Role of lipopolysaccharide and cecal ligation and puncture on blood coagulation and inflammation in sensitive and resistant mice models

The hemostatic system is severely disturbed during endotoxemia, leading to a hypercoagulable state. However, it remains uncertain to what extent hypercoagulability is the critical factor in determining the clinical course rather than just the consequence of a severe systemic inflammatory response. To answer this question, we evaluated the evolution of hemostatic and inflammatory markers, as well as histological features, in mice sensitive and resistant to two models of endotoxemia: lipopolysaccharide-injection and cecal ligation puncture. Genetic (knockout mice) and pharmacological (PJ34) blockade of the nuclear enzyme PARP-1 was used to achieve resistance to the endotoxemia. In both models, endotoxemia resulted in antithrombin deficiency, decreased platelets, and fibrin deposition in organs, which were similar in all groups of mice. By contrast, proinflammatory mediators, inflammatory cell infiltration (especially that mediated by mononuclear cells), and organ degeneration were more intense in sensitive animals. Further studies supported a negative role for the triggering of the coagulation cascade in the mortality associated with the endotoxic shock. Hirudin had a minor effect on cell infiltration and organ damage, despite causing a potent inhibition of fibrin deposition. On the other hand, a sublethal dose of lipopolysaccharide yielded significant fibrin deposition but weak activation of the inflammatory response. Our results suggest that activation of coagulation by endotoxemia is severe and independent of the inflammatory response. However, such activation may act with fibrin deposition to have a minor influence on survival in sepsis.     

Neonatal hyperphenylalaninemia, perinatal hemochromatosis, and renal tubulopathy: a unique patient or a novel metabolic disorder?

A neonate presented with hyperphenylalaninemia (HPA), with a persistently elevated phenylalanine/tyrosine ratio. The HPA was responsive to tetrahydrobiopterin (BH4). His clinical course was dominated by liver failure, associated with perinatal hemochromatosis. He also developed renal tubulopathy. HPA has not previously been reported in association with any of these features. We investigated the etiology of his condition, and discuss the possibility that this represents a novel single-gene disorder.     

Effects of luminal ATPase inhibitors on electrogenic ion transport in rat distal colon

BACKGROUND: The involvement of transport proteins, other than chloride channels, expressed in the luminal membrane of epithelial cells in regulated chloride secretion in native colon remains poorly understood. There are at least two distinct ATPases expressed in the apical membrane of rat colonocytes. They can be distinguished by their different sensitivity to the vanadium-derived compound orthovanadate. The objective was to study the effects of luminal ATPase inhibitors on regulated chloride secretion using elecrophysiological and pharmacological approaches. MATERIALS AND METHODS: Unstripped rat distal colon segments were mounted in Ussing chambers. Potential difference, transepithelial resistance, and short-circuit current across unstripped colon segments were monitored with a dual voltage/current clamp. RESULTS: Luminal application of VO4(3-) did not alter baseline electrical values in rat distal colon but dose-dependently inhibited forskolin-stimulated Isc. Luminal ouabain (1 mm) did not blunt the response to the cAMP agonist. The inhibitory effect of luminal VO4(3-) occurred at a site distal to cAMP generation and was rather specific for the cyclic nucleotide-dependent signaling pathway, because the response to the Ca2+ agonist carbachol was largely preserved. CONCLUSION: VO4(3-) inhibits cAMP-stimulated Cl- secretion in rat distal colon at a site distal to cAMP generation without altering intestinal permeability. Ouabain-sensitive luminal K+-ATPases do not seem to contribute to forskolin-stimulated electrogenic ion transport. These findings may suggest new therapeutic targets for secretory diarrhea.     

Ultrasonographic findings in knee osteoarthritis: a comparative study with clinical and radiographic assessment

OBJECTIVE: To compare ultrasonographic (US) findings with clinical and radiographic assessment in knee osteoarthritis (OA). METHODS: Fifty patients with primary knee OA were studied. Clinical assessment of both knees was performed by the same rheumatologist who recorded a visual analogue scale (VAS) for pain (VASP). All patients underwent a US examination of their knees by a second blinded rheumatologist. Weight-bearing anteroposterior and lateral knee radiographs were read by a third blinded rheumatologist who assessed the Kellgren and Lawrence (K-L) grade, the femorotibial (FT) space width and the presence of patello-femoral degenerative signs. RESULTS: Forty patients had bilateral symptomatic knee OA and 10 unilateral symptomatic OA. All knees showed radiographic FT degenerative signs. US findings in symptomatic knees were effusion (47%), protrusion of the medial meniscus (MMP) with displacement of the medial collateral ligament (MCLD) (61%) and Baker's cyst (22%). US effusion, MMP and MCLD were associated with a significantly higher VAS score for pain (P<0.05). MMP was associated with medial FT space width (P<0.05). Patients who had a difference between VAS score for pain in each knee greater than 30 (28 patients) showed significantly more unilateral effusion, MMP, MCLD and worse K-L grade in the more symptomatic knee than those with a difference lesser than 30 (22 patients). CONCLUSION: Knee effusion and MMP with MCLD are associated with pain in knee OA. In addition, MMP may contribute to the radiographic medial FT space narrowing. We propose US for assessing periarticular and intraarticular abnormalities involved in the pathophysiology of knee OA.     

Cutaneous marginal zone B-cell lymphoma treated with rituximab

Marginal zone B-cell lymphoma (MZL) is probably the most frequent of the primary cutaneous B-cell lymphomas, which are entities with indolent behavior. Clinically, it appears in middle-aged patients as papules, nodules or erythematous plaques, solitary or multiple, on the trunk and proximal part of the limbs. The prognosis is excellent despite frequent cutaneous recurrences. We present the case of a 40-year-old male who, after having several recurrences of MZL over a ten-year period, was treated with rituximab for multiple skin lesions. The patient showed full remission after four weeks of treatment, and developed cytokine-release syndrome after the first infusion of the drug.     

Hematocrit influences immunoassay performance for the measurement of tacrolimus in whole blood

The comparison between the MEIA II and the EMIT assays for tacrolimus measurement and the interference by the hematocrit were evaluated in 93 samples from routine therapeutic monitoring at tacrolimus concentrations less than 9 microg/L (group A). Additionally, the incidence of false-positive results were determined in samples (n=46) from patients who were not receiving the drug (group B). In group A, no statistical differences were observed between the mean+/-SD values obtained by MEIA II (5.14+/-2.28 microg/L) and EMIT (4.61+/-1.79 microg/L). The correlation coefficient and the regression equation (95% CI) between both assays, were 0.761 and EMIT=1.088 (0.90, 1.35) MEIA II -0.38 (-1.65, -0.46), respectively. When the samples were stratified according to the hematocrit, the median differences between the methods (MEIA II minus EMIT) were as follows: hematocrit35%, 0.25 microg/L (P=0.02). In group B, false-positive results (above the detection limit) were observed in 63.04% of samples analyzed by MEIA II and in 2.17% of samples analyzed by EMIT. The median differences in apparent tacrolimus results were significantly higher in the samples with the lowest hematocrit: 2.2 microg/L, 1.4 microg/L, and 0.0 microg/L in samples with hematocrit35%, respectively. In conclusion, the differences in the tacrolimus results obtained by MEIA and EMIT assays were higher in samples from patients with hematocrit less than 25%, and the MEIA assay demonstrated a high incidence of false-positive results.