specifically modulates spontaneous and IL-15-induced TNF-α production in mice and prevents experimental murine CIA. These data suggest that TNF production by T cells is an important target of MTX and may serve as a basis to understand and further analyse MTX-mediated mechanisms of immunosuppression in patients with RA.     

Endometriosis of the urinary tract in women of reproductive age

AIM: We present our experience with diagnosing and treating 22 cases of urinary tract endometriosis in women of reproductive age. PATIENTS AND METHODS: From January 2001 to January 2003, 22 women of reproductive age (mean age 34.8 years) were diagnosed suffering from endometriosis of the urinary tract. We used the Endoscopic Endometriosis Classification (EEC) for assessing the stage of endometriosis. RESULTS: Endometriosis was present in the bladder, the lower third of the ureter, and in a postnephrectomy ureteral stump in 15 (68.1%), six (27.2%) and one (4.5%) cases, respectively. The EEC classification revealed stages I, II, III and IV in four (18.1%), one (4.5%), one (4.5%), and 16 (72.7%) patients, respectively. Urinary symptoms were present in 14 (63.6%) patients. For the treatment of bladder endometriosis, 10 patients underwent partial cystectomy, while the remaining five patients were treated with transurethral resection. In four patients ureterolysis was performed, by laparoscopy in two cases and by open surgery in the other two cases. Ureterectomy and re-implantation with bladder psoas hitching took place in six patients. In the case of endometriosis of the ureteral stump, open surgical excision took place. During the mean follow-up period of 20 months (range 16-40) no long-term complication or relapse was diagnosed. CONCLUSIONS: Bladder and ureteral endometriosis should be considered in women of reproductive age with non-specific urinary tract or abdominal symptoms, and surgical treatment is recommended.     

Selectivity of protoporphyrin IX fluorescence for condylomata after topical application of 5-aminolaevulinic acid: implications for photodynamic treatment

Summary To examine the potential of using photodynamic therapy (PDT) in condylomata , we studied the distribution and kinetics of protoporphyrin IX (PpIX) formation in condylomata acuminata and adjacent normal skin after topical application of 5-aminolaevulinic acid (ALA). PpIX fluorescence spectra were measured hourly in vivo after ALA application. After gross fluorescence imaging, the lesions were biopsied, and fluorescence microscopy was performed. All three PpIX fluorescence detection modalities suggested selectivity of PpIX formation in condylomata after topical ALA application. In 17 of 25 condylomata. there was significantly greater fluorescence compared with adjacent normal skin. The greatest lesiomal to normal skin fluorescence ratios occurred after 2 h. The most likely mechanism for increased lesicmal PpIX formation in condylomata is enhanced stratum corneum permeability. Based on our results , ALA/PDT is a potential field therapy for condylomata. PpfX fluorescence imaging after ALA application may also be useful for localizing condylomata prior to treatment.     

Drug‐Induced Brugada Syndrome by Noncardiac Agents

Drug‐induced Brugada syndrome (BrS) represents a great challenge for the prescribing clinicians as well as for those involved in the development of novel pharmaceuticals and in the regulatory bodies responsible with monitoring drug safety. Apart from well‐known cardiac agents (mainly Class I antiarrhythmics), an increasing number of noncardiac agents, including psychotropic and anesthetic drugs, have been shown to induce the characteristic Brugada electrocardiogram pattern predisposing to fatal ventricular arrhythmias. Up to now, both repolarization and depolarization abnormalities are thought to be related to the development of ventricular fibrillation in BrS patients. This review highlights the mechanisms and the noncardiac medical agents that unmask a genetic predisposition to BrS.