Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis

OBJECTIVE: To examine the role of chemokines, S100A8, and S100A9 in neutrophil accumulation induced by the causative agent of gout, monosodium urate monohydrate (MSU) crystals. METHODS: MSU crystal-induced neutrophil migration was studied in the murine air-pouch model. Release of chemokines, S100A8, S100A9, and S100A8/A9 in response to MSU crystals was quantified by enzyme-linked immunosorbent assays. Recruited cells were counted following acetic blue staining, and the subpopulations were characterized by Wright-Giemsa staining of cytospins. RESULTS: MSU crystals induced the accumulation of neutrophils following injection in the air pouch, which correlated with the release of the chemokines CXCL1, CXCL2, CCL2, and CCL3. However, none of these was found to play an important role in neutrophil migration induced by MSU crystals by passive immunization with antibodies directed against each chemokine. S100A8, S100A9, and S100A8/A9 were also found at high levels in the pouch exudates following injection of MSU crystals. In addition, injection of S100A8, S100A9, or S100A8/A9 led to the accumulation of neutrophils in the murine air pouch, demonstrating their proinflammatory activities in vivo. Passive immunization with anti-S100A8 and anti-S100A9 led to a total inhibition of the accumulation of neutrophils. Finally, S100A8/A9 was found at high concentrations in the synovial fluid of patients with gout. CONCLUSION: S100A8 and S100A8/A9 are essential to neutrophil migration induced by MSU crystals. These results suggest that they might be involved in the pathogenesis of gout.     

Encephalomyocarditis virus induced diabetes mellitus in mice: Long-term changes in the structure and function of islets of langerhans

Diabetologia - Adult male mice infected with the M variant of encephalomyocarditis virus develop hyperglycaemia acutely as a consequence of B cell injury. The severity of the metabolic disease is...     

A pilot study of the relationship between Doppler‐estimated carotid and brachial artery flow and cardiac index

We measured carotid and brachial artery blood flow by Doppler ultrasound in 11 human volunteers, and related these to cardiac index and to each other. The median (IQR [range]) carotid arterial blood flow was 0.334 (0.223–0.381 [0.052–0.563]) l.min^?1 on the right and 0.315 (0.223–0.369 [0.061–0.690]) l.min^?1 on the left. The brachial arterial blood flow was 0.049 (0.033–0.062 [0.015–0.204]) l.min^?1 on the right and 0.039 (0.027–0.054 [0.011–0.116]) on the left. Cardiac index was 3.2 (2.8–3.5 [1.9–5.4]) l.min^?1.m^?2. There was a moderate to good correlation between right‐and left‐sided flows (brachial: ρ = 0.45; carotid: ρ = 0.567). Brachial and carotid flow had no or a negative correlation with cardiac index (right brachial: ρ = ?0.145, left brachial: ρ = ?0.349; right carotid: ρ = ?0.376, left carotid: ρ = ?0.285). In contrast to some previous studies, we found that Doppler‐estimated peripheral arterial blood flows only show a weak correlation with cardiac index and cannot be used to provide non‐invasive estimates of cardiac index in man.     

Immature platelet fraction and high-on treatment platelet reactivity with ticagrelor in patients with acute coronary syndromes

Residual high-on treatment platelet reactivity (HRPR) has been associated with a 2–9 fold increased risk of acute ischemic events in patients with acute coronary syndromes or coronary stenting. However, the mechanism of suboptimal platelet inhibition are still poorly understood. Aim of present study was to evaluate the role of the percentage of reticulated platelets on HRPR with ticagrelor. In patients treated with ASA (100–160 mg) and ticagrelor (90 mg twice a day) platelet reactivity and the reticulated platelets fraction (immature platelets fraction, IPF) were assessed at 30–90 days after acute coronary syndrome. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined as ADP test >417 AU*min. Our population is represented by 190 patients, divided according to tertiles values of IPF (<2.5; 2.5–3.99; ≥4 %). Higher IPF was associated to a larger platelet volume and lower platelets count (p < 0.001), and inversely related with a history of previous coronary revascularization (p = 0.03). Twenty-one out of 190 (11.0 %) patients displayed HRPR. No difference in the levels of circulating IPF was found in patients with or without HRPR (p = 0.25), with no correlation between the rate of reticulated platelets and platelet reactivity at ADP test (r = ?0.084, p = 0.26). In fact no association was observed between high levels of IPF and the occurrence of HRPR (adjusted OR[95 % CI] = 0.69[0.34–1,37], p = 0.28), even after correction for baseline differences. In patients treated with ticagrelor, the levels of circulating reticulated platelets assessed at 30–90 days post-ACS are not associated with platelet reactivity or the occurrence of HRPR.     

Treatment of benign cold thyroid nodules: a randomized clinical trial of percutaneous laser ablation versus levothyroxine therapy or follow-up.

AIM OF THE STUDY: To compare clinical and ultrasound (US) changes induced in cold thyroid nodules by US-guided percutaneous laser ablation (PLA) versus follow-up or levothyroxine (LT4) suppressive therapy. METHODS: 62 patients randomly assigned to a single PLA (Group 1), LT4 (Group 2), or follow-up (Group 3). Entry criteria: euthyroid patients with a solid thyroid nodule >5 mL and benign cytological findings. TREATMENT: Group 1: PLA was performed with a 1.064 mum neodymium yttrium-aluminum-garnet laser with output power of 3 W for 10 minutes; Group 2: the LT4 dose was adjusted to induce thyrotropin suppression; Group 3: no treatment. RESULTS: In Group 1 a significant nodule reduction was found 6 and 12 months after PLA (delta volume: -42.7 +/- 13.6%; p = 0.001). A reduction >50% was found in 33.3% of cases. In Group 2 a nonsignificant nodule shrinkage was observed. A nonsignificant volume increase was observed in Group 3. Improvement of local symptoms was registered in 81.2% of patients in Group 1 vs. 13.3% in Group 2 and 0.0% in Group 3 ( p = 0.001). No complications were noted. CONCLUSIONS: A single PLA induced significant volume reduction and improvement of local symptoms. PLA was more effective than LT4. Follow-up was associated with nodule growth and progression of local symptoms. PLA should be considered a potential mini-invasive alternative to surgery in symptomatic patients with benign cold thyroid nodules.     

Intravenous amino acid therapy for kidney function in critically ill patients: a randomized controlled trial

Importance

Acute kidney injury (AKI) is characterized by severe loss of glomerular filtration rate (GFR) and is associated with a prolonged intensive care unit (ICU) stay and increased risk of death. No interventions have yet been shown to prevent AKI or preserve GFR in critically ill patients. Evidence from mammalian physiology and small clinical trials suggests higher amino acid intake may protect the kidney from ischemic insults and thus may preserve GFR during critical illness.

Objective

To determine whether amino acid therapy, achieved through daily intravenous (IV) supplementation with standard amino acids, preserves kidney function in critically ill patients.

Design, setting, and participants

Multicenter, phase II, randomized clinical trial conducted between December 2010 and February 2013 in the ICUs of 16 community and tertiary hospitals in Australia and New Zealand. Participants were adult critically ill patients expected to remain in the study ICU for longer than 2 days.

Interventions

Random allocation to receive a daily supplement of up to 100 g of IV amino acids or standard care.

Main outcomes and measures

Duration of renal dysfunction (primary outcome); estimated GFR (eGFR) derived from creatinine; eGFR derived from cystatin C; urinary output; renal replacement therapy (RRT) use; fluid balance and other measures of renal function.

Results

474 patients were enrolled and randomized (235 to standard care, 239 to IV amino acid therapy). At time of enrollment, patients allocated to receive amino acid therapy had higher APACHE II scores (20.2 ± 6.8 vs. 21.7 ± 7.6, P = 0.02) and more patients had pre-existing renal dysfunction (29/235 vs. 44/239, P = 0.07). Duration of renal dysfunction after enrollment did not differ between groups (mean difference 0.21 AKI days per 10 patient ICU days, 95 % CI ?0.27 to 1.04, P = 0.45). Amino acid therapy significantly improved eGFR (treatment group × time interaction, P = 0.004), with an early peak difference of 7.7 mL/min/1.73 m² (95 % CI 1.0–14.5 mL/min/1.73 m², P = 0.02) on study day 4. Daily urine output was also significantly increased (+300 mL/day, 95 % CI 145–455 mL, P = 0.0002). There was a trend towards increased RRT use in patients receiving amino acid therapy (13/235 vs. 25/239, P = 0.062); however, this trend was not present after controlling for baseline imbalance (P = 0.21).

Conclusion and relevance

Treatment with a daily IV supplement of standard amino acids did not alter our primary outcome, duration of renal dysfunction.

Trial registration

anzctr.org.au Identifier: ACTRN12609001015235.