BackgroundTraumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment. Despite promising outcomes from many preclinical studies, clinical evaluations have failed to identify effective pharmacological therapies, suggesting that the translational potential of preclinical models may require improvement. Rodents continue to be the most widely used species for preclinical TBI research. As most human TBIs result from impact to an intact skull, closed head injury (CHI) models are highly relevant, however, traditional CHI models suffer from extensive experimental variability that may be due to poor control over biomechanical inputs. Here we describe a novel CHI model called CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) that fully integrates biomechanical, behavioral, and neuropathological analyses. CHIMERA is distinct from existing neurotrauma model systems in that it uses a completely non-surgical procedure to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement. In this study, we characterized head kinematics as well as functional, neuropathological, and biochemical outcomes up to 14d following repeated TBI (rTBI) in adult C57BL/6 mice using CHIMERA.ResultsHead kinematic analysis showed excellent repeatability over two closed head impacts separated at 24h. Injured mice showed significantly prolonged loss of righting reflex and displayed neurological, motor, and cognitive deficits along with anxiety-like behavior. Repeated TBI led to diffuse axonal injury with extensive microgliosis in white matter from 2-14d post-rTBI. Injured mouse brains also showed significantly increased levels of TNF-α and IL-1β and increased endogenous tau phosphorylation.ConclusionsRepeated TBI using CHIMERA mimics many of the functional and pathological characteristics of human TBI with a reliable biomechanical response of the head. This makes CHIMERA well suited to investigate the pathophysiology of TBI and for drug development programs.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-55) contains supplementary material, which is available to authorized users.

BackgroundBrain lipoprotein metabolism is dependent on lipoprotein particles that resemble plasma high‐density lipoproteins but that contain apolipoprotein (apo) E rather than apoA‐I as their primary protein component. Astrocytes and microglia secrete apoE but not apoA‐I; however, apoA‐I is detectable in both cerebrospinal fluid and brain tissue lysates. The route by which plasma apoA‐I enters the central nervous system is unknown.Methods and ResultsSteady‐state levels of murine apoA‐I in cerebrospinal fluid and interstitial fluid are 0.664 and 0.120 μg/mL, respectively, whereas brain tissue apoA‐I is ≈10% to 15% of its levels in liver. Recombinant, fluorescently tagged human apoA‐I injected intravenously into mice localizes to the choroid plexus within 30 minutes and accumulates in a saturable, dose‐dependent manner in the brain. Recombinant, fluorescently tagged human apoA‐I accumulates in the brain for 2 hours, after which it is eliminated with a half‐life of 10.3 hours. In vitro, human apoA‐I is specifically bound, internalized, and transported across confluent monolayers of primary human choroid plexus epithelial cells and brain microvascular endothelial cells.ConclusionsFollowing intravenous injection, recombinant human apoA‐I rapidly localizes predominantly to the choroid plexus. Because apoA‐I mRNA is undetectable in murine brain, our results suggest that plasma apoA‐I, which is secreted from the liver and intestine, gains access to the central nervous system primarily by crossing the blood–cerebrospinal fluid barrier via specific cellular mediated transport, although transport across the blood–brain barrier may also contribute to a lesser extent.

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Traumatic brain injury (TBI) increases Alzheimer’s disease (AD) risk and leads to the deposition of neurofibrillary tangles and amyloid deposits similar to those found in AD. Agonists of Liver X receptors (LXRs), which regulate the expression of many genes involved in lipid homeostasis and inflammation, improve cognition and reduce neuropathology in AD mice. One pathway by which LXR agonists exert their beneficial effects is through ATP-binding cassette transporter A1 (ABCA1)-mediated lipid transport onto apolipoprotein E (apoE). To test the therapeutic utility of this pathway for TBI, we subjected male wild-type (WT) and apoE−/− mice to mild repetitive traumatic brain injury (mrTBI) followed by treatment with vehicle or the LXR agonist GW3965 at 15 mg/kg/day. GW3965 treatment restored impaired novel object recognition memory in WT but not apoE−/− mice. GW3965 did not significantly enhance the spontaneous recovery of motor deficits observed in all groups. Total soluble Aβ40 and Aβ42 levels were significantly elevated in WT and apoE−/− mice after injury, a response that was suppressed by GW3965 in both genotypes. WT mice showed mild but significant axonal damage at 2 d post-mrTBI, which was suppressed by GW3965. In contrast, apoE−/− mice showed severe axonal damage from 2 to 14 d after mrTBI that was unresponsive to GW3965. Because our mrTBI model does not produce significant inflammation, the beneficial effects of GW3965 we observed are unlikely to be related to reduced inflammation. Rather, our results suggest that both apoE-dependent and apoE-independent pathways contribute to the ability of GW3965 to promote recovery from mrTBI.

Breast cancer is the most common malignancy in women and the main cause of cancer death in the UK. Gastrointestinal (GI) tract metastasis and carcinomatosis from primary breast cancer are rare but breast cancer is the second most common primary malignancy to metastasise to the GI tract after malignant melanoma. The metastatic patterns of invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) have been shown to differ considerably. Liver, lung and brain metastases are more common in IDC. Most series report a greater prediliction for lobular carcinoma to metastasise to the GI tract, gynaecological organs or peritoneum.The presentation of GI metastasis due to breast cancer is typically vague and the clinical, radiological, endoscopic and histopathologic findings are often difficult to distinguish from primary gastric carcinoma. Such a patient is more likely to present to a luminal surgeon or gastroenterologist than a breast surgeon. Therefore a high index of clinical suspicion with early endoscopy in those with non-specific symptoms and a past history of breast cancer, particularly ILC, are recommended.It is imperative to differentiate between metastatic breast cancer and primary gastric carcinoma as treatment strategies differ hugely. Therefore, correlation of endoscopic biopsy histology with the primary breast cancer histology is essential. Treatment modalities are limited to appropriate systemic therapy, which may have a palliative effect in up to 50%. Surgical intervention is nearly always limited to palliative bypass only. Prognosis is consistent with the median survival of all women with metastatic disease secondary to breast cancer. Ann R Coll Surg Engl 2011; 93: e49-e50 doi 10.1308/147870811X582800Breast cancer is the most common malignancy in women and the main cause of cancer death in the UK. Gastrointestinal (GI) tract metastasis and carcinomatosis from primary breast cancer are rare but breast cancer is the second most common primary malignancy to metastasise to the GI tract after malignant melanoma.1 The metastatic patterns of invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) have been shown to differ considerably. Liver, lung and brain metastases are more common in IDC. Most series report a greater prediliction for lobular carcinoma to metastasise to the GI tract, gynaecological organs or peritoneum. 2,3 case historyWe present a 62-year old woman who was diagnosed with metastatic carcinoma of the stomach. Eight years earlier she had been treated for a grade 2 ILC that was oestrogen receptor positive with 8 of 9 axillary lymph nodes positive for metastatic disease. She underwent mastectomy and level 2 axillary clearance, followed by adjuvant chemotherapy (epirubicin/cyclophosphamide/methotrexate/fluorouracil), adjuvant chest wall and supraclavicular radiotherapy and adjuvant hormonal therapy with 5 years of tamoxifen followed by 3 years of letrozole. There was no relevant family history.The patient had presented to the gastroenterologist with loose stools, normo...