Glycaemic control for patients with severe acute brain injury: Protocol for a systematic review

Background

Hyperglycaemia is common in patients with acute brain injury admitted to an intensive care unit (ICU). Many studies have found associations between development of hyperglycaemia and increased mortality in hospitalised patients. However, the optimal target for blood glucose control is unknown. We want to conduct a systematic review with meta-analysis and trial sequential analysis to explore the beneficial and harmful effects of restrictive versus liberal glucose control on patient outcomes in adults with severe acute brain injury.

Methods

We will systematically search medical databases including CENTRAL, Embase, MEDLINE and trial registries. We will search the following websites for ongoing or unpublished trials: http://www.controlled-trials.com/ , http://www.clinicaltrials.gov/ , www.eudraCT.com , http://centerwatch.com/ , The Cochrane Library's CENTRAL, PubMed, EMBASE, Science Citation Index Expanded and CINAHL. Two authors will independently review and select trials and extract data. We will include randomised trials comparing levels of glucose control in our analyses and observational studies will be included to address potential harms. The primary outcomes are defined as all-cause mortality, functional outcome and health-related quality of life. Secondary outcomes include serious adverse events including hypoglycaemia, length of ICU stay and duration of mechanical ventilation, and explorative outcomes including intracranial pressure and infection. Trial Sequential Analysis will be used to investigate the risk of type I error due to repetitive testing and to further explore imprecision. Quality of trials will be evaluated using the Cochrane Risk of Bias tool, and quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.

Discussion

The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice.     

Drug related hospital admissions

Summary As part of a high-intensity monitoring study of drug events as the cause of admission to departments of internal medicine, the effect of an educational intervention programme was studied. Two departments were included, one specialising in geriatrics and one that received patients by non-selected referral. The series consisted of 607 consecutive admissions studied before and 703 after the intervention. The drug events considered were adverse drug reactions and dose-related therapeutic failures, mainly due to non-compliance.A modest, statistically non-significant decrease in drug related hospital admissions (DRH) was seen, from 14% before to 13% after the intervention period. However, DRHs classified as definitely avoidable showed the significant decrease of 83%.There was no apparent relationship between the topics selected for the intervention programme and changes in the pattern of DRHs. No relationship between alterations in sales data and hospital admissions caused by a given drug could be demonstrated. A blinded external evaluation of case abstracts did not disclose any significant shift in the investigators' assessments.The intervention may have had an non-specific effect on avoidable DRHs.     

Fatal intoxications in Denmark following intake of morphine from opium poppies

Summary In Denmark it is legal to grow opium poppies for the production of poppy seeds and until 1986 for decoration purposes, too. Danish poppy capsules contain 0.3–5 mg morphine per capsule and the content of morphine in opium exuded from the capsules may amount to 24%. This has resulted in misuse as both fresh and dried poppy capsules have been used for the production of opium tea. During the period 1982–1985, seven casualties occurred among drug addicts in Denmark which were solely or partly caused by these opium poppies.     

Peanut-induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry

Background

Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%–1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents.

Methods

Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre.

Results

3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004).

Conclusions

The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.

     

CD40-mediated lymphotoxin α expression in human B cells is tyrosine kinase dependent

