Donanemab (LY3002813) Phase 1b Study in Alzheimer's Disease: Rapid and Sustained Reduction of Brain Amyloid Measured by Florbetapir F18 Imaging.

BACKGROUND: Donanemab (LY3002813) is an IgG1 antibody directed at an N­terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. OBJECTIVES: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. DESIGN: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. SETTING: Patients recruited at clinical research sites in the United States and Japan. PARTICIPANTS: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer's disease and mild-to-moderate Alzheimer's disease dementia. INTERVENTION: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). MEASUREMENTS: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. RESULTS: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). CONCLUSIONS: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

Location-specific reflex epilepsy: a novel reflex epilepsy phenotype.

Reflex epilepsies are rare syndromes where seizures are triggered by particular stimuli or activities that may be motor, sensory or cognitive in nature. Triggers are diverse, may be extrinsic or intrinsic in nature and heterogeneous phenotypes have been described over the years. We give an account of a case of location-specific reflex epilepsy which we suggest is a novel reflex epilepsy phenotype relating to higher cortical function (HCF), and review the literature in relation to features of HCF reflex epilepsies described to date.

Amplified Ras-MAPK signal states correlate with accelerated EGFR internalization, cytostasis and delayed HER2 tumor onset in Fer-deficient model systems.

The non-receptor tyrosine kinase Fer belongs to a distinct subfamily of F-BAR domain containing kinases implicated in vesicular trafficking and signaling downstream of adhesion and growth factor receptors. Targeted inactivation of the fer gene in a transgenic mouse model of HER2(+), breast cancer was associated with delayed tumor onset and reduced proliferative rates in tumor cells. Fer deficiency was associated with increased rates of epidermal growth factor (EGF)-induced epidermal growth factor receptor (EGFR) internalization and amplified Ras-Raf-Mek-Erk (Ras-MAPK) signaling in primary mammary tumor epithelial cells, as well as increased cytotoxic and anti-proliferative sensitivity to the dual EGFR/HER2 inhibitor Lapatinib (LPN). These observations suggest a model in which accelerated ligand-induced EGFR internalization in Fer-deficient cells hypersensitizes the Ras-MAPK pathway to EGF, resulting in MAPK signal amplification to levels that induce cytostasis, rather than proliferation. Thus, Ras-MAPK cytostatic signaling delays HER2 tumor initiation and increases LPN cytotoxicity in Fer-deficient model systems. Taken together, these data suggest that targeting Fer alone, or in combination with LPN, may be of therapeutic benefit in HER2(+) breast cancer.

Approaching families for organ donation-intensivists' perspectives.

In Australia the initial approach to families for organ donation is almost always undertaken by intensivists. There is, however, a paucity of literature on intensivists' views on this approach and how their approach compares with recommendations in published literature on this subject. This study consisted of a survey of the views of intensive care consultants and senior intensive care registrars in the four major teaching hospitals in Perth, Western Australia, on how they approached families for organ donation. The study also includes a review of recently published literature on approaching families for organ donation. The survey results indicate that most intensive care consultants felt adequately trained to approach families for organ donation, but almost half of the group surveyed would prefer a collaborative approach with either a donor co-ordinator or a colleague with additional training on this subject. Despite recommendations in the literature and from the Australian and New Zealand Intensive Care Society to determine the registration status of potential donors on the Australian Organ Donation Registry prior to discussions with families, this was not always undertaken. In addition, the benefits of organ donation were not always discussed with families, nor were the reasons for refusal of consent sensitively explored.

Primary angiitis of the central nervous system with diffuse cerebral mass effect and giant cells.

Primary angiitis of the central nervous system (PACNS), also called primary CNS vasculitis, is an idiopathic inflammatory condition affecting only intracranial and spinal cord vessels, particularly medium-sized and smaller arteries and arterioles. Angiography and histopathology typically do not reveal evidence of systemic vasculitis.(1,2) Histopathology usually reveals granulomatous inflammation affecting arterioles and small arteries of the parenchyma and/or leptomeninges, similar to that seen in Takayasu's or giant cell arteritis.(1-3) We report a patient with biopsy-proven PACNS with giant cells and cerebral mass effect on MRI. Magnetic resonance angiography and cerebral angiography appeared normal and there was no evidence of extracranial vasculitis.

A review of nerve conduction studies in cases of suspected compression neuropathies of the upper limb.

INTRODUCTION: Entrapment neuropathies, particularly those affecting upper limbs, are common reasons for referral for nerve conduction studies (NCS). However, concordance between clinical findings and NCS findings, especially in patients being considered for intervention including decompressive surgery, has not been assessed. METHODS: We conducted a retrospective study using records from a tertiary referral centre's neurophysiology database. We aimed to establish the proportions of agreement between the suspected clinical diagnosis as defined by the referring clinician and NCS findings in the setting of an upper limb entrapment neuropathy. RESULTS: Of the 571 referrals for NCS, suspected bilateral carpal tunnel syndrome was the commonest reason for referral (30.5%). In total, there was 51.5% concordance between suspected clinical diagnosis and NCS findings. Patients with NCS evidence of an entrapment neuropathy (n = 437) were more likely to be older compared to those with normal studies (54.0 +/- 15.6 years vs. 45.9 +/- 13.4 years, p < 0.001). Those with normal NCS findings were more likely to be female (72%, p = 0.001). An alternative or additional diagnosis was found in 14%. CONCLUSION: This study raises concerns regarding the appropriateness of referral for decompressive surgery based on clinical diagnosis alone as many have an additional or alternative diagnosis as suggested by NCS findings.

Acute aseptic meningitis and diffuse myelitis as the presenting features of neurological Behcet disease.

We report an explosive presentation of neurological Behcet disease, in an Irish male patient. We present the clinical and radiological findings in our patient and discuss a novel and effective therapeutic approach. We review other treatment modalities of patients with neurological involvement.

A rare cause of fatal intracranial haemorrhage.

INTRODUCTION: We report the case of a 53-year-old farmer with a 5-day history of severe headache, photophobia and neck stiffness. Full blood count (platelets 173), coagulation screen were normal throughout. Liver function tests remained normal apart from an elevated gamma-GT (156). CT Brain was normal. CSF analysis showed a WCC of 454/mm(3) (60% lymphocytes), elevated CSF protein (1.42 g/l) and a normal CSF glucose. He was commenced on IV antibiotics and IV acyclivor and improved. On day 3 of admission, he complained of a sudden severe headache, became unresponsive (GCS 3/15). INVESTIGATIONS: CT Brain showed a massive left intraventricular haemorrhage. He died 4 days later. Subsequent serum serology for leptospirosis was positive. A repeat sample taken 4 days post-admission, showed a rising IgM indicating active leptospirosis. Detailed pathological examination confirmed intracerebral haemorrhage with normal cerebral vasculature. CONCLUSION: Leptospirosis is a rare cause of intracerebral haemorrhage even in the absence of coagulopathy.

Aetiology and prognosis of encephalopathic patterns on electroencephalogram in a general hospital.

The purpose of this study was to investigate the frequency and clinical outcome of patients with encephalopathic electroencephalograms (EEGs) in a neurophysiology department based in a general hospital. We performed a retrospective review of all EEGs obtained during an 18-month period in a large tertiary referral hospital. The referral reasons for EEG, the diagnoses reached, and patient outcomes were reviewed according to EEG severity. One hundred and twenty-three patients with encephalopathic EEGs were reviewed. The most common referral reason found was for an assessment of a possible first-onset seizure. The most common diagnosis found was one of dementia or learning disability. Of patients who were followed-up for a median of 19 months, 20.7% had died. The mortality rate generally increased according to the severity of the encephalopathy on EEG. However, 21.4% of those patients with excessive theta activity only on EEG had died. This study highlights an increased mortality even in the apparently 'milder' degrees of EEG abnormalities.

Venous and arterial thrombo-embolic complications of hormonal treatment in a male-to-female transgender patient.

We present a male-to-female (MTF) transgender patient admitted with a pulmonary embolism. The patient had been treated with high-dose oestrogens since the age of 16. Following a prolonged period of hypotension, our patient sustained cerebral border zone infarcts. There was evidence of bilateral carotid stenosis on Doppler ultrasound. We discuss the treatment and vascular complications of gender dysphoria.

Non-traumatic brachial plexopathies, clinical, radiological and neurophysiological findings from a tertiary centre.

OBJECTIVE: To establish the clinical characteristics, aetiology, neuro-physiological characteristics, imaging findings and other investigations in a cohort of patients with non-traumatic brachial plexopathy (BP). METHODS: A 3-year retrospective study of patients with non-traumatic BP identified by electromyography (EMG) and nerve conduction studies (NCS). Clinical information was retrieved from patients' medical charts. RESULTS: Twenty-five patients were identified. Causes of BP included neuralgic amyotrophy (NA) (48%), neoplastic (16%), radiation (8%), post infectious (12%), obstetric (4%), rucksack injury (4%), thoracic outlet syndrome (4%) and iatrogenic (4%). Patients with NA presented acutely in 50%. The onset was subacute in all others. Outcome was better for patients with NA. All patients with neoplastic disease had a previous history of cancer. MRI was abnormal in 3/16 patients (18.8%). PET scanning diagnosed metastatic plexopathy in two cases. CONCLUSIONS: NA was the most common cause of BP in our cohort and was associated with a more favourable outcome. The authors note potentially discriminating clinical characteristