Differential Interleukin-8 thresholds for chemotaxis and netosis in human neutrophils

In humans, IL-8 (CXCL8) is a key chemokine for chemotaxis of polymorphonuclear leukocytes and monocytes/macrophages when acting on CXCR1 and CXCR2. CXCL8 activity on neutrophils includes chemotaxis and eliciting the extrusion of neutrophil extracellular traps (NETs). In this study, we show that concentrations of IL-8 that induce NETosis surpass in at least one order of magnitude those required to elicit chemoattraction in human neutrophils. IL-8-induced NETosis was less dependent on G-proteins than migration, while extracellular Ca⁺² chelation similarly inhibited both processes. Reactive oxygen species (ROS) were more important for NETosis than for chemotaxis as evidenced by neutralization with N-acetyl -cysteine. Interestingly, selective blockade with anti-CXCR1 mAb inhibited NETosis much more readily than chemotaxis, while pharmacological inhibition of both CXCR1 and CXCR2, or selective inhibition for CXCR2 alone, similarly inhibited both functions. Together, these results propose a model according to which low concentrations of IL-8 in a gradient attract neutrophils to the inflammatory foci, while high receptor-saturating concentrations of IL-8 give rise to NETosis once leukocytes reach the core of the inflammatory insult.     

Evolution of endodontic medicine: a critical narrative review of the interrelationship between endodontics and systemic pathological conditions

Odontology - Endodontics has gained emphasis in the scientific community in recent years due to the increase in clinical and in animal models studies focused on endodontic medicine, which aims to...     

Intercostal nerve transfer to the biceps motor branch in complete traumatic brachial plexus injuries

The purpose of this report is to critically evaluate our results of two intercostal nerve transfers directly to the biceps motor branch in complete traumatic brachial plexus injuries. From January 2007 to November 2012, 19 patients were submitted to this type of surgery, but only 15 of them had a follow‐up for ≥2 years and were included in this report. The mean interval from trauma to surgery was 6.88 months (ranging from 3 to 9 months). Two intercostals nerves were dissected and transferred directly to the biceps motor branch. The mean follow‐up was 38.06 months (ranging from 24 to 62 months). Ten patients (66.6%) recovered an elbow flexion strength ≥M3. Four of them (26.66%) recovered a stronger elbow flexion ≥M4. One patient (6.25%) recovered an M2 elbow flexion and four patients (26.66%) did not regain any movement. We concluded that two intercostal nerve transfers to the biceps motor branch is a procedure with moderate results regarding elbow flexion recovery, but it is still one of the few options available in complete brachial plexus injuries, especially in five roots avulsion scenario. © 2015 Wiley Periodicals, Inc. Microsurgery 35:428–431, 2015.     

Healthcare use by varied highly active antiretroviral therapy (HAART) strata: HAART use, discontinuation, and naivety

OBJECTIVES: Prior reports have found a temporal association between the introduction of highly active antiretroviral therapy (HAART) and population rates of health service use among persons living with HIV. Our objective was to explore further the effect of HAART by comparing healthcare use among persons who use HAART and persons who discontinue HAART to that among HAART-naive and HIV-negative persons. METHODS: Longitudinal analyses of 1485 women with and at-risk for HIV who contributed data to the Women's Interagency HIV Study between April 1997 and March 2000. RESULTS: Compared with HAART-naive women, those using HAART had a higher probability of more than three primary care visits per 6 months [odds ratio (OR), 1.38; 95% confidence interval (CI), 1.16-1.65), a lower probability of more than one emergency room visit per 6 months (OR, 0.75; CI, 0.59-0.95), and a lower probability of more than one hospitalization per 6 months (OR, 0.67; CI, 0.51-0.88). Compared with HAART-naive women, women who had discontinued HAART had a higher frequency of primary care visits (OR, 1.57; CI, 1.26-1.97) but did not demonstrate a significant change in emergency room or hospital use. Modeling of a standardized population HIV-positive women without AIDS indicated hospitalization and emergency room use among HAART users was equivalent to that among HIV-negative women. CONCLUSIONS: HIV-positive HAART users (without AIDS) exhibited emergency room and hospitalization use patterns equivalent to those of HIV-negative women. Furthermore, the discontinuation of HAART was associated with a loss of the reduction in hospital use that was achieved with HAART.     

Assessment of in vivo complement activation on the Echinococcus granulosus hydatid cyst wall

The larval stage of the parasite Echinococcus granulosus causes hydatid disease. The hydatid cyst is potentially capable of activating host complement, since it is a large, persistent, carbohydrate-rich structure, coated with host immunoglobulins, and localized in the host's internal organs. Nonetheless, in vitro studies have suggested that the cyst surface, the hydatid cyst wall (HCW), is a poor complement activator. In this study, we assessed the occurrence of in vivo complement activation on the hydatid cyst by measuring the levels of two complement activation products, C3d and complexes bearing a C9 activation neoepitope (TCC/MAC), in extracts from HCW of human origin. Low amounts of C3d and TCC/MAC were found in HCW in comparison with their levels in normal human plasma and activated human sera, suggesting that in vivo complement activation on HCW is efficiently down-regulated. This regulation may contribute to limit host inflammation which has been observed to correlate with parasite degeneration and death.     

Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays

Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.