The cytokine lymphotoxin (LT)α is known to play a role in B cell activation. As the engagement of the B cell antigen CD40 is known to lead to B cell proliferation and differentiation, we studied LTα expression in human B cells after CD40 ligation. We demonstrate that anti-CD40 monoclonal antibody (mAb) induces strong LTα mRNA and surface expression in human tonsil B cells. Induction of LTα mRNA and surface expression by CD40 ligation is inhibited by the protein tyrosine kinase (PTK) inhibitors herbimycin and genistein in a dose-dependent manner. The protein kinase C (PKC)-specific inhibitors sphingosine and bisindolylmaleimide caused negligible inhibition of anti-CD40-induced LTα mRNA and surface expression. No inhibition is observed with the protein kinase (PKA) inhibitors H89 and HA1004. Cross-linking of the transmembrane phosphatase CD45 to CD40 by using goat-anti-mouse F(ab')₂ fragments strongly inhibits CD40-mediated LTα expression in human B cells, confirming the role of PTK activation in CD40-mediated induction of LTα expression. Inhibitors of the serine/threonine protein phosphatases PP1 and PP2A, okadaic acid and calyculin induce LTα mRNA expression. In contrast, cyclosporin A, an inhibitor of the serine/threonine phosphatase calcineurin has no effect on anti-CD40-induced LTα expression. These results suggest that induction of LTα expression in B cells following engagement of CD40 involves activation of protein tyrosine kinases.     

Retinoic acid inhibits CD40 plus IL-4 mediated IgE production through alterations of sCD23, sCD54 and IL-6 production

Background: All-trans retinoic acid (ATRA) inhibits IgE synthesis from anti-CD40 plus IL-4 stimulated human B lymphocytes.Objective: To study the underlying mechanisms, we examined here molecules which are known to have an impact on IgE production, namely CD23, CD54 and IL-6.Methods: Human anti-CD40 plus IL-4 stimulated B cells were cultured in the absence and presence of ATRA (10^–6–10^–10 M). ELISAs were performed to determine soluble (s) CD23 and sCD54, IL-6 and IgE-levels. CD23 and CD54 surface expression were determined by flow cytometric analysis. Semiquantitative-RT-PCR was employed to analyse IL-6, CD23 and CD54 mRNA expression.Results: ATRA induced a dose-dependent increase of percent CD23 (3.4 fold) or CD54 (1.6 fold) positive B cells. At the mRNA level, this was reflected by a modest increase of CD54 mRNA (46.5 ± 15.8%) only. By contrast, levels of sCD54 were decreased dose-dependently in the presence of ATRA (56.6 ± 7.6%). Cytokine analysis showed that IL-6 secretion was significantly inhibited by ATRA (53.6 ± 0.6%) and also IL-6 mRNA synthesis was reduced (66.3 ± 11.6%). The observed inhibition of IgE production mediated by ATRA was significantly reversed to 90.5 ± 12% by the addition of 100 pg/mL recombinant IL-6.Conclusions: ATRA interferes through several pathways with the anti-CD40 plus IL-4 mediated B cell activation, namely IL-6, CD23 and CD54.Received 8 June 2004; returned for revision 19 July 2004; accepted by M. J. Parnham 5 November 2004     

Effects of retinoids on in vitro and in vivo IgE production

BACKGROUND: Retinoids modulate the growth and number of different cell types, including B cells. We could previously show that retinoic acid (RA) strongly inhibits CD40 + IL-4-mediated IgE production in vitro. The aim of the present study was to extend these findings regarding the potential use of retinoids for the treatment of allergic diseases. METHODS: In vitro IgE production was studied in anti-CD40 + IL-4-stimulated peripheral blood mononuclear cells (PBMC) from allergic donors in the presence of 10(-15)-10(-5) M all-trans and 13-cis RA and in ovalbumin (OVA)-sensitized BALB/c mice treated with RA (20 mg/kg) before and during sensitization. IgE and IgG1 levels were determined in the sera of the mice at day 21 after 2 injections (days 1 and 8) of aluminum hydroxide-absorbed OVA. RESULTS: All-trans and 13-cis RA inhibited in vitro IgE production from PBMC in a dose-dependent manner, but were more efficient in atopic dermatitis patients with low total serum IgE levels (< 400 kU/ml), maximal inhibition for all-trans RA at 10(-7) M (87%) and for 13-cis RA at 10(-5) M (96%) compared to patients with high serum IgE levels (>2,000 kU/ml), maximal inhibition for both all-trans and 13-cis RA at 10(-5) M (53 and 39%, respectively). In contrast, the in vivo data from OVA-sensitized mice revealed comparable total IgE and IgG1 levels in control versus all-trans RA or CD336-treated groups, specific IgE was even higher in the CD336-treated group (n = 10, 2,814 ng/ml), and was comparable in mice treated with OVA alone or with additional all-trans RA (n = 10, 1,447 and 1,354 ng/ml, respectively). CONCLUSIONS: These results indicate that the efficacy of retinoids to inhibit IgE production in vitro depends on the frequency of switched cells in the peripheral blood and that in an in vivo model using OVA-sensitized mice, retinoids fail to inhibit IgE production.     

