No abstract

Background-Doxycycline has been shown to effectively inhibit aneurysm formation in animal models of abdominal aortic aneurysm. Although this effect is ascribed to matrix metalloproteinase-9 inhibition, such an effect is unclear in human studies. We reevaluated the effect of doxycycline on aortic wall protease content in a clinical trial and found that doxycycline selectively reduces neutrophil-derived proteases. We thus hypothesized that doxycycline acts through an effect on vascular inflammation. Methods and Results-Sixty patients scheduled for elective open aneurysmal repair were randomly assigned to 2 weeks of low-, medium-, or high-dose doxycycline (50, 100, or 300 mg/d, respectively) or no medication (control group). Aortic wall samples were collected at the time of operation, and the effect of doxycycline treatment on vascular inflammation was evaluated. Independently of its dose, doxycycline treatment resulted in a profound but selective suppression of aortic wall inflammation as reflected by a selective 72% reduction of the aortic wall neutrophils and a 95% reduction of the aortic wall cytotoxic T-cell content (median values; PϽ0.00003). Evaluation of major inflammatory pathways suggested that doxycycline treatment specifically quenched AP-1 and C/EBP proinflammatory transcription pathways (PϽ0.0158, NS) and reduced vascular interleukin-6 (PϽ0.00115), interleukin-8 (PϽ0.00246, NS), interleukin-13 (PϽ0.0184, NS), and granulocyte colony-stimulating factor (PϽ0.031, NS) protein levels. Doxycycline was well tolerated; there were no adverse effects. Conclusions-A brief period of doxycycline treatment has a profound but selective effect on vascular inflammation and reduces aortic wall neutrophil and cytotoxic T-cell content. Results of this study are relevant for pharmaceutical stabilization of the abdominal aneurysm and possibly for other inflammatory conditions that involve neutrophils and/or cytotoxic T cells.

This study aimed to identify clinical and histologic prognostic indicators of renal outcome in patients with ANCA-associated vasculitis and severe renal involvement (serum creatinine >500 mol/L). One hundred patients who were enrolled in an international, randomized, clinical trial to compare plasma exchange with intravenous methylprednisolone as an additional initial treatment were analyzed prospectively. Diagnostic renal biopsies were performed upon entry into the study. Thirty-nine histologic and nine clinical parameters were determined as candidate predictors of renal outcome. The end points were renal function at the time of diagnosis (GFR 0 ) and 12 mo after diagnosis (GFR 12 ), dialysis at entry and 12 mo after diagnosis, and death. Multivariate analyses were performed. Predictive of GFR 0 were age (r ‫؍‬ ؊0.40, P ‫؍‬ 0.04), arteriosclerosis (r ‫؍‬ ؊0.53, P ‫؍‬ 0.01), segmental crescents (r ‫؍‬ 0.35, P ‫؍‬ 0.07), and eosinophilic infiltrate (r ‫؍‬ ؊0.41, P ‫؍‬ 0.04). Prognostic indicators for GFR 12 were age (r ‫؍‬ ؊0.32, P ‫؍‬ 0.01), normal glomeruli (r ‫؍‬ 0.24, P ‫؍‬ 0.04), tubular atrophy (r ‫؍‬ ؊0.28, P ‫؍‬ 0.02), intraepithelial infiltrate (r ‫؍‬ ؊0.26, P ‫؍‬ 0.03), and GFR 0 (r ‫؍‬ 0.29, P ‫؍‬ 0.01). Fibrous crescents (r ‫؍‬ 0.22, P ‫؍‬ 0.03) were predictive of dialysis at entry. Normal glomeruli (r ‫؍‬ ؊0.30, P ‫؍‬ 0.01) and treatment arm (r ‫؍‬ ؊0.28, P ‫؍‬ 0.02) were predictive of dialysis after 12 mo. No parameter predicted death. Both chronic and acute tubulointerstitial lesions predicted GFR 12 in severe ANCA-associated glomerulonephritis, whereas plasma exchange was a positive predictor of dialysis independence after 12 mo for the entire patient group. Plasma exchange remained a positive predictor when patients who were dialysis dependent at presentation were analyzed separately (r ‫؍‬ ؊0.36, P ‫؍‬ 0.01). Normal glomeruli were a positive predictor of dialysis independence and improved renal function after 12 mo, indicating that the unaffected part of the kidney is vital in determining renal outcome.

Background and Purpose-The merits of transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) in the management of transient ischemic attack (TIA) and stroke patients remains matter of debate. Methods-Two hundred and thirty-one consecutive patients with a recent TIA or stroke for which no definite cause and indication for anticoagulation was assessed after standardized work-up underwent TTE and TEE. Echocardiographic findings were categorized into minor and major risk factors. Results-A potential cardiac source of embolism was detected in 55% (127/ 231) of the patients by echocardiography, in 39% (90/231) only identified on TEE. Major risk factors, with an absolute indication for oral anticoagulation, were detected in 20% (46/231) of the patients, in 16% (38/231) of all patients identified on TEE only. A thrombus in the left atrial appendage was the most common major risk factor (38 patients, 16%). The presence of major risk factors was independent of age ( 2 ϭ1.48; Pϭ0.224). The difference in proportions of cardiac sources detected in favor of TEE was highly significant in both patients Յ45 years of age (10/39, Pϭ0.002) and in those Ͼ45 years of age (80/192; PϽ0.004). Conclusions-TEE proved superior to TTE for identification of a cardiac embolic source in patients with TIA or stroke without pre-existent indication or contraindication for anticoagulation. In patients with normal TTE, a cardiac source of embolism was detected by TEE in Ϸ40% of patients, independent of age. More than 1 of 8 patients of any age with normal TTE revealed a major cardiac risk factor on TEE, in whom anticoagulation is warranted. (Stroke. 2006;37:2531-2534.)

Our results demonstrate that macrophages are present in the glomeruli and interstitium of type 2 diabetic patients with DN and of controls. Although patients and controls had similar numbers of glomerular macrophages, glomerular anti-inflammatory CD163+ macrophages were associated with pathological lesions in DN. Taken together with the correlation between interstitial macrophages and interstitial fibrosis and tubular atrophy, DN class, and renal function, this finding suggests that macrophages may play a role in DN progression. Therefore, targeting macrophages may be a promising new therapy for inhibiting the progression of DN.