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.     

A challenge to chronic kidney disease in Asia: The report of the second Asian Forum of Chronic Kidney Disease Initiative

Background: The Asian Forum of Chronic Kidney Disease Initiative started in 2007 in Hamamatsu, Japan when delegates from 16 countries joined together to facilitate collaboration in studying chronic kidney disease (CKD) in the Asia–Pacific region. Based on the outcome of the first meeting, the second meeting was organized as a consensus conference to frame the most relevant issues, and develop research recommendations and action plan. Proceedings: The meeting was held on 4 May 2008 as a pre‐conference meeting to the 11th Asian Pacific Congress of Nephrology in Kuala Lumpur. This meeting consisted of three sessions: Session I was dedicated to the estimation of glomerular filtration rate and the standardization of serum creatinine measurements. Session II discussed specific considerations in the aetiology of and risk factors for end‐stage renal disease in Asia. We concluded that there were regional specific problems that might lead to a very high prevalence of end‐stage renal disease. Session III discussed the issue of facilitation of coordination and integration of the CKD initiative between developed and developing countries in the Asia–Pacific region. Conclusion: The following action plans were formulated: (i) validating the existing global estimated glomerular filtration rate equation or creating a new one using serum creatinine standardized by a central laboratory; (ii) establishing a pan‐Asian CKD registry to facilitate risk analysis of CKD and its comorbidities; (iii) adapting existing clinical practice guidelines for CKD detection and management to address specific problems in this region; and (iv) working closely with other international professional organizations to promote manpower development and education in different aspects of CKD in developing countries.     

Reliability of an Automatic Sensing Algorithm

Automatic adaptation of the atrial sensitivity was evaluated in 18 patients with dual chamber pacemakers (Intermedics, Inc., Relay) in the unipolar mode. After atrial sensitivity was stabilized in the upright position, patients underwent a 1.0 W/kg body weight exercise for 5 minutes. A 24-hour Holter EGG was recorded, and the maximum and minimum atrial sensitivity values reached were stored in the memory of the pulse generator. In a second series of 12 patients, Holter ECGs were recorded twice, starting with the same sensitivity but with automatic adaptation alternately switched "on" or "off." Results of the exercise test: mean atrial sensitivity declined from 2.30 ± 0.77 mV to 2.03 ± 0.68 mV. There was no change in five patients, a slight increase in two patients, and lowering of the atrial sensitivity was observed in 11 patients, the difference ranging from 0.2 to 1.0 mV. A total of two P waves in two patients were missed by the atrial amplifier. The minimum and maximum sensitivity reached during Holter monitoring averaged 2.31 ± 0.67 mV versus 1.72 ± 0.71 mV (difference 0-1.7 mV). Normal pacemaker function was found in six patients, including one patient without any intrinsic atrial activity. Malsensing of less than five P waves occurred in four patients. More than 50 sensing defects resulted from ectopic atrial beats (four patients). We observed atrial oversensing in three cases; one patient showed atrial over- and undersensing. The comparison between fixed and variable sensitivity did not reveal any superiority of automatic adaptation. Conclusion: earlier findings of atrial signal variation during daily life are confirmed. Although quite reliable during exercise studies, automatic adaptation of atrial sensitivity is not able to compensate for sudden changes in atrial electrogram or to sufficiently suppress extracardiac noise.     

2-(2‘-Pyridyl)-ethyl-ester (Pet ester) derivatives of polyfunctional amino acids

The 2-(2′-pyridyl)-ethyl-esters (Pet-esters) of bi- and tri-functional amino acids are introduced as a semipermanent protecting group in peptide synthesis.     

Bacterial endocarditis of the aortic valve with septic coronary embolism and myocardial infarction in a 4-month old baby

4-month old baby, who developed infective endocarditis of theaortic valve following purulent arthritis of the hip joint,is presented. The baby developed signs of myocardial infarctionand died suddenly at the age of 6 months. Autopsy revealed alocalized healed coronary arteritis, almost certainly due toan infected embolus, as the underlying cause.     

Sudden death in a young competitive athlete with Wolf--Parkinson--White syndrome

The case history is documented of a young competitive athleteknown to have the electrocardiographic pattern of the Wolff—Parkinson—Whitesyndrome, but considered asymptomatic. On that basis competitivesport was not proscribed. In retrospect, he had experiencedoccasional tachycardias which were of short duration and endedspontaneously. He never requested medical advice. The boy wasfirst admitted for an attack of rapid heart beating which didnot readily subside. He was medicated with prajmalium and leftthe hospital in stable condition. He died suddenly 10 days afterdischarge. Autopsy examination of the heart revealed an accessoryatrioventricular connection in the posterior septal region.The case history underlines that in some patients with the Wolff—Parkinson—Whitesyndrome the clinical manifestation can be minimal and may beeasily ignored by the patient. In retrospect, benign episodesof rapid heart beating most likely were due to a circus movementtachycardia, related to an accessory atrioventricular connection.The sudden death can be attributed to atrial fibrillation withrapid ventricular response via the anomalous connection, despitemedical treatment. The observation endorses the potential dangerof the Wolff—Parkinson—White syndrome in patientswith minimal clinical manifestations. A meticulous histologicstudy of the atrioventricular function in hearts of young athleteswith sudden and unexplained death is a necessity.     

Apoptosis and resolution of experimental renal infective tubulointerstitial nephritis

Summary: Resolution of tubulointerstitial nephritis represents an important step in limiting renal fibrogenesis. However, the mechanism of this resolution remains poorly understood. to determine if apoptosis has a role in this process, we studied its incidence in an experimental model of renal infection and scarring, induced by direct inoculation of Escherichia coli into the renal cortex of Sprague-Dawley rats. the focal lesion produced was studied in animals killed at various time points up to 100 days post inoculation. Apoptosis was identified by electron microscopy (EM) and in-situ labelling of fragmented DNA using terminal transferasemediated deoxy-uridine-5'-triphospate (UTP) nick end labelling (TUNEL). Results were compared with morphological assessment of tubulointerstitial cellularity and macrophage localization. Terminal transferasemediated UTP nick end labelling localized apoptosis to interstitial cells, tubular casts and occasional tubular epithelia and double labelling demonstrated apoptotic body incorporation in macrophages. Interstitial cellularity was maximum at day 3, decreasing significantly by 100 days ( P < 0.01). the incidence of interstitial apoptosis was increased by 3 days and remained significantly higher than day 0 controls throughout ( P < 0.05). Tubular cellularity was significantly less than in control animals throughout the experimental time period. Although the rate of tubular apoptosis was increased, this difference was not statistically significant. In conclusion, apoptosis may represent an important mechanism in the reduction of tubulointerstitial cellularity after experimental renal infection. This in turn, may be important in limiting subsequent interstitial scarring.