Reverse transcriptase polymerase chain reaction as a reliable method to detect epidermal growth factor receptor exon 2-7 gene deletion in human glioblastomas

Epidermal growth factor receptor (EGFR) gene amplification has been reported to occur in diverse carcinoma types such as lung, ovarian, and breast carcinomas and in glioblastomas. A 801-bp in-frame deletion close to the aminoterminus of the receptor protein has been found to occur more or less frequently within at least three of these tumor entities. We studied EGFR gene alterations using the polymerase chain reaction and EGFR gene expression of 65 astrocytic tumors (51 glioblastomas World Health Organization [WHO] IV, five anaplastic astrocytomas WHO III, and nine astrocytomas WHO II). EGFR gene amplification, as determined by Southern blotting using a full-length cDNA probe, was observed in 22 of 51 glioblastomas (43%) but in none of the grade II astrocytomas. Two of five anaplastic astrocytomas at WHO III showed a considerable degree of EGFR amplification but, according to the neuroradiological data, these two tumors had to be considered as glioblastomas. The most frequently found genetic alteration was the 801-bp deletion near the receptor aminoterminus comprising a complete loss of exon 2 to exon 7 (del2-7). We showed that RT-PCR is superior to Southern blot analysis in detection of this type of deletion and can be assigned to 9 of 38 (24%) glioblastomas examined. Expression of a EGF receptor protein was enhanced in most of the tumors with gene amplification. However, 5 of 18 tumors that express a receptor protein in the absence of EGFR gene amplification also showed elevated levels of EGFR gene expression. In addition to the full-length receptor protein, a signal in the 140-kDa range was observed in 17 of 35 glioblastomas (49%). This fragment may correspond to the truncated de12-7 receptor protein or might be due to proteolysis of the full-length receptor protein.     

Opposing effects on immune function and skin barrier regulation by the proteasome inhibitor bortezomib in an allergen‐induced eczema model

Proteasome inhibition (PI) has been reported to interfere with antibody‐driven autoimmune diseases. The impact of PI on the allergic immune response and on skin diseases like atopic dermatitis (AD) has not been thoroughly explored, however. Here, we examined whether the PI bortezomib interferes with the allergic immune response and the severity of AD by using an established mouse model of allergen‐driven dermatitis, to which bortezomib was applied after the establishment of systemic sensitization to ovalbumin. The treatment indeed resulted in a remarkable decrease in total and allergen‐specific plasma cells/antibody‐secreting cells, as evidenced by flow cytometry and ELISpot, respectively. This was accompanied by rapid reductions in serum antibody titres, including a prominent reduction of the IgE isotype. CD4+ and CD8+ cells were greatly diminished in lesional skin on immunohistological staining. The impressive effects at the level of immune modulation did not result in any improvement in the eczema, however. Following up on this unexpected result, we found that the skin itself was susceptible to bortezomib, by which it was instructed to lower the expression of critical skin barrier genes, especially transglutaminase‐1 and filaggrin. Together, bortezomib eliminates plasma cells and decreases immunoglobulin responses, including allergenic IgE. Although anti‐inflammatory effects are detectable in the skin, counter‐regulatory effects from PI on resident skin cells likely undermine improvement in the eczema. These results caution against the therapeutic use of bortezomib for inflammatory skin disorders, which are characterized by inherently impaired barrier function, especially AD.