CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver

IL-17 secreting CD4 (Th17) and CD8 (Tc17) T cells have been implicated in immune-mediated liver diseases, but the molecular basis for their recruitment and positioning within the liver is unknown.

Progenitor cell recruitment during individualized high-flow, very-large-volume apheresis for autologous transplantation improves collection efficiency

BACKGROUND: Individual adaptation of processed patient's blood volume (PBV) should reduce number and/or duration of autologous peripheral blood progenitor cell (PBPC) collections. STUDY DESIGN AND METHODS: The durations of leukapheresis procedures were adapted by means of an interim analysis of harvested CD34+ cells to obtain the intended yield of CD34+ within as few and/or short as possible leukapheresis procedures. Absolute efficiency (AE; CD34+/kg body weight) and relative efficiency (RE; total CD34+ yield of single apheresis/total number of preapheresis CD34+) were calculated, assuming an intraapheresis recruitment if RE was greater than 1, and a yield prediction models for adults was generated. RESULTS: A total of 196 adults required a total of 266 PBPC collections. The median AE was 7.99 x 10(6), and the median RE was 1.76. The prediction model for AE showed a satisfactory predictive value for preapheresis CD34+ only. The prediction model for RE also showed a low predictive value (R2 = 0.36). Twenty-eight children underwent 44 PBPC collections. The median AE was 12.13 x 10(6), and the median RE was 1.62. Major complications comprised bleeding episodes related to central venous catheters (n = 4) and severe thrombocytopenia of less than 10 x 10(9) per L (n = 16). CONCLUSION: A CD34+ interim analysis is a suitable tool for individual adaptation of the duration of leukapheresis. During leukapheresis, a substantial recruitment of CD34+ was observed, resulting in a RE of greater than 1 in more than 75 percent of patients. The upper limit of processed PBV showing an intraapheresis CD34+ recruitment is higher than in a standard large-volume leukapheresis. Therefore, a reduction of individually needed PBPC collections by means of a further escalation of the processed PBV seems possible.

Effects of an alveolar recruitment maneuver on cardiovascular and respiratory parameters during total intravenous anesthesia in ponies

OBJECTIVE: To evaluate pulmonary and cardiovascular effects of a recruitment maneuver (RM) combined with positive end-expiratory pressure (PEEP) during total intravenous anesthesia in ponies. ANIMALS: 6 healthy adult Shetland ponies. PROCEDURE: After premedication with detomidine (10 microg/kg, IV), anesthesia was induced with climazolam (0.06 mg/kg, IV) and ketamine (2.2 mg/kg, IV) and maintained with a constant rate infusion of detomidine (0.024 mg/kg/h), climazolam (0.036 mg/kg/h), and ketamine (2.4 mg/kg/h). The RM was preceded by an incremental PEEP titration and followed by a decremental PEEP titration, both at a constant airway pressure difference (deltaP) of 20 cm H2O. The RM consisted of a stepwise increase in deltaP by 25, 30, and 35 cm H2O obtained by increasing peak inspiratory pressure (PIP) to 45, 50, and 55 cm H2O, while maintaining PEEP at 20 cm H2O. Hemodynamic and pulmonary variables were analyzed at every step of the PEEP titration-RM. RESULTS: During the PEEP titration-RM, there was a significant increase in PaO 2 (+12%), dynamic compliance (+ 62%), and heart rate (+17%) and a decrease in shunt (-19%) and mean arterial blood pressure (-21%) was recorded. Cardiac output remained stable. CONCLUSIONS AND CLINICAL RELEVANCE: Although baseline oxygenation was high, Pa(O2) and dynamic compliance further increased during the RM. Despite the use of high PIP and PEEP and a high tidal volume, limited cardiovascular compromise was detected. A PEEP titration-RM may be used to improve oxygenation in anesthetized ponies. During stable hemodynamic conditions, PEEP titration-RM can be performed with acceptable adverse cardiovascular effects.

Maintenance of end-expiratory recruitment with increased respiratory rate after saline-lavage lung injury

Cyclical recruitment of atelectasis with each breath is thought to contribute to ventilator-associated lung injury. Extrinsic positive end-expiratory pressure (PEEPe) can maintain alveolar recruitment at end exhalation, but PEEPe depresses cardiac output and increases overdistension. Short exhalation times can also maintain end-expiratory recruitment, but if the mechanism of this recruitment is generation of intrinsic PEEP (PEEPi), there would be little advantage compared with PEEPe. In seven New Zealand White rabbits, we compared recruitment from increased respiratory rate (RR) to recruitment from increased PEEPe after saline lavage. Rabbits were ventilated in pressure control mode with a fraction of inspired O(2) (Fi(O(2))) of 1.0, inspiratory-to-expiratory ratio of 2:1, and plateau pressure of 28 cmH(2)O, and either 1) high RR (24) and low PEEPe (3.5) or 2) low RR (7) and high PEEPe (14). We assessed cyclical lung recruitment with a fast arterial Po(2) probe, and we assessed average recruitment with blood gas data. We measured PEEPi, cardiac output, and mixed venous saturation at each ventilator setting. Recruitment achieved by increased RR and short exhalation time was nearly equivalent to recruitment achieved by increased PEEPe. The short exhalation time at increased RR, however, did not generate PEEPi. Cardiac output was increased on average 13% in the high RR group compared with the high PEEPe group (P < 0.001), and mixed venous saturation was consistently greater in the high RR group (P < 0.001). Prevention of end-expiratory derecruitment without increased end-expiratory pressure suggests that another mechanism, distinct from intrinsic PEEP, plays a role in the dynamic behavior of atelectasis.

Effect of a lung recruitment maneuver by high-frequency oscillatory ventilation in experimental acute lung injury on organ blood flow in pigs

INTRODUCTION: The objective was to study the effects of a lung recruitment procedure by stepwise increases of mean airway pressure upon organ blood flow and hemodynamics during high-frequency oscillatory ventilation (HFOV) versus pressure-controlled ventilation (PCV) in experimental lung injury. METHODS: Lung damage was induced by repeated lung lavages in seven anesthetized pigs (23-26 kg). In randomized order, HFOV and PCV were performed with a fixed sequence of mean airway pressure increases (20, 25, and 30 mbar every 30 minutes). The transpulmonary pressure, systemic hemodynamics, intracranial pressure, cerebral perfusion pressure, organ blood flow (fluorescent microspheres), arterial and mixed venous blood gases, and calculated pulmonary shunt were determined at each mean airway pressure setting. RESULTS: The transpulmonary pressure increased during lung recruitment (HFOV, from 15 +/- 3 mbar to 22 +/- 2 mbar, P < 0.05; PCV, from 15 +/- 3 mbar to 23 +/- 2 mbar, P < 0.05), and high airway pressures resulted in elevated left ventricular end-diastolic pressure (HFOV, from 3 +/- 1 mmHg to 6 +/- 3 mmHg, P < 0.05; PCV, from 2 +/- 1 mmHg to 7 +/- 3 mmHg, P < 0.05), pulmonary artery occlusion pressure (HFOV, from 12 +/- 2 mmHg to 16 +/- 2 mmHg, P < 0.05; PCV, from 13 +/- 2 mmHg to 15 +/- 2 mmHg, P < 0.05), and intracranial pressure (HFOV, from 14 +/- 2 mmHg to 16 +/- 2 mmHg, P < 0.05; PCV, from 15 +/- 3 mmHg to 17 +/- 2 mmHg, P < 0.05). Simultaneously, the mean arterial pressure (HFOV, from 89 +/- 7 mmHg to 79 +/- 9 mmHg, P < 0.05; PCV, from 91 +/- 8 mmHg to 81 +/- 8 mmHg, P < 0.05), cardiac output (HFOV, from 3.9 +/- 0.4 l/minute to 3.5 +/- 0.3 l/minute, P < 0.05; PCV, from 3.8 +/- 0.6 l/minute to 3.4 +/- 0.3 l/minute, P < 0.05), and stroke volume (HFOV, from 32 +/- 7 ml to 28 +/- 5 ml, P < 0.05; PCV, from 31 +/- 2 ml to 26 +/- 4 ml, P < 0.05) decreased. Blood flows to the heart, brain, kidneys and jejunum were maintained. Oxygenation improved and the pulmonary shunt fraction decreased below 10% (HFOV, P < 0.05; PCV, P < 0.05). We detected no differences between HFOV and PCV at comparable transpulmonary pressures. CONCLUSION: A typical recruitment procedure at the initiation of HFOV improved oxygenation but also decreased systemic hemodynamics at high transpulmonary pressures when no changes of vasoactive drugs and fluid management were performed. Blood flow to the organs was not affected during lung recruitment. These effects were independent of the ventilator mode applied.

Impaired pericyte recruitment and abnormal retinal angiogenesis as a result of angiopoietin-2 overexpression

Angiopoietin-2 (Ang2) is among the relevant growth factors induced by hypoxia and plays an important role in the initiation of retinal neovascularizations. Ang2 is also involved in incipient diabetic retinopathy, as it may cause pericyte loss. To investigate the impact of Ang2 on developmental and hypoxia-induced angiogenesis, we used a transgenic mouse line overexpressing human Ang2 in the mouse retina. Transgenic mice displayed a reduced coverage of capillaries with pericytes (-14%; p < 0.01) and a 46% increase of vascular density of the capillary network at postnatal day 10 compared to wild type mice. In the model of oxygen-induced retinopathy (OIR), Ang2 overexpression resulted in enhanced preretinal (+103%) and intraretinal neovascularization (+29%). Newly formed intraretinal vessels in OIR were also pericyte-deficient (-26%; p < 0.01). The total expression of Ang2 in transgenic mice was seven-fold, compared with wild type controls. Ang2 modulated expression of genes encoding VEGF (+65%) and Ang1 (+79%) in transgenic animals. These data suggest that Ang2 is involved in pericyte recruitment, and modulates intraretinal, and preretinal vessel formation in the eye under physiological and pathological conditions.

Recruitment limitation constrains local species richness and productivity in dry grassland

Species coexistence and local-scale species richness are limited by the availability of seeds and microsites for germination and establishment. We conducted a seed addition experiment in seminatural grassland at three sites in southern Switzerland and repeated the experiment in two successive years to evaluate various circumstances under which seed limitation and establishment success affect community functioning. A collection of 144000 seeds of 22 meadow species including grasses and forbs of local provenance was gathered, and seeds were individually sown in a density that resembled natural seed rain. The three communities were seed limited. Three years after sowing, single species varied in emergence (0–50%), survival (0–69%), and establishment rates (0–27%). One annual and 13 perennial species reached reproductive stage. Low establishment at one site and reduced growth at another site indicated stronger microsite limitation compared to the third site. Recruitment was influenced by differences in abiotic environmental conditions between sites (water availability, soil minerals) and by within-site differences in biotic interaction (competition). At the least water-limited site, sowing resulted in an increase in phytomass due to establishment of short-lived perennials in the second and third years after sowing. This increase persisted over the following two years due to establishment of longer-lived perennials. After sowing in a wetter year with higher phytomass, however, productivity did not increase, because higher intensity of competition in an early phase of establishment resulted in less vigorous plants later on. Due to the generally favorable weather conditions during this study, sowing year had a small effect on numbers of established individuals over all species. Recruitment limitation can thus constrain local-scale species richness and productivity, either by a lack of seeds or by reduced seedling growth, likely due to competition from the established vegetation.

Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment study (SPR Study): recruitment list evaluation. Study report no. 2

BACKGROUND: Accompanying the patient recruitment within the "Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment multicentre trial (SPR)", all patients with primary rhegmatogenous retinal detachment (RRD) had to be documented in a detailed recruitment list. The main goal of this analysis was to estimate the prevalence of "medium-severe" RRD (SPR Study eligible) as defined by the SPR Study inclusion criteria. In addition, the detailed anatomical situation of medium-severe RRD is investigated. METHODS: SPR Study recruitment was evaluated via a standardised questionnaire, which contained a coloured fundus drawing and information regarding possible reasons for exclusion from the SPR Study in each case. A team of three experienced vitreoretinal surgeons evaluated all fundus drawings from a 1-year period. The review led to a decision on SPR Study eligibility on the pure basis of anatomical assessment. The main outcome measures were assessment of feasible inclusion into the SPR Study by the evaluation team based on the fundus drawing and anatomical details. RESULTS: A total of 1,115 patients with RRD from 13 European centres were prospectively enrolled in the year 2000. The quality of the drawings sufficed for assessment in 1,107 cases (99.3%). Three hundred and twelve fundus drawings (28.2%) met the anatomic inclusion criteria of the SPR Study. RRD of medium severity is characterised by an average number of 2.6 (SD 2.4) retinal breaks, 5.8 (SD 2.8) clock hours of detached retina, unclear hole situation in 15.1% of cases (n=47), attached macula in 42.9% (n=134), bullous detachment in 15.1% (n=47) and vitreous haemorrhage/opacity in 7.7% (n=24). CONCLUSIONS: In the recruitment lists of the SPR Study of the year 2000, RRD of medium severity was present in nearly one third of the patients with primary RRD. These findings emphasise the clinical relevance of the SPR Study.

Effect of chest compressions only during experimental basic life support on alveolar collapse and recruitment

AIM: The importance of ventilatory support during cardiac arrest and basic life support is controversial. This experimental study used dynamic computed tomography (CT) to assess the effects of chest compressions only during cardiopulmonary resuscitation (CCO-CPR) on alveolar recruitment and haemodynamic parameters in porcine model of ventricular fibrillation. MATERIALS AND METHODS: Twelve anaesthetized pigs (26+/-1kg) were randomly assigned to one of the following groups: (1) intermittent positive pressure ventilation (IPPV) both during basic life support and advanced cardiac life support, or (2) CCO during basic life support and IPPV during advanced cardiac life support. Measurements were acquired at baseline prior to cardiac arrest, during basic life support, during advanced life support, and after return of spontaneous circulation (ROSC), as follows: dynamic CT series, arterial and central venous pressures, blood gases, and regional organ blood flow. The ventilated and atelectatic lung area was quantified from dynamic CT images. Differences between groups were analyzed using the Kruskal-Wallis test, and a p<0.05 was considered statistically significant. RESULTS: IPPV was associated with cyclic alveolar recruitment and de-recruitment. Compared with controls, the CCO-CPR group had a significantly larger mean fractional area of atelectasis (p=0.009), and significantly lower PaO(2) (p=0.002) and mean arterial pressure (p=0.023). The increase in mean atelectatic lung area observed during basic life support in the CCO-CPR group remained clinically relevant throughout the subsequent advanced cardiac life support period and following ROSC, and was associated with prolonged impaired haemodynamics. No inter-group differences in myocardial and cerebral blood flow were observed. CONCLUSION: A lack of ventilation during basic life support is associated with excessive atelectasis, arterial hypoxaemia and compromised CPR haemodynamics. Moreover, these detrimental effects remain evident even after restoration of IPPV.

Statins induce regulatory T cell recruitment via a CCL1 dependent pathway

The statins, a group of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are reported to influence a variety of immune system activities through 3-hydroxy-3-methylglutaryl coenzyme A reductase-dependent and -independent mechanisms. How statin treatment regulates immune system function in vivo nonetheless remains to be fully defined. We analyzed the immunomodulatory effects of lovastatin in a Candida albicans-induced delayed-type hypersensitivity reaction in mice. In this model, lovastatin administration reduced the acute inflammatory response elicited by C. albicans challenge. This anti-inflammatory activity of lovastatin was associated with a shift from a Th1 to a Th2 immune response, as well as an increase in the percentage of regulatory T cells at the inflammation site and in the regional draining lymph node. The lovastatin-induced increase in regulatory T cells in the inflamed skin was dependent on expression of CCL1, a chemokine that is locally up-regulated by statin administration. The anti-inflammatory effect of lovastatin was abrogated in CCL1-deficient mice. These results suggest that local regulation of chemokine expression may be an important process in statin-induced modulation of the immune system.

Visualization of alveolar recruitment in a porcine model of unilateral lung lavage using 3He-MRI

BACKGROUND: In the acute respiratory distress syndrome potentially recruitable lung volume is currently discussed. (3)He-magnetic resonance imaging ((3)He-MRI) offers the possibility to visualize alveolar recruitment directly. METHODS: With the approval of the state animal care committee, unilateral lung damage was induced in seven anesthetized pigs by saline lavage of the right lungs. The left lung served as an intraindividual control (healthy lung). Unilateral lung damage was confirmed by conventional proton MRI and spiral-CT scanning. The total aerated lung volume was determined both at a positive end-expiratory pressure (PEEP) of 0 and 10 mbar from three-dimensionally reconstructed (3)He images, both for healthy and damaged lungs. The fractional increase of aerated volume in damaged and healthy lungs, followed by a PEEP increase from 0 to 10 mbar, was compared. RESULTS: Aerated gas space was visualized with a high spatial resolution in the three-dimensionally reconstructed (3)He-MR images, and aeration defects in the lavaged lung matched the regional distribution of atelectasis in proton MRI. After recruitment and PEEP increase, the aerated volume increased significantly both in healthy lungs from 415 ml [270-445] (median [min-max]) to 481 ml [347-523] and in lavaged lungs from 264 ml [71-424] to 424 ml [129-520]. The fractional increase in lavaged lungs was significantly larger than that in healthy lungs (healthy: 17% [11-38] vs. lavage: 42% [14-90] (P=0.031). CONCLUSION: The (3)He-MRI signal might offer an experimental approach to discriminate atelectatic vs. poor aerated lung areas in a lung damage animal model. Our results confirm the presence of potential recruitable lung volume by either alveolar collapse or alveolar flooding, in accordance with previous reports by computed tomography.