Detrimental effect of apoptosis of lymphocytes at an early time point of experimental abdominal sepsis

<p>Abstract</p> <p>Background</p> <p>Apoptosis of lymphocytes is considered a late sequelum in the sepsis cascade. The role of apoptosis of lymphocytes as a driver of final outcome was investigated.</p> <p>Methods</p> <p>Abdominal sepsis was induced after cecal ligation and puncture (CLP) in 31 rabbits. Blood was sampled at serial time intervals and peripheral blood mononuclear cells (PBMCs) were isolated. Apoptosis of lymphocytes and monocytes was measured through flow cytometric analysis. PBMCs were stimulated with LPS and Pam3Cys for the release of tumor necrosis factor-alpha (TNFα). Tissue bacterial growth was quantitatively measured. In a second set of experiments, CLP was performed in another 40 rabbits; 20 received single intravenous infusions of ciprofloxacin and of metronidazole 4 hours after surgery.</p> <p>Results</p> <p>Animals were divided into two groups based on the percentage of lymphocyte apoptosis at 4 hours after surgery; less than or equal to 32% and more than 32%. Survival of the former was shorter than the latter (p: 0.017). Tissue growth was similar between groups. Apoptosis of lymphocytes and of monocytes was lower in the former group over follow-up. Release of ΤNFα did not differ. The above findings on survival were repeated in the second set of experiments. Administration of antimicrobials prolonged survival of the former group (p: 0.039) but not of the latter group (pNS).</p> <p>Conclusions</p> <p>Lymphocyte apoptosis at an early time point of experimental peritonitis is a major driver for death. A lower percentage of apoptosis leads earlier to death. Antimicrobials were beneficial even at that disease state.</p

Septic patient's genetic polymorphisms study

Debatable findings exist among various studies regarding the impact of single nucleotide polymorphisms (SNPs) within the promoter region of the tumor necrosis factor (TNF) gene for susceptibility to infections. Their impact was investigated in a cohort of mechanically ventilated patients who developed ventilator associated pneumonia (VAP). Two-hundred and thirteen mechanically ventilated patients who developed VAP were enrolled. Genomic DNA was extracted and SNPs at the -376,-308 and-238 position of the promoter region of the TNF gene were assessed by restriction fragment length polymorphisms. Monocytes were isolated from 47 patients when they developed sepsis and stimulated by bacterial endotoxin forthe production of TNFa and of interleukin-6 (IL-6). Patients were divided into two groups; 166 patientsbearing only wild-type alleles of all three studied polymorphisms; and 47 patients carrying at least one A- allele of the three studied SNPs. Time between start of mechanical ventilation and advent of VAP was significantly shorter in the second group than in the first group (log-rank: 4.416, p: 0.041). When VAP supervened, disease severity did not differ between groups. Stimulation of TNF-a and of IL-6 was much greater by monocytes for patients carrying A alleles. Carriage of at least one A allele of the three studied.SNPs at the promoter region of the TNF-gene are associated with shorter time to development of VAP but are not associated with disease severity. Findings may be related with a role of the studied SNPs in the production of pro-inflammatory cytokines.Ένας μεγάλος αριθμός μελετών έχει εκπονηθεί μέχρι στιγμής εξετάζοντας την επίδραση των μονονουκλεοτιδικών πολυμορφισμών στην περιοχή του εκκινητή του γονιδίου του TNF-α σε ό,τι αφορά την ευπάθεια στις λοιμώξεις, τα αποτελέσματα όμως είναι μέχρι στιγμής αντικρουόμενα. Ο αντίκτυπος των πολυμορφισμών μελετήθηκε σε μια ομάδα ασθενών υπό μηχανικό αερισμό που τελικά ανέπτυξαν πνευμονία σχετιζόμενη με μηχανικό αερισμό (ΠΑ). 213 ασθενείς με ΠΑ εισήχθησαν τελικά στην μελέτη. Από αυτούς απομονώθηκε γονιδιακό DNA και μελετήθηκαν οι πολυμορφισμοί στις θέσεις -376, -238 και -308 του εκκινητή του γονιδίου με την μέθοδο ανάλυσης πολυμορφισμών μήκους θραυσμάτων DNA μετά από πέψη με αντίστοιχες νουκλεάσες περιορισμού. Επιπλέον απομονώθηκαν μονοκύτταρα από 47 ασθενείς που ανέπτυξαν σήψη και ακολούθως διεγέρθηκαν με βακτηριακή ενδοτοξίνη προς παραγωγή TNF-α και IL-6. Οι ασθενείς διαχωρίστηκαν σε δύο ομάδες: 166 οι οποίοι ήταν φορείς του αγρίου τύπου του αλληλίου και για τους τρεις υπό μελέτη πολυμορφισμούς και 47 οι οποίοι ήταν φορείς έστω και ενός μεταλλαγμένου Α-αλληλομόρφου από τους τρεις πολυμορφισμούς που εξετάσθηκαν. Ο χρόνος μεταξύ της έναρξης του μηχανικού αερισμού και της επέλευσης ΠΑ ήταν σημαντικά βραχύτερος στη δεύτερη ομάδα (log-rank: 4.416, p: 0.041). Μετά την εκδήλωση της ΠΑ, η βαρύτητα της νόσου δε διέφερε μεταξύ των δύο ομάδων. Η διέγερση προς παραγωγή TNF-α και IL-6 ήταν σημαντικά μεγαλύτερη στα μονοκύτταρα των ασθενών φορέων του Α-αλληλομόρφου. Φορεία έστω και ενός μεταλλαγμένου αλληλίου από τους τρεις υπό μελέτη πολυμορφισμούς της περιοχής του εκκινητή του γονιδίου συσχετίστηκε με βραχύτερο χρονικό διάστημα έως την επέλευση ΠΑ χωρίς όμως να φαίνεται να επηρεάζει τη βαρύτητα της νόσου. Τα ανωτέρω ευρήματα πιθανόν να σχετίζονται με τον ρόλο των πολυμορφισμών στην παραγωγή προφλεγμονωδών κυτταροκινών

Long-term efficacy of etanercept in hidradenitis suppurativa: results from an open-label phase II prospective trial

Objective: To evaluate the long-term efficacy of etanercept for the management of hidradenitis suppurativa. Methods: Analysis was based on the long-term follow-up (weeks 24-144) of 10 patients enrolled in a prospective open-label phase II study; etanercept was initially administered subcutaneously 50 mg once weekly for 12 weeks in 10 patients. Disease recurrence and the need to restart etanercept were recorded. Results: Three patients did not report any disease recurrence. A second course of treatment with etanercept was needed in seven patients. Favourable responses were found in five; two patients failed treatment. Conclusions: The first treatment course achieved long-term disease remission in almost one-third of patients. The remaining needed a second treatment course but even in that case, their disease severity at restart was significantly lower compared with baseline

Angiopoietin-2 primes infection-induced preterm delivery.

Current knowledge on the participation of angiopoietin-2 (Ang-2) in the inflammatory process and on the importance of bacterial endotoxins (LPS) in the induction of preterm delivery (PTD) led us to investigate the role of Ang-2/LPS interplay in the pathogenesis of PTD. At a first stage, Ang-2 was measured at the end of the first trimester of pregnancy in the serum of 50 women who delivered prematurely; of 88 women well-matched for age and parity who delivered full-term; and of 20 non-pregnant healthy women. Ang-2 was greater in pregnant than in non-pregnant women. The time until delivery was shorter among those with Ang-2 greater than 4 ng/ml (odds ratio for delivery until week 34; p: 0.040). To further investigate the role of Ang-2 for PTD, an experimental model of PTD induced by the intraperitoneal injection of LPS in mice was used. Ang-2 was administered intraperitoneally before LPS on day 14 of pregnancy. When Ang-2 was administered before the LPS diluent, all mice delivered full-term. However, administration of Ang-2 prior LPS accelerated further the time until delivery. Sacrifice experiments showed that the effect of Ang-2 was accompanied by decrease of the penetration of Evans Blue in the embryos and by increase of its penetration in maternal tissues. In parallel, the concentration of tumour necrosis factor-alpha in the maternal circulation, in fetal tissues and in the placentas was significantly decreased. Results indicate that Ang-2 accelerated the phenomena of PTD induced by LPS. This is related with deprivation of fetal perfusion

Role of tumor necrosis factor gene single nucleotide polymorphisms in the natural course of 2009 influenza A H1N1 virus infection

Objectives: To identify the role of single nucleotide polymorphisms (SNPs) of the tumor necrosis factor (TNF) gene in the natural course of 2009 influenza A H1N1 virus infection. Methods: Genomic DNA was isolated from 109 patients with an H1N1 infection and from 108 healthy volunteers. SNPs of the TNF gene were assessed after electrophoresis of the digested PCR products by restriction enzymes. Results: The frequency of the -238 A allele was significantly greater among patients than among controls. Viral pneumonia developed in 20 of 96 non-carriers of at least one -238 A allele (20.8%) and in seven of 13 carriers of at least one -238 A allele (53.8%, p = 0.016). Logistic regression analysis showed that the most important factors associated with the development of pneumonia were the presence of an underlying disease (p = 0.021, odds ratio (OR) 3.08) and the carriage of at least one -238 A allele (p = 0.041, OR 3.74). Gene transcripts of the TNF gene were greater among non-carriers of the -238 A allele than among carriers of the -238 A allele. Conclusions: The -238 A SNP allele of the TNF gene imposes on the course of 2009 H1N1 virus infection and is an independent risk factor for pneumonia. (C) 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved

Angiopoietin-2 Primes Infection-Induced Preterm Delivery

Current knowledge on the participation of angiopoietin-2 (Ang-2) in the inflammatory process and on the importance of bacterial endotoxins (LPS) in the induction of preterm delivery (PTD) led us to investigate the role of Ang-2/LPS interplay in the pathogenesis of PTD. At a first stage, Ang-2 was measured at the end of the first trimester of pregnancy in the serum of 50 women who delivered prematurely; of 88 women well-matched for age and parity who delivered full-term; and of 20 non-pregnant healthy women. Ang-2 was greater in pregnant than in non-pregnant women. The time until delivery was shorter among those with Ang-2 greater than 4 ng/ml (odds ratio for delivery until week 34; p: 0.040). To further investigate the role of Ang-2 for PTD, an experimental model of PTD induced by the intraperitoneal injection of LPS in mice was used. Ang-2 was administered intraperitoneally before LPS on day 14 of pregnancy. When Ang-2 was administered before the LPS diluent, all mice delivered full-term. However, administration of Ang-2 prior LPS accelerated further the time until delivery. Sacrifice experiments showed that the effect of Ang-2 was accompanied by decrease of the penetration of Evans Blue in the embryos and by increase of its penetration in maternal tissues. In parallel, the concentration of tumour necrosis factor-alpha in the maternal circulation, in fetal tissues and in the placentas was significantly decreased. Results indicate that Ang-2 accelerated the phenomena of PTD induced by LPS. This is related with deprivation of fetal perfusion