Custom-engineered hydrogels for delivery of human iPSC-derived neurons into the injured cervical spinal cord.

Cervical damage is the most prevalent type of spinal cord injury clinically, although few preclinical research studies focus on this anatomical region of injury. Here we present a combinatorial therapy composed of a custom-engineered, injectable hydrogel and human induced pluripotent stem cell (iPSC)-derived deep cortical neurons. The biomimetic hydrogel has a modular design that includes a protein-engineered component to allow customization of the cell-adhesive peptide sequence and a synthetic polymer component to allow customization of the gel mechanical properties. In vitro studies with encapsulated iPSC-neurons were used to select a bespoke hydrogel formulation that maintains cell viability and promotes neurite extension. Following injection into the injured cervical spinal cord in a rat contusion model, the hydrogel biodegraded over six weeks without causing any adverse reaction. Compared to cell delivery using saline, the hydrogel significantly improved the reproducibility of cell transplantation and integration into the host tissue. Across three metrics of animal behavior, this combinatorial therapy significantly improved sensorimotor function by six weeks post transplantation. Taken together, these findings demonstrate that design of a combinatorial therapy that includes a gel customized for a specific fate-restricted cell type can induce regeneration in the injured cervical spinal cord.

PARAGON II - A single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead in patients with resectable liver metastases from colorectal cancer.

PURPOSE: Perioperative chemotherapy confers a 3-year progression free survival advantage following resection of colorectal liver metastases (CRLM), but is associated with significant toxicity. Chemoembolisation using drug eluting PVA microspheres loaded with irinotecan (DEBIRI) allows sustained delivery of drug directly to tumour, maximising response whilst minimising systemic exposure. This phase II single arm study examined the safety and feasibility of DEBIRI before resection of CRLM. METHODS: Patients with resectable CRLM received lobar DEBIRI 1 month prior to surgery, with a radiological endpoint of near stasis. The trial had a primary end-point of tumour resectability (R0 resection). Secondary end-points included safety, pathologic tumour response and overall survival. RESULTS: 40 patients received DEBIRI, with a median dose of 103 mg irinotecan (range 64-175 mg). Morbidity was low (2.5%, CTCAE grade 2) with no evidence of systemic chemotoxicity. All patients proceeded to surgery, with 38 undergoing resection (95%, R0 resection rate 74%). 30-day post-operative mortality was 5% (n = 2), with neither death TACE related. 66 lesions were resected, with histologic major or complete pathologic response seen in 77.3% of targeted lesions. At median follow up of 40.6 months, 12 patients (34.3%) had died of recurrent disease with a median overall survival of 50.9 months. Nominal 1, 3 and 5-year OS was 93, 78 & 49% respectively. CONCLUSIONS: Resection after neoadjuvant DEBIRI for CRLM is feasible and safe. Single treatment with DEBIRI resulted in tumour pathologic response and median overall survival comparable to that seen after systemic neoadjuvant chemotherapy. Registered at clinicaltrials.gov (NCT00844233).

Diagnostic features of the autoimmune retinopathies.

The term autoimmune retinopathy encompasses a spectrum of rare autoimmune diseases that affect retinal function, often but not exclusively at the level of the photoreceptor. They typically present with painless visual loss, which may be accompanied by normal fundus examination. Some are progressive, often rapidly. They present a diagnostic challenge because there are no standardised clinical or laboratory based diagnostic criteria. Included within the spectrum are cancer-associated retinopathy, melanoma-associated retinopathy and presumed non-paraneoplastic autoimmune retinopathy. Differentiation from other retinopathies can be challenging, with overlap in symptoms, signs, and investigation findings, and an absence of pathognomonic features. However, technological developments in ophthalmic imaging and serological investigation over the past decade are adding novel dimensions to the investigation and classification of patients with these rare diseases. This review addresses the clinical, imaging, and serological features of the autoimmune retinopathies, and discusses the relative strengths and limitations of candidate diagnostic features.

A 'web app' for diagnosing hemianopia.

BACKGROUND: Hemianopia commonly complicates stroke and, less frequently, head injury and brain tumours. Patients' activities of daily living are often affected although these can be ameliorated by appropriate behavioural therapy. Identifying a field defect is the first step in the rehabilitation process. An online visual field test (an 'app') was developed as part of a free to use web based therapy site for patients with hemianopic alexia, called Read-Right (http://www.readright.ucl.ac.uk). This study is an attempt to validate this test by comparing with a clinical 'gold standard'-the Humphrey automated visual field analyser. METHODS: 22 patients had their visual fields assessed with both techniques on the same day. The criterion validity of the Read-Right was examined by comparing it with Humphrey 10-2 and 24-2 perimetry using the following measures: (1) sensitivity and specificity; (2) κ statistics; and (3) intraclass correlation. RESULTS: Read-Right demonstrated high sensitivity and specificity, particularly for the undamaged field. In the damaged field, κ values were highly significant, especially for points along the horizontal meridian. The intraclass correlation score for the damaged field indicated excellent correlation between the two tests. Read-Right perimetry performed well on all measures. It had a tendency to under call damaged points offset from the horizontal meridian, and this and other aspects of the test will be revamped. CONCLUSION: Read-Right is not designed to replace standardised visual perimetry; it does, however, offer a quick and easy assessment that can be used to screen patients. The test is available as part of two free to use web based therapy applications.

Neural correlates of hemianopic completion across the vertical meridian.

Hemianopic completion refers to the perceptual completion of figures located across the vertical meridian in the context of hemianopia, such that one half of the figure falls within the blind hemifield. It can occur whether the figure is itself complete (veridical completion) or incomplete (paracompletion). Psychophysical evidence suggests that this phenomenon may be a constructive one, and may share features with completion phenomena in normal vision. The neural structures mediating hemianopic completion are unknown. Here we studied the neural activity evoked by hemianopic completion using event-related fMRI in an individual (POV) with a large right visual field homonymous hemianopic scotoma due to left occipital damage. Either a large achromatic circular contour straddling the vertical meridian or a semicircular contour within the left hemifield just crossing the vertical meridian was presented to POV on each trial. POV indicated by button press whether he perceived a semicircular contour, a patchy circular contour or a complete circular contour. On trials where he reported perceiving a complete circular contour despite being presented with a semicircular contour (paracompletion), activity was increased in a region of ipsilateral extrastriate cortex (contralateral to the lesion, ipsilateral to the illusory edge of the circle). These results are discussed in the context of illusory contour completion in healthy subjects and more generally in the recovery of function after brain damage.

Culture conditions affect proliferative responsiveness of olfactory ensheathing glia to neuregulins.

Olfactory ensheathing glia (OEG) have been used to improve outcome after experimental spinal cord injury and are being trialed clinically. Their rapid proliferation in vitro is essential to optimize clinical application, with neuregulins (NRG) being potential mitogens. We examined the effects of NRG-1beta, NRG-2alpha, and NRG3 on proliferation of p75-immunopurified adult OEG. OEG were grown in serum-containing medium with added bovine pituitary extract and forskolin (added mitogens) or in serum-containing medium (no added mitogens). Cultures were switched to chemically defined medium (no added mitogens or serum), NRG added and OEG proliferation assayed using BrdU. OEG grown initially with added mitogens were not responsive to added NRGs and pre-exposure to forskolin and pituitary extract increased basal proliferation rates so that OEG no longer responded to added NRG. However, NRG promoted proliferation but only if cells were initially grown in mitogen-free medium. Primary OEG express ErbB2, ErbB3, and small levels of ErbB4 receptors; functional blocking indicates that ErbB2 and ErbB3 are the main NRG receptors utilized in the presence of NRG-1beta. The long-term stimulation of OEG proliferation by initial culture conditions raises the possibility of manipulating OEG before therapeutic transplantation.

Molecular chaperons, amyloid and preamyloid lesions in the BRI2 gene-related dementias: a morphological study.

