Lipopolysaccharide delays demyelination and promotes oligodendrocyte precursor proliferation in the central nervous system

Systemic infection can influence the course in many diseases of the central nervous system (CNS) such as multiple sclerosis (MS), yet the relationship between infection outside the CNS and potential damage and/or protection within the CNS is still not understood. Activation of microglia is a characteristic feature of most CNS autoimmune disorders, including MS, and both protective and degenerative functions of microglia have been proposed. Hence, we analyzed the effects of a systemic inflammatory reaction induced by peripheral treatment with lipopolysaccharide (LPS) on microglial reaction and cuprizone induced de- and remyelination. We found that LPS administration delayed demyelination, which was linked with inhibition of microglial proliferation and reduced numbers of activated microglia. The phenotype of microglia changed as an increase of Toll-like receptor 4 was found. During remyelination, LPS treatment delayed the onset of myelin protein re-expression, but later there was a beneficial effect via an increase of proliferating oligodendrocyte precursor cells (OPC) and mature oligodendrocytes. Moreover, the expression of ciliary neurotrophic factor was increased in response to LPS, a growth factor known to mediate OPC proliferation. Additional experiments showed that the time window to induce LPS effects was limited and associated with the presence of microglia. In conclusion, LPS delayed demyelination and caused beneficial effects on remyelination via increasing the proliferation of OPC. These differences seem to be an effect of LPS induced microglial modulation and indicate that exposure to certain infectious agents within a given time window may be beneficial in promoting tissue repair.     

Does rapid enteral feeding increase intestinal morbidity in very low birth weight infants? A retrospective analysis

Purpose: To investigate the association of a standardized rapid enteral feeding strategy (established in 2011 in our unit) with intestinal morbidity in very low birth weight (VLBW) infants.

Methods: A total of 301 inborn VLBW infants were included in this single-centre retrospective cohort study. We compared the incidence of intestinal morbidity (defined as necrotizing enterocolitis or intestinal perforation) in slowly enterally fed infants in 2008–2010 (10?ml/kg/day increase of milk feeds) to a corresponding cohort of rapidly enterally fed infants in 2011–2013 (20?ml/kg/day increase of milk feeds). Univariate and multivariable logistic and linear regression analyses, respectively, were performed to control for confounding variables.

Results: Both groups were similar regarding baseline demographic and perinatal characteristics. In univariate modeling, intestinal morbidity did not significantly differ between the two groups (p?=?0.25), neither did all-cause mortality nor incidence of late onset sepsis in multivariable modeling. In contrast, length of hospital stay (HS) and duration of parenteral nutrition (PEN) were significantly shorter in the rapid group (HS: ?8.35 days, p?=?0.012 and PEN: ?7.13 days, p?Conclusions: Implementation of a more rapid enteral feeding regime is safe in VLBW infants and may significantly shorten length of HS and PEN in this cohort.     

Magnetic resonance imaging identifies early effects of sunitinib treatment in human melanoma xenografts

Background

Antiangiogenic treatment may change the tumor microenvironment and hence influence the effect of conventional therapies. The potential of diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced MRI (DCE-MRI) in assessing microenvironmental effects of sunitinib treatment was investigated in this preclinical study.

Methods

Sunitinib-treated and untreated A-07 tumors were subjected to DW-MRI and DCE-MRI, and parametric images of ADC and K^trans were produced. Microvascular density, hypoxic fraction, and necrotic fraction were assessed from immunohistochemical preparations, and tumor interstitial fluid pressure (IFP) was assessed with probe measurement.

Results

Sunitinib-treated tumors showed reduced microvascular density, increased hypoxic fraction, increased necrotic fraction, increased ADC, and reduced K^trans, but did not differ from untreated tumors in growth rate and IFP.

Conclusions

Sunitinib treatment affected the tumor microenvironment without affecting tumor size. DW-MRI and DCE-MRI were sensitive to the sunitinib-induced changes in the tumor microenvironment.

     

Safety,Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers

AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This study reports the initial, first‐in‐man, single and repeat dose‐escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once‐daily treatment. Plasma exposure suggested dose‐proportional pharmacokinetics and dose‐related effects on 24‐hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (osteocalcin, TRAP5b, DHEA‐S and 4β‐OH‐cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus–pituitary–adrenal (HPA) effects appeared to be marginally greater in the Japanese‐ versus the Caucasian‐dominant study population. AZD5423, inhaled via nebulization, can be used in healthy individuals at doses of at least 300 μg for 2 weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit–risk ratio may be improved relative to conventional inhaled steroids.     

