Predictive value of intrathecal interleukin-6 for ventriculostomy-related Infection.

BACKGROUND AND STUDY AIM: Early diagnosis of ventriculostomy-related infection (VRI) is crucial for the early treatment and course of this disease. In neurosurgical patients the diagnostic criteria are equivocal, mostly because of bloodstained cerebrospinal fluid (CSF). The predictive value, sensitivity and specificity of intrathecal interleukin-6 (IL-6 (CSF)) has been proven for VRI compared with classical diagnostic CSF parameters, i.e. cell countCSF (CC (CSF)) and total protein (CSF). PATIENTS AND METHODS: We prospectively analyzed the daily clinical data and CSF samples of 75 neurosurgical patients with an external ventricular drainage (EVD), which had been inserted predominantly because of poor-grade subarachnoid hemorrhage (SAH). The intrathecal interleukin-6 concentrations (IL-6 (CSF)) were correlated with the clinical course and VRI incidence, as diagnosed by the classical VRI criteria (CC (CSF), total protein (CSF), clinical symptoms). RESULTS: Based on classical criteria, bacterial meningitis occurred in 26.7% of patients. Patients with VRI manifested significantly (p<0.001) higher median values of IL-6 (CSF) (up to 2,000-fold increase) the day before (day -1) infection was diagnosed by conventional parameters. Using a cut-off value of IL-6 (CSF)>or=2,700 pg/ml [4,050 pg/ml after WHO standardization] on day -1, the relative risk for VRI was 6.09 (95% CI: 2.62-14.18%). A predictive value of IL-6 (CSF)>or=2,700 pg/ml [4,050 pg/ml] for VRI was calculated of 89% (95% CI: 79.6-98.0%), a sensitivity of 73.7% and a specificity of 91.4%. The amount of intrathecal blood was an independent risk factor for VRI occurrence, whereas the mean duration of EVD in place showed no impact on the rate of infection. CONCLUSION: Our data indicate that IL-6 (CSF) is a reliable marker for predicting VRI prior to clinically manifest meningitis, one day earlier than the common diagnostic criteria of CSF infection (CC (CSF), total protein (CSF), clinical symptoms).

Hormone-triggered conformational changes within the insulin-receptor ectodomain: requirement for transmembrane anchors.

Interaction between two alphabeta half-receptors within the (alphabeta)(2) holoreceptor complex is required for insulin binding with high affinity and for insulin-triggered changes of size and shape. To understand the underlying structure-function relationship, two truncated receptor constructs have been characterized. Reduction in the Stokes radius and increase in the sedimentation coefficient, which are characteristic for wild-type receptors, were entirely lacking for the recombinant human insulin receptor (HIR) ectodomain (HIR-ED). Stokes radii of about 5.8 nm and sedimentation coefficients of 10.2 S were found for both insulin-bound and free HIR-EDs. However, attaching the membrane anchors to the ectodomain, as with the recombinant membrane-anchored ectodomain (HIR-MAED) construct, was sufficient to restore not only high-affinity hormone binding but also the marked insulin-inducible alterations in hydrodynamic properties. The Stokes radii of HIR-MAED complexes, as assessed by non-denaturing PAGE, decreased upon insulin binding from 9.5 nm to 7.9 nm. In parallel, the sedimentation coefficient was increased from 9.0 S to 9.8 S. CD and fluorescence spectroscopy of HIR-MAED revealed only minor insulin-induced changes in the secondary structure. Similarity with wild-type receptors has also been demonstrated by the differential insertion of insulin-bound and free HIR-MAED complexes into artificial bilayer membranes of Triton X-114. The results are consistent with a model of receptor function that ensures a global insulin-triggered reorientation of subdomains within the ectodomain moieties while the secondary structure is essentially retained. For the rearrangement of such subdomains, the transmembrane anchors confer essential structural constraints on the receptor ectodomain.