Molecular chaperons or amyloid-associated proteins (AAPs) are deposited in vascular and parenchymal amyloid lesions in Alzheimer's disease (AD) and other amyloidoses. AAPs, such as apolipoprotein E (ApoE) or apolipoprotein J (ApoJ) have been strongly implicated in the pathogenesis of AD in vitro and in vivo. Furthermore the possession of the ApoE in4 allele is a well-studied risk factor for AD. In view of the similarities between AD and both familial British dementia (FBD) and familial Danish dementia (FDD), we investigated the presence of AAPs in these two diseases to understand better their role in the general process of amyloidogenesis. Immunohistochemistry for ApoE, ApoJ, serum amyloid P (SAP), alpha-1-antichymotrypsin, cystatin C, heparan sulphate proteoglycans, such as agrin, perlecan, syndecans, glypican-1 and for heparan sulphate glycosaminoglycan (HS GAG) side chains was carried out together with immunohistochemical preparations specific to the amyloid subunits. Significant or extensive staining for ApoE, ApoJ, agrin, glypican-1 and HS GAG side chains was found in both amyloid (fibrillar) and preamyloid (nonfibrillar) deposits in FBD and FDD. The remaining AAPs, including SAP, were predominantly found in amyloid lesions. Only very weak staining was present in a small proportion of the amyloid lesions using perlecan immunohistochemistry. These findings suggest that the deposition patterns of AAPs in FBD and FDD are mostly similar to those in AD. The presence of AAPs in the preamyloid lesions supports the notion that chaperon molecules may play a role in the early steps of fibrillogenesis.

AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells.

We compared the effects of intravitreal injection of bi-cistronic adeno-associated viral (AAV-2) vectors encoding enhanced green fluorescent protein (GFP) and either ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) or growth-associated protein-43 (GAP43) on adult retinal ganglion cell (RGC) survival and regeneration following (i) optic nerve (ON) crush or (ii) after ON cut and attachment of a peripheral nerve (PN). At 7 weeks after ON crush, quantification of betaIII-tubulin immunostaining revealed that, compared to AAV-GFP controls, RGC survival was not enhanced by AAV-GAP43-GFP but was increased in AAV-CNTF-GFP (mean RGCs/retina: 17 450+/-358 s.e.m.) and AAV-BDNF-GFP injected eyes (10 200+/-4064 RGCs/retina). Consistent with increased RGC viability in AAV-CNTF-GFP and AAV-BDNF-GFP injected eyes, these animals possessed many betaIII-tubulin- and GFP-positive fibres proximal to the ON crush. However, only in the AAV-CNTF-GFP group were regenerating RGC axons seen in distal ON (1135+/-367 axons/nerve, 0.5 mm post-crush), some reaching the optic chiasm. RGCs were immunoreactive for CNTF and quantitative RT-PCR revealed a substantial increase in CNTF mRNA expression in retinas transduced with AAV-CNTF-GFP. The combination of AAV-CNTF-GFP transduction of RGCs with autologous PN-ON transplantation resulted in even greater RGC survival and regeneration. At 7 weeks after PN transplantation there were 27 954 (+/-2833) surviving RGCs/retina, about 25% of the adult RGC population. Of these, 13 352 (+/-1868) RGCs/retina were retrogradely labelled after fluorogold injections into PN grafts. In summary, AAV-mediated expression of CNTF promotes long-term survival and regeneration of injured adult RGCs, effects that are substantially enhanced by combining gene and cell-based therapies/interventions.

Genetic alterations of the BRI2 gene: familial British and Danish dementias.

Classic arguments sustaining the importance of amyloid in the pathogenesis of dementia are usually centered on amyloid beta (Abeta) and its role in neuronal loss characteristic of Alzheimer disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias, share many aspects of Alzheimer disease, including the presence of neurofibrillary tangles, parenchymal pre-amyloid and amyloid deposits, cerebral amyloid angiopathy, and a widespread inflammatory response. Both early-onset conditions are linked to specific mutations in the BRI2 gene, causing the generation of longer-than-normal protein products and the release of 2 de novo created peptides ABri and ADan, the main components of amyloid fibrils in these inherited dementias. Although the molecular mechanisms and signal transduction pathways elicited by the amyloid deposits and their relation to cognitive impairment remain to be clarified, new evidence indicates that, independent of the differences in their primary structures, Abeta, ABri, and ADan subunits are able to form morphologically compatible ion-channel-like structures and elicit single ion-channel currents in reconstituted lipid membranes. These findings reaffirm the notion that non-Abeta amyloidosis constitute suitable alternative models to study the role of amyloid deposition in the mechanism of neuronal cell death.

