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.     

Bare Stent Implantation Through a Side Slot of Another Stent in a Bifurcation Lesion

A case of a patient with significant (≈ 90%) stenosis of the circumflex at its origin from the left main artery and of the first marginal branch, 20 mm after its origin from the circumflex, is described. The case was treated with implantation of two stents, one at the marginal and another at the circumflex through a side slot of the first stent.     

Left‐Sided Atrial Flutter Originating in the Coronary Sinus after Radiofrequency Ablation of Atrial Fibrillation

We describe a case of atypical atrial flutter presenting 1 year after radiofrequency ablation for atrial fibrillation (AF). Electrophysiologic study showed a reentry circuit involving the inferolateral aspect of the mitral annulus and the coronary sinus (CS); however, a mitral isthmus line did not terminate the arrhythmia. Participation of the proximal CS musculature in the circuit suggested a possible target for ablation. Radiofrequency energy applications from within the CS terminated the tachycardia. Mapping and ablation within the CS should be considered in patients with post‐AF ablation arrhythmias, particularly when the mitral annulus appears to be involved in the tachycardia circuit. (PACE 2010; 33:e96–e99)     

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.     

SERUM CYFRA 21–1 IN PATIENTS WITH INVASIVE BLADDER CANCER AND ITS RELEVANCE AS A TUMOR MARKER DURING CHEMOTHERAPY

Purpose:

Previous studies have shown that serum levels of the degradation products of cytokeratins could be used as surrogate markers in the diagnosis and followup of patients with solid tumors, including tumors of the bladder.

Materials and Methods:

The soluble cytokeratin 19 fragment CYFRA 21-1 was measured by solid phase radioimmunoassay in the serum of 142 patients with invasive transitional cell cancer of the bladder. Of the patients 56 had clinical stage I to III locally confined disease (T1-4aN0M0) and 86 had stage IV metastatic disease with lymph node and/or distant metastases. A control group consisted of 33 healthy volunteers. In a subgroup of 49 patients with metastatic disease receiving combined platinum based chemotherapy serum CYFRA 21-1 was determined prior to the initiation of therapy and after the documentation of response.

Results:

Abnormal CYFRA 21-1 was observed in 7% of patients with locally invasive disease and in 66% of those with metastatic disease (p <0.0001). There was no correlation of CYFRA 21-1 with tumor differentiation. Patients with abnormal CYFRA 21-1 showed statistically significant worse median overall survival. Moreover, in the subgroup of patients with metastatic disease receiving chemotherapy CYFRA 21-1 levels correlated with the response to treatment.

Conclusions:

Patients with transitional cell cancer of the bladder with evidence of distant metastases showed a significant increase in serum CYFRA 21-1. During chemotherapy CYFRA 21-1 appears to be a potentially sensitive and useful indicator for monitoring treatment response.     

Retroperitoneal seminoma with ''burned out'' phenomenon in the testis

The rare 'burned out' phenomenon in germ cell tumors is known as the presence of an extragonadal germ cell tumor without traces of neoplasm in the testis. This condition is different and less common from the primary extragonadal germ cell malignancies. These malignancies are treated surgically with or without adjuvant chemotherapy or radiotherapy and their prognosis is better than that of other types of primary extragonadal tumors.     

Defibrillation Threshold Testing in Patients with Hypertrophic Cardiomyopathy

Introduction: Implantable cardioverter‐defibrillators (ICDs) decrease sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). One of the vital aspects of ICD implantation is the demonstration that the myocardium can be reliably defibrillated, which is defined by the defibrillation threshold (DFT). We hypothesized that patients with HCM have higher DFTs than patients implanted for other standard indications. Methods: We retrospectively reviewed the medical records of patients implanted with an ICD at the University of Maryland from 1996 to 2008. All patients with HCM who had DFTs determined were included. Data were compared to selected patients implanted for other standard indications over the same time period. All patients had a dual‐coil lead with an active pectoral can system and had full DFT testing using either a step‐down or binary search protocol. Results: The study group consisted of 23 HCM patients. The comparison group consisted of 294 patients. As expected, the HCM patients were younger (49 ± 18 years vs 63 ± 12 years; P < 0.00001) and had higher left ventricular ejection fractions (66% vs 32%; P < 0.000001). The average DFT in the HCM group was 13.9 ± 7.0 Joules (J) versus 9.8 ± 5.1 J in the comparison group (P = 0.0004). In the HCM group, five of the 23 patients (22%) had a DFT ≥ 20 J compared to 19 of 294 comparison patients (6%). There was a significant correlation between DFT and left ventricle wall thickness in the HCM group as measured by echocardiography (r = 0.44; P = 0.03); however, there was no correlation between DFT and QRS width in the HCM group (r = 0.1; P = NS). Conclusions: Our results suggest that patients with HCM have higher DFTs than patients implanted with ICDs for other indications. More importantly, a higher percentage of HCM patients have DFTs ≥ 20 J and the DFT increases with increasing left ventricle wall thickness. These data suggest that DFT testing should always be considered after implanting ICDs in HCM patients. (PACE 2010; 1342–1346)