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 We will search the following websites for ongoing or unpublished trials: http://www.controlled-trials.com/ , http://www.clinicaltrials.gov/ , www.eudraCT.com , http://centerwatch.com/ , The Cochrane Library's CENTRAL,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.     

Specification of the Dose to Organs at Risk in External Beam Radiotherapy

Reporting of the clinical relevant dose to organs at risk (OR) and other normal tissues is crucial in trials and protocols where the aim is to assess late complications and to increase the therapeutic ratio for external beam radiotherapy. The dose distribution in normal tissues and ORs are, however, most often heterogeneous, at least when more than two opposing beams are applied. To decide the most clinical relevant dose with respect to late occurring complications is therefore not a straight forward problem. In this work we discuss what parameters characterise the dose-volume-histogram (DVH) best by calculating normal tissue complication probabilities (NTCPs) by using the Lyman model and various sets of statistical parameters drawn out from the DVHs. These NTCPs are compared to NTCPs calculated from the full DVHs, when the sets of parameters are evaluated. Our calculations indicate that the NTCP based on the Lyman model is best correlated to the D_max value, for serially organised tissues such as the spinal cord. For organs, described largely as tissues organised in parallel, the D_median or D_mean of the DVH may be applied. Our calculations reveal that D_mean is the parameter of choice when D_meclian is quite small, but when the two parameters approach each other, D_mediarl will be a better choice, using a unity volume fraction. For ORs characterised by a mixed serial and parallel functional structure, as the heart, neither D_max, D_median, nor D_mi,_an may predict the actual NTCP.     

Clusterin expression in cutaneous CD30-positive lymphoproliferative disorders and their histologic simulants

Background:  Clusterin is a ubiquitous 80 kDa heterodimeric glycoprotein previously shown to be expressed on tumor cells of systemic and, to a lesser extent, primary cutaneous anaplastic large cell lymphoma (PC-ALCL). Lymphomatoid papulosis (LyP), an important differential diagnosis of ALCL, has been studied for clusterin expression in only a small number of cases. The aim of this study was to compare clusterin immunostaining patterns in LyP and other cutaneous histologic simulants with those of PC-ALCL.
Methods:  Formalin-fixed, paraffin-embedded sections of PC-ALCL (6), LyP (20), mycosis fungoides with large cell transformation (MF-LCT, 12), pityriasis lichenoides et varioliformis acuta (PLEVA, 12), arthropod bite reaction (ABR, 12) and lymphomatoid reactions (LR, 9) were immunostained for clusterin and evaluated for staining pattern and distribution. All diagnoses were made with clinicopathologic correlation.
Results:  Characteristic dot-like Golgi staining was identified in 10/20 LyP (50%), 4/6 PC-ALCL (67%) and 9/12 MF-LCT (75%). Two of 12 PLEVA (17%), 1 of 12 ABR (8%) and 2 of 8 LR (25%) had lymphocytes (< 25%) with diffuse cytoplasmic staining. Dermal dendritic cells stained strongly for clusterin. High background staining occurred in some cases.
Conclusion:  Clusterin immunostaining does not reliably distinguish between LyP, PC-ALCL or MF-LCT, but could distinguish LyP from its reactive histologic simulants.     

Chemical differences in lipopolysaccharides from Actinobacillus (Haemophilus) actinomycetemcomitans and Haemophilus aphrophilus: clues to differences in periodontopathogenic potential and taxonomic distinction.

While Actinobacillus actinomycetemcomitans has been associated with rapidly progressive periodontal destruction in man, the closely related Haemophilus aphrophilus has not been related to periodontal disease. This may be due to differences in composition and structure of the lipopolysaccharides (LPS) of these dental-plaque bacteria, since LPS probably exerts a series of detrimental effects on the periodontium. LPS was prepared by the phenol-water procedure from the type strains of A. actinomycetemcomitans and H. aphrophilus, purified by hexane extraction and ultracentrifugation, and analyzed with gas chromatography and gas chromatography-mass spectrometry. While the lipid content of LPS from A. actinomycetemcomitans constituted 35.4%, it was only 18.4% in H. aphrophilus: 3-hydroxytetradecanoic and tetradecanoic acids were 21.1 and 14.3% in A. actinomycetemcomitans and 10.9 and 7.5% in H. aphrophilus. There were qualitative and quantitative differences in the polysaccharide portions of their LPS. A actinomycetemcomitans contained both D-glycero-D-mannoheptose and L-glycero-D-mannoheptose (7.8 and 11.3%); H. aphrophilus contained only L-glycero-D-mannoheptose (17.4%). The rhamnose, fucose, galactose, glucose, and glucosamine/galactosamine contents in A. actinomycetemcomitans were 2.6, 5.2, 10.1, 22.4, and 5.2%, respectively; in H. aphrophilus, they were 2.1, 2.6, 19.4, 36.4, and 3.7%. Chemical differences in LPS from A. actinomycetemcomitans and H. aphrophilus may contribute to the divergence in periodontopathogenic potential of these organisms and help taxonomic differentiation.     

Diagnostic tests in Raynaud''s phenomena in workers exposed to vibration: a comparative study.

Four objective tests to evaluate Raynaud's phenomena (RP) in workers exposed to handarm vibrations were applied on 23 exposed men with RP (vibration induced white finger 18, primary Raynaud's phenomenon 5), 56 exposed men without RP, and 15 male controls. Finger systolic blood pressure was measured by a cuff and strain gauge technique after combined body cooling and finger cooling during five minute ischaemia to 30 degrees, 15 degrees, and 6 degrees C. An attack of RP was detected as a zero pressure, FSP(0) test, whereas a pressure, reduced to a value below the normal 95% confidence limit at 6 degrees C, was regarded as an abnormal response, FSP(A) test. A hand cooling, preceded by 30 minute body precooling, was performed in water at 10 degrees C during five minute ischaemia. The finger colours after hand cooling were evaluated by a directly visual inspection, FCV test, and by a blind assessment of slides of the photographed hand, FCS test. A medical interview was used as a method of reference. The sensitivity did not differ significantly between FSP(0) (74%), FCS (61%), and FCV (57%) (p greater than 0.10). FSP(A) had a significantly higher sensitivity (96%) and lower specificity (64%) than those of FCV and FCS (p less than 0.0005) and of FSP(0) (p less than 0.05). Six of the seven men with a false positive FSP(0) had a positive FCV or FCS, and the seventh had a history of previously active RP. The six false negative FSP(0) test results did not correspond significantly to milder cases of RP (p greater than 0.20). The results indicate that a finger colour test may be as valuable as a FSP(0) test for diagnostic purposes. FSP(A) only indicates if a cold response is exaggerated and does not diagnose RP. The pressure measurements may further be of guidance in evaluating preventive measures and effects of treatments for RP.     

Stereoselective S-oxygenation of 2-aryl-1,3-dithiolanes by the flavin-containing and cytochrome P-450 monooxygenases

The reaction of NalO4, highly purified flavin-containing monooxygenase (EC 1.14.13.8), and microsomes from hog liver with 2-aryl-1,3-dithiolanes and 2-aryl-1,3-dithiolane S-oxides was investigated. The initial rates determined for the microsome- and purified flavin-containing monooxygenase-catalyzed rate of S-oxidation of para-substituted 2-aryl-1,3-dithiolanes were similar, demonstrating that S-oxidation of these substrates occurred with similar velocities at saturating concentrations of substrate and, at least for the first S-oxidation, the reaction was insensitive to the nature of the para-substituent. The diastereoselectivity of S-oxygenation of 2-aryl-1,3-dithiolanes was determined and, in general, a marked preference for addition of oxygen to the sulfide sulfur atom was observed to occur trans to the aryl groups. In all cases examined, enantioselective enzymatic S-oxidation was observed. For S-oxide formation in microsomes, the data provided evidence for a minor role of cytochrome P-450 in S-oxide formation, but the flavin-containing monooxygenase was mainly responsible for production of S-oxide. In contrast to previous reports, the enantioselectivity of S-oxidation catalyzed by highly purified cytochrome P-450IIB-1 and cytochrome P-450IIB-10 was not always opposite to that catalyzed by hog liver flavin-containing monooxygenase activity. 2-Aryl-1,3-dithiolane S-oxides were also oxidized a second time by NalO4, microsomes, or highly purified flavin-containing monooxygenase from hog liver but not cytochrome P-450IIB-1 or P-450IIB-10. The rate of the second oxidation was 10-15-fold slower than the corresponding first S-oxidation and S,S'-dioxide formation was markedly dependent on the electronic nature of the para-substituent (Hammett correlation rho value of -1.3 and -1.1 for microsomes and highly purified flavin-containing monooxygenase from hog liver, respectively). The large dependence of the rate of S,S'-dioxide formation on the nature of the para-substituent demonstrates that velocity values at saturating concentrations of S-oxide were not the same for all 2-aryl-1,3-dithiolane S-oxides and suggests that the chemical nature of the 2-aryl-1,3-dithiolane S-oxide contributes to the rate-determining step of this enzymatic reaction.