Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study

Background

Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function.

Methods

Plasma levels of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, high-sensitivity C-Reactive protein (hs-CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory.

Results

LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs-CRP (OR 1.26 [95% CI 1.16, 1.37], p<0.001), IL-1RA (1.23 [1.13, 1.34], p<0.0001), IL-6 (1.25 [1.14, 1.36], p<0.001) and TNF-α (1.14 [1.04, 1.25], p = 0.004) were associated with LVH. The odds for systolic dysfunction were greater for subjects with elevated levels of hs-CRP (1.32 [1.18, 1.48], p<0.001) and IL-6 (1.34 [1.21, 1.49], p<0.001). Only hs-CRP was associated with diastolic dysfunction (1.14 [1.04, 1.26], p = 0.005).

Conclusion

In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction.     

Fusarium javanicum Koorders in Israel

Fusarium javanicum Kds. has been isolated from wilted vegetable marrows and melons and from the soil of a citrus grove in Israel. The morphology of the species is described, and measurements and drawings of macroconidia are presented.In vitro tests showed thatF. javanicum failed to develop at either 12 or 40° C, and developed better at 24° C than 18 or 30° C. Mycelial growth on potato dextrose agar was always better at pH 7 than at pH 4.2. Darkness favored such growth to a marked extent only at 18° C and pH 4.2. In glasshouse inoculation tests one isolate ofF. javanicum from vegetable marrow proved clearly pathogenic to cucumber, melon, watermelon and marrow. Measurements of macroconidia have been made, for comparative purposes, on isolates ofF. javanicum var.ensiforme and ofF. solani f.cucurbitae furnished from abroad, and on isolates ofF. solani from cucurbits in Israel. Comparing the data for 3-septate macroconidia with those given in literature forF. solani and forF. javanicum and its var.radicicola and var.ensiforme, it is concluded that two groups can be distinguished: One group comprises, with one exception, all isolates ofF. javanicum and its varieties as well asF. solani f.cucurbitae, and is characterized by slender macroconidia. The other group is represented byF. solani with its typically sausage shaped conidia. It is concluded thatF. javanicum should be maintained as a species distinct fromF. solani. It is further suggested that what has been calledF. solani f.cucurbitae may have closer affinity toF. javanicum than toF. solani.

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Zusammenfassung Fusarium javanicum Koorders wurde in Israel von verwelkten Cucurbitaceen(Cucurbita pepo Kussa andCucumis melo) sowie von dem Boden einer Citruspflanzung isoliert. Die Morphologie des Pilzes wird hier beschreiben. Inin vitro Versuchen entwickelte sichF. javanicum auf Kartoffel-Dextrose Agar weder bei 12 noch bei 40° C, und wuchs besser bei 24 als bei 18 oder 30° C. Das Wachstum des Myzeliums war stets besser bei pH 7 als bei pH 4.2. Dunkelheit förderte dieses Wachstum erheblich nur bei 18° C und pH 4.2. In Impfungsversuchen im Glasshaus wirkte ein Isolat desF. javanicum vonC. pepo stark pathogenisch auf Gurken, Melonen, Wassermelonen undC. pepo. Zwecks taxonomischer Vergleiche wurden Makrokonidien aus dem Ausland erhaltener Isolate vonF. javanicum var.ensiforme undF. solani f.cucurbitae gemessen, sowie solche desF. solani von Cucurbitaceen in Israel. Die Resultate dieser Messungen wurden mit den in der Literatur angegebenen Werten fürF. solani, F. javanicum und dessen var.radicicola und var.ensiforme verglichen. Dieser Vergleich zeigte 2 klar getrennte Gruppen: Die erste enthält, mit einer Ausnahme, alle Isolate desF. javanicum und desF. solani f.cucurbitae, und besitzt typisch schlanke Makrokonidien. Die zweite Gruppe besteht ausF. solani mit seinen typisch dickeren, Würstchenartigen Sporen. Dies führt zu dem Schluß daßF. javanicum weiterhin als eine vonF. solani getrennte Spezies zu betrachten ist.

     

Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs)

A series of phenylaminopyrimidines has been identified as inhibitors of Janus kinases (JAKs). Development of this initial series led to the potent JAK2/JAK1 inhibitor CYT387 (N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]-benzamide). Details of synthesis and SAR studies of these compounds are reported.     

Nifedipine does not impair the hormonal responses to graded exercise in healthy subjects

The aim of this study was to assess whether the potent calcium antagonist nifedipine was capable of modifying the hormonal response to graded exercise in 7 healthy young men. After fasting overnight, each subject came to the laboratory on 2 consecutive mornings. On one day he was given 10 mg of nifedipine sublingually and on the other an identical placebo capsule; the order was randomised in a double-blind fashion over the 2 days. Thereafter each subject performed 2 successive short treadmill runs, equivalent to 60 and 100%, respectively, of maximal aerobic power. While significantly blunting the rise in mean systolic blood pressure and inducing a greater fall in diastolic blood pressure during and after exercise compared with the placebo, nifedipine did not impair the brisk response to pituitary-adrenal hormones (ACTH, cortisol and total catecholamines). Nifedipine also did not modify the effects of short-term exercise in raising mean plasma glucose levels, stimulating pancreatic glucagon secretion and producing a delayed increase in plasma insulin concentrations. Nor did the drug blunt the significant rise of growth hormone and prolactin levels occurring during and after the treadmill run. It was concluded that, apart from inducing significant changes in blood pressure, a single dose of nifedipine does not appear to suppress the counterregulatory hormonal responses to short-term physical activity in healthy men.     

Atypical and complicated Kawasaki disease in infants. Do we need criteria?

Case reports suggest that infants with Kawasaki disease have atypical presentations and a high complication rate, likely related to delayed diagnosis and treatment. To date, no study of consecutive cases has compared infants with older children who have both atypical and typical Kawasaki disease. We retrospectively reviewed 44 cases of Kawasaki disease treated at our hospital from March 1980 to 1990: 11 (25%) were infants; 9 (20%) had atypical Kawasaki disease, of which 5 (56%) were infants; the male to female ratio was 1.7:1. Infants had a higher incidence of atypical Kawasaki disease (5 [45%] versus 4 [12%]; P = .007) and of coronary artery complications (7 [64%] versus 3 [9%]; P = .002), and coronary artery complications developed in all of the infants with atypical Kawasaki disease (5 [100%] versus 0 [0%]; P < .01). Yet, the other manifestations and laboratory changes were at least as common as in the older children. Coronary artery complications did not develop in any patient who received early intravenous immune globulin therapy. We suggest that in infants with Kawasaki disease, accepted criteria are too restrictive to allow early diagnosis and effective treatment. Until a definitive test is available, clinical judgment is required in the diagnosis of atypical Kawasaki disease. Intravenous immune globulin is known to be safe, and its early use in patients with suspected atypical Kawasaki disease is appropriate.     

Biomarkers of endothelial dysfunction,cardiovascular risk factors and atherosclerosis in rheumatoid arthritis

Cardiovascular event rates are markedly increased in rheumatoid arthritis (RA), and RA atherogenesis remains poorly understood. The relative contributions of traditional and nontraditional risk factors to cardiovascular disease in RA await elucidation. The present study comprises three components. First, we compared biomarkers of endothelial dysfunction (vascular cell adhesion molecule [VCAM]-1, intercellular adhesion molecule [ICAM]-1 and endothelial leucocyte adhesion molecule [ELAM]-1) in 74 RA patients and 80 healthy control individuals before and after controlling for traditional and nontraditional cardiovascular risk factors, including high-sensitivity C-reactive protein (hs-CRP), IL-1, IL-6 and tumor necrosis factor-α. Second, we investigated the potential role of an extensive range of patient characteristics in endothelial dysfunction in the 74 RA patients. Finally, we assessed associations between biomarkers of endothelial dysfunction and ultrasonographically determined common carotid artery intima–media thickness and plaque in RA. The three biomarkers of endothelial dysfunction, as well as hs-CRP, IL-1, IL-6 and tumor necrosis factor-α, were higher in patients than in control individuals (P < 0.0001). Patients were also older, exercised less and had a greater waist circumference, blood pressure and triglyceride levels (P ≤ 0.04). Five patients had diabetes. Differences in endothelial function were no longer significant between patients and controls (P = 0.08) only after both traditional and nontraditional cardiovascular risk factors were controlled for. In the 74 RA patients, IL-6 predicted levels of all three biomarkers (P ≤ 0.03), and rheumatoid factor titres and low glomerular filtration rate (GFR) both predicted levels of VCAM-1 and ICAM-1, independent of traditional cardiovascular risk factors (P ≤ 0.02). VCAM-1 was associated with common carotid artery intima–media thickness (P = 0.02) and plaque (P = 0.04) in RA. Patients had impaired endothelial function, less favourable traditional cardiovascular risk factor profiles, and higher circulating concentrations of hs-CRP and cytokines compared with healthy control individuals. Both traditional and nontraditional cardiovascular risk factors contributed to the differences in endothelial function between RA patients and healthy control individuals. IL-6, rheumatoid factor titres and low GFR were independently predictive of endothelial dysfunction in RA. Disease-modifying agents that effectively suppress both cytokine and rheumatoid factor production, and interventions aimed at preserving renal function may attenuate cardiovascular risk in RA.