Haemoglobin is released into the CNS during the breakdown of red blood cells after intracranial bleeding. Extracellular free haemoglobin is directly neurotoxic. Haemoglobin scavenging mechanisms clear haemoglobin and reduce toxicity; these mechanisms include erythrophagocytosis, haptoglobin binding of haemoglobin, haemopexin binding of haem and haem oxygenase breakdown of haem. However, the capacity of these mechanisms is limited in the CNS, and they easily become overwhelmed. Targeting of haemoglobin toxicity and scavenging is, therefore, a rational therapeutic strategy. In this Review, we summarize the neurotoxic mechanisms of extracellular haemoglobin and the peculiarities of haemoglobin scavenging pathways in the brain. Evidence for a role of haemoglobin toxicity in neurological disorders is discussed, with a focus on subarachnoid haemorrhage and intracerebral haemorrhage, and emerging treatment strategies based on the molecular pathways involved are considered. By focusing on a fundamental biological commonality between diverse neurological conditions, we aim to encourage the application of knowledge of haemoglobin toxicity and scavenging across various conditions. We also hope that the principles highlighted will stimulate research to explore the potential of the pathways discussed. Finally, we present a consensus opinion on the research priorities that will help to bring about clinical benefits.

Presence of the apolipoprotein E (APOE) 4 allele has been associated with increased incidence and faster progression of neurodegenerative diseases, poorer recovery from neurologic insult, and decreased cognitive function in the well-elderly. The specific association between APOE genotype and recovery from severe traumatic brain injury (TBI) is conflicting with many groups finding the APOE 4 allele to be associated with poorer outcome while others have found no association. The purpose of this study was to investigate the association between APOE 4 allele presence and recovery during the two years after injury from severe TBI in light of other potential covariates, such as age, race, gender, hypotension or hypoxia before hospital admission and severity of injury. APOE genotype was determined for 123 subjects with severe TBI. Glasgow outcome score (GOS) and mortality were collected at 3, 6, 12, and 24 months after injury. Results showed individuals improved over the two year period following injury and those with the 4 allele had a slower recovery rate than those without the APOE 4 allele over the two year period. We did not however find significant differences in GOS at individual time points when controlling for other covariates. Our findings suggest that APOE 4 allele presence influences recovery rate from severe TBI independent of other covariates. The findings of this study are unique in that they address not only the relationship between APOE 4 allele presence and outcome from severe TBI, but also describe differences in trajectory of recovery by APOE 4 allele presence.

This investigation was undertaken to determine whether either d-primaquine or l-primaquine has sufficient advantage over primaquine to warrant evaluation for curative activity in human volunteers infected with Plasmodium vivax. It was found: (i) that the capacities of the isomers and the racemate to cure infections with Plasmodium cynomolgi in rhesus monkeys were essentially identical; (ii) that the subacute toxicities of the isomers and racemate for this monkey were qualitatively the same, but that l-primaquine was three to five times as toxic as d-primaquine and at least twice as toxic as primaquine; and (iii) that the acute single-dose. toxicities of the isomers for mice were not only qualitatively different, but that the d isomer was at least four times as toxic as 1-primaquine. Since previous appraisals of curative activity and tolerability of 8-aminoquinolines in rhesus monkeys have correlated well with appraisals in human volunteers, attention was focused on results acquired with these test subjects. The relevant evaluations showed that d-primaquine had a therapeutic index at least twice that of primaquine. If this advantage carries over to man, problems that now complicate routine use of primaquine might be obviated. Therefore, a critical comparison of d-primaquine and primaquine in human volunteers seems indicated.

This study examined the relationship between admission serum alcohol level (ETOH) and cerebral blood flow (CBF) and outcomes in the adult traumatic brain injured (TBI) population. We hypothesized that individuals with ETOH > 100 mg/dL will have decreased blood flow on admission and poorer outcomes. Eighty subjects, age 16-65, with severe TBI (Glasgow Coma Score [GCS] 100 mg/dL at the time of admission after a TBI were associated with a decrease in global CBF. Elevated serum ETOH level at time of injury did not, however, impact outcomes.

BACKGROUND Nonpharmacologic delirium-prevention strategies are commonly used in the intensive care unit by bedside nurses. With up to 80% of intensive care unit patients becoming delirious, and lacking treatment options, prevention is key. However, with increasing nurse workloads, innovative delirium-prevention strategies such as involving the patient’s family are needed. OBJECTIVE To gain insight into opinions of patients’ families regarding active participation in delirium-prevention activities to inform specific recommendations for involving patients’ families in such activities. METHODS Purposeful sampling was used. Patients’ families were contacted to be interviewed about their opinions and attitudes on participation in nonpharmacologic delirium prevention activities while visiting the intensive care unit. An interview guide was created and used to facilitate discussion. Interviews were conducted, transcribed verbatim, and coded by 2 independent coders. Themes were identified, defined, and compared between independent coders; disagreements were resolved by the study team. RESULTS After 10 interviews were conducted, thematic saturation occurred. Three major themes emerged: (1) consistent family presence and participation in care, (2) improving ease of interactions between family and patient, and (3) delirium education for families. CONCLUSION Family members want to be involved with care and delirium prevention; however, many times they do not know what to do without the direction of a health care provider. Family members would benefit from open dialogue with the bedside nurse to increase family comfort and involvement in care.

In patients with subarachnoid hemorrhage, the expression of the E4 allele is associated with a higher risk of a negative outcome and delayed ischemia.

Health care providers and family members are supportive of the latter performing delirium-prevention activities. Family of patients in the intensive care unit may work collaboratively with nurses to reduce the incidence and duration of delirium in these patients.

Traumatic brain injury (TBI) triggers a cascade of apoptotic-related events that include BCL2 expression, a prosurvival protein in the apoptosis pathway. The purpose of this study was to use tagging single nucleotide polymorphism (tSNP) genotypes to screen the BCL2 gene to determine if genetic variability in the BCL2 gene influences outcomes in 205 patients with severe TBI. Outcomes (Glasgow Outcome Scale [GOS], Disability Rating Scale [DRS], mortality, and Neurobehavioral Rating Scale-Revised [NRS-R]) were analyzed at 3, 6, 12, and 24 months. Multivariate analysis demonstrates that there were four tSNPs of significant interest: rs17759659, rs1801018, rs7236090, and rs949037. Presence of the variant allele for rs17759659 was associated with poorer outcomes (GOS p ¼ 0.001; DRS p ¼ 0.002), higher mortality ( p ¼ 0.02; OR ¼ 4.23; CI 1.31,13.61), and worse NRS-R scores ( p ¼ 0.05). Presence of the variant allele for rs1801018 was associated with poorer outcomes (GOS p ¼ 0.02; DRS p ¼ 0.009), and mortality ( p ¼ 0.03; OR ¼ 3.86; CI 1.18,12.59). Being homozygous for the wild-type allele for rs7236090 was associated with favorable outcomes on the NRS-R ( p ¼ 0.007), while homozygosity for the variant genotype was associated with favorable outcomes on the GOS ( p ¼ 0.007) and DRS ( p ¼ 0.006). The homozygous variant for rs949037 was associated with favorable outcomes (GOS p ¼ 0.04; DRS p ¼ 0.03), and the homozygous wild-type was associated with increased mortality at 3 months ( p ¼ 0.005; OR ¼ 3.67; CI 1.08,12.49). The only finding that stood up to Bonferroni correction was rs17759659 for GOS. These data support the possibility that genetic variability for pro-survival proteins, particularly genetic variation in the BCL2 gene, impacts outcomes after severe TBI.