The zebrafish embryo is transparent and can tolerate absence of blood flow because its oxygen is delivered by diffusion rather than by the cardiovascular system. It is therefore possible to attribute cardiac failure directly to particular genes by ruling out the possibility that it is due to a secondary effect of hypoxia. We focus here on pickwickm171 (pikm171), a recessive lethal mutation discovered in a large-scale genetic screen. There are three other alleles in the pik complementation group with this phenotype (pikm242, pikm740, pikm186; ref. 3) and one allele (pikmVO62H) with additional skeletal paralysis. The pik heart develops normally but is poorly contractile from the first beat. Aside from the edema that inevitably accompanies cardiac dysfunction, development is normal during the first three days. We show by positional cloning that the 'causative' mutation is in an alternatively-spliced exon of the gene (ttn) encoding Titin. Titin is the biggest known protein and spans the half-sarcomere from Z-disc to M-line in heart and skeletal muscle. It has been proposed to provide a scaffold for the assembly of thick and thin filaments and to provide elastic recoil engendered by stretch during diastole. We found that nascent myofibrils form in pik mutants, but normal sarcomeres are absent. Mutant cells transplanted to wildtype hearts remain thin and bulge outwards as individual cell aneurysms without affecting nearby wildtype cardiomyocytes, indicating that the contractile deficiency is cell-autonomous. Absence of Titin function thus results in blockage of sarcomere assembly and causes a functional disorder resembling human dilated cardiomyopathies, one form of which is described in another paper in this issue.

J. Neurochem. (2010) 113, 637–648. Abstract Traumatic brain injury is a devastating neurological injury associated with significant morbidity and mortality. Medical therapies to limit cerebral edema, a cause of increased intracranial hypertension and poor clinical outcome, are largely ineffective, emphasizing the need for novel therapeutic approaches. In the present study, pre‐treatment with curcumin (75, 150 mg/kg) or 30 min post‐treatment with 300 mg/kg significantly reduced brain water content and improved neurological outcome following a moderate controlled cortical impact in mice. The protective effect of curcumin was associated with a significant attenuation in the acute pericontusional expression of interleukin‐1β, a pro‐inflammatory cytokine, after injury. Curcumin also reversed the induction of aquaporin‐4, an astrocytic water channel implicated in the development of cellular edema following head trauma. Notably, curcumin blocked IL‐1β‐induced aquaporin‐4 expression in cultured astrocytes, an effect mediated, at least in part, by reduced activation of the p50 and p65 subunits of nuclear factor κB. Consistent with this notion, curcumin preferentially attenuated phosphorylated p65 immunoreactivity in pericontusional astrocytes and decreased the expression of glial fibrillary acidic protein, a reactive astrocyte marker. As a whole, these data suggest clinically achievable concentrations of curcumin reduce glial activation and cerebral edema following neurotrauma, a finding which warrants further investigation.

Long-term outcome after surgery is a new safety concern in perioperative care. We are faced with enormous challenges in healthcare and research. As providers, tailoring an anesthetic plan to patients' needs will become increasingly critical, and immunology should help in this pursuit.

Objective Intracerebral hemorrhage (ICH) is associated with significant patient morbidity and mortality. Acute hematoma enlargement is an important predictor of neurological injury and poor clinical prognosis; however, neurosurgical clot evacuation may not be feasible in all patients and treatment options remain largely supportive. Thus, novel therapeutic approaches to promote hematoma resolution are needed. In the present study, we investigated whether the curry spice, curcumin, limited neurovascular injury following ICH in mice. Methods ICH was induced in adult male CD-1 mice by the intracerebral administration of collagenase or autologous blood. Clinically-relevant doses of curcumin (75–300 mg/kg) were administered up to 6 hours after ICH and hematoma volume, inflammatory gene expression, blood-brain barrier permeability, and brain edema were assessed over the first 72 hours. Neurological assessments were performed to correlate neurovascular protection with functional outcomes. Results Curcumin increased hematoma resolution at 72 hours post-ICH. This effect was associated with a significant reduction in the expression of the pro-inflammatory mediators, tumor necrosis factor-α, interleukin-6, and interleukin-1β. Curcumin also reduced disruption of the blood-brain barrier and attenuated the formation of vasogenic edema following ICH. Consistent with the reduction in neuroinflammation and neurovascular injury, curcumin significantly improved neurological outcome scores after ICH. Conclusion Curcumin promoted hematoma resolution and limited neurological injury following ICH. These data may indicate clinical utility for curcumin as an adjunct therapy to reduce brain injury and improve patient outcome.