ALK positive inflammatory myofibroblastic tumour of the pineal region.

Inflammatory myofibroblastic tumours (IMTs) are an uncommon spindle cell neoplasm with a dense inflammatory infiltrate, usually encountered in children. IMTs of the central nervous system are extremely rare. This report describes the case of an IMT in a 61 year old man, in the pineal region. The tumour was completely excised, and immunohistochemistry demonstrated anaplastic lymphoma kinase 1 expression. There was no tumour recurrence during 18 months of follow-up. Our case extends both the age range and sites of occurrence of this rare tumour.

Biopsy of resectable colorectal liver metastases causes tumour dissemination and adversely affects survival after liver resection.

BACKGROUND: Liver resection is increasingly being performed for metastatic colorectal cancer. This study assessed the need for preoperative biopsy of suspected metastases and whether biopsy has any effect on long-term survival. METHODS: Prospectively collected data on patients who underwent liver resection for colorectal metastases between 1986 and 2003 were reviewed retrospectively. The endpoints of morbidity, operative mortality and long-term survival were compared between patients who had biopsy before referral (group 1) and those who did not (group 2). RESULTS: Patient demographics and disease distribution were similar for 90 patients in group 1 and 508 in group 2. Seventeen patients (19 per cent) who had undergone biopsy either at the time of colorectal resection or radiologically had evidence of needle-track deposits. Operative mortality and morbidity rates in the two groups were similar. The 4-year survival rate after liver resection was 32.5 (s.e. 5.5) per cent in group 1, compared with 46.7 (2.8) per cent in group 2 (P = 0.008). CONCLUSION: Needle-track deposits are common after biopsy of suspected colorectal liver metastases. Biopsy of metastases confers poorer long-term survival on patients after liver resection and cannot be justified in patients with potentially resectable disease.

Chromosome 13 dementias.

The importance of cerebral amyloid deposition in the mechanism of neurodegeneration is still debatable. Classic arguments are usually centered on amyloid beta(Abeta) and its role in the neuronal loss characteristic of Alzheimer's disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias (FBD and FDD), share many aspects of Alzheimer's disease, including the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy and a variety of amyloid-associated proteins and inflammatory components. Both early-onset conditions are linked to specific mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. Furin-like processing of these longer precursors releases two de novo-created peptides, ABri and ADan, which deposit as amyloid fibrils in FBD and FDD, respectively. Due to the similar pathology generated by completely unrelated amyloid subunits, FBD and FDD, collectively referred to as chromosome 13 dementias, constitute alternative models for studying the role of amyloid deposition in the mechanism of neuronal cell death.

Brain biopsy in dementia.

Brain biopsy has an uncertain role in the diagnosis of dementia. Here we report a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults at a tertiary referral centre between 1989 and 2003. In most cases (90%), biopsy consisted of a right frontal full thickness resection of cortex, white matter and overlying leptomeninges. Fifty-seven per cent of biopsies were diagnostic: the most frequent diagnoses were Alzheimer's disease (18%), Creutzfeldt-Jakob disease (12%) and inflammatory disorders (9%). Other diagnoses in individual patients included Pick's disease, corticobasal degeneration and other tauopathies, Lewy body dementia, multiple sclerosis, Whipple's disease, progressive multifocal leucoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical ischaemic leucoencephalopathy, vasculopathies and paraneoplastic encephalopathy. The most frequent biopsy finding in the non-diagnostic group and for the series as a whole (37%) was non-specific gliosis variably affecting both cortex and white matter. Complications (11%) included seizures, intracranial and wound infections, and intracranial haemorrhage; there were no deaths or lasting neurological sequelae attributable to the procedure. No trends in diagnostic yield or complication rate over the course of the series were identified. Information obtained at biopsy determined treatment in 11%. A raised cerebrospinal fluid cell count was the only robust predictor of a potentially treatable (inflammatory) process at biopsy. The constellation of behavioural change, raised CSF protein and matched oligoclonal bands in CSF and serum was associated with non-specific gliosis at biopsy. This series underlines the value of cerebral biopsy in the diagnosis of dementia, and suggests that certain clinical and laboratory features may be useful in guiding the decision to proceed to brain biopsy where a treatable disease cannot be excluded by other means.