How do carious root lesions develop after the end of professional preventive measures?—Preliminary findings of a randomized clinical trial

Odontology - Aim of this randomized clinical trial was to assess the development of root caries lesions with and without (adjuvant) professional prevention treatment over 24 months. 20...     

Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis

Introduction  

Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding. Because of safety concerns, aprotinin was withdrawn from the market in 2007. Since then, tranexamic acid (TXA) has become the antifibrinolytic treatment of choice in many heart centers. The safety profile of TXA has not been extensively studied. Therefore, the aim of this study was to evaluate safety and efficiency of TXA compared with aprotinin in cardiac surgery.     

Protective effect of resin adsorption on septic plasma-induced tubular injury

Introduction

Recent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation.

Methods

We performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality.

Results

One hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury.

Conclusions

Mechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation.

Trial registration

ISRCTN82533884     

Postoperative vasopressin and copeptin levels in noncardiac surgery patients: a prospective controlled trial

Further information on the endogenous arginine vasopressin (AVP) response in patients with postoperative systemic inflammatory response syndrome (SIRS) and vasodilatory shock would provide more insight into the pathophysiology of SIRS-associated cardiovascular failure and help indicate AVP therapy. Patients after uncomplicated abdominal surgery without SIRS (n = 10), critically ill patients after noncardiac surgery with SIRS (n = 9), and patients with SIRS plus vasodilatory shock (n = 22) were included in this prospective trial. Plasma AVP (radioimmunoassay) and copeptin (immunoluminometric assay) concentrations together with clinical parameters were documented daily during the first 7 days postoperative. The AVP response significantly differed between the three groups. Patients without SIRS had lower AVP concentrations than SIRS patients with (P = 0.001) or without shock (P = 0.003). Patients with SIRS and shock had higher AVP levels than patients with SIRS alone (P < 0.001). Arginine vasopressin decreased over time (P = 0.007) in all groups. At day 28, nonsurvivors had higher AVP levels than did survivors (P < 0.001). In SIRS patients without shock, serum osmolarity was indirectly associated with AVP levels, whereas mean arterial blood pressure and serum osmolarity were associated with AVP in SIRS patients with shock. Arginine vasopressin and copeptin correlated significantly with each other (P < 0.001; r = 0.76). In patients without hemofiltration, copeptin levels predicted 28-day mortality with high sensitivity and specificity. The postoperative AVP response in noncardiac surgery patients seems well maintained. The possibility that AVP plays a contributory role in the failure to restore vascular tone in patients with vasodilatory shock cannot be excluded but seems less important than in septic or postcardiotomy shock.     

Unsuspected rejection episodes on routine surveillance endomyocardial biopsy post-heart transplant in paediatric patients

The use of routine endomyocardial biopsies post-heart transplant in children remains controversial. It is generally accepted as the gold standard for detecting rejection, but details of the surveillance protocol, such as number and timing of biopsies, remain uncertain, with suggestions that recent advances in immunosuppressant therapy have obviated the need to perform surveillance biopsies. We retrospectively analysed results of endomyocardial biopsies performed in our unit since the introduction of a policy of three routine biopsies in the first six months post-transplantation. We specifically examined only routine surveillance biopsies in order to determine whether clinically unsuspected cases of rejection were identified. Between January 2002 and April 2006, 63 children completed three biopsies in the first six months post-transplant. Of 189 surveillance endomyocardial biopsies, 19 (10%) patients showed significant, grade III or above, rejection. One patient had two episodes of rejection. In only one case the child was haemodynamically unstable, four cases were mildly unwell, and 14 of 19 (74%) cases demonstrated no cardiac symptoms. Four of eight cases treated with sirolimus for some part of their post-transplant course had an episode of rejection and of 54 tacrolimus-treated patients, 13 had an episode of asymptomatic rejection detected. One of the seven infants had significant episode of rejection. Asymptomatic, clinically significant rejection is detected in about 10% of biopsies overall using a three-biopsy protocol in the first six months after paediatric heart transplantation, and occurs in 24% of tacrolimus-treated patients. More frequent surveillance appears needed in children treated with sirolimus, but less frequent surveillance may be possible in infants.