Paroxysmal raised intracranial pressure associated with spinal meningeal cysts.

Raised intracranial pressure in association with spinal meningeal cysts has rarely been reported. We describe four patients in whom evidence of paroxysmal raised intracranial pressure was found in association with spinal meningeal cysts. Cerebrospinal fluid diversion procedures have previously been shown to relieve local symptoms due to spinal cysts. In our patients symptoms of paroxysmal headache were alleviated by this method, suggesting a causal relationship with the raised pressure. This association may be an under diagnosed cause of paroxysmal headaches. We review the medical literature on the classification of spinal meningeal cysts, evaluate the theories of their origin and offer suggestions on the pathogenesis of the abnormal CSF dynamics that may allow an interplay between raised intracranial pressure and spinal meningeal cysts to produce paroxysmal symptoms.

Optic chiasm enhancement associated with giant aneurysm and yttrium treated pituitary adenoma.

A patient with a history of pituitary tumour treated with yttrium 29 years before presented with an asymmetrical chiasmal neuropathy. Magnetic resonance imaging showed a partially thrombosed giant aneurysm of the right internal carotid artery, with enhancement of the chiasm and right optic tract adjacent to the aneurysm. It was thought that, in addition to the effects of compression, a peri-aneurysmal inflammatory reaction had developed, causing breakdown of the blood-brain barrier and consequent inflammatory changes in the optic chiasm. High dose steroid treatment led to significant improvement in vision within two weeks. Steroids may have a role in the acute preservation of vision in similar cases, as well as in cases of deterioration following coiling or embolisation of aneurysms where thrombosis within the aneurysm has been induced.

Giant cell arteritis mimicking idiopathic orbital inflammatory disease.

PURPOSE: To report an unusual presentation of giant cell arteritis, referred from primary care, mimicking orbital apex syndrome. CASE REPORT: A 72 year old woman was referred with a two week history of pyrexia, dull right eye ache, 2mm of right proptosis, mild conjunctival chemosis and restriction of right eye movements. RESULTS: An erythrocyte sedimentation rate (ESR) was 90 and fluorescein angiography showed almost complete choroidal non-perfusion suggestive of giant cell arteritis. Temporal artery biopsy confirmed the diagnosis. CONCLUSIONS: Giant cell arteritis (GCA) typically presents with anterior ischemic optic neuropathy (AION), choroidal ischemia, central retinal artery occlusion, infrequently manifesting as an ocular motility problem, but has rarely been known to mimick idiopathic orbital inflammatory disease. Prompt recognition and therapy can minimize the chance of ipsilateral ocular involvement and protect the fellow eye.

Chronic relapsing inflammatory optic neuropathy (CRION).

We describe the clinical characteristics and early natural history of a form of inflammatory optic neuropathy which is frequently bilateral and often painful, and is characterized by relapses and remissions. MRI scans of the brain are normal and those of the optic nerves often, but not always, show high signal abnormalities which enhance. The symptoms and signs respond well to corticosteroid treatment, although long-term immuno suppression is often necessary. The syndrome behaves in a way which is typical of the condition known as granulomatous optic neuropathy, but during a median follow-up of 8 (2-26) years in no case has evidence for systemic sarcoidosis been identified. We suggest that the disorder be named chronic relapsing inflammatory optic neuropathy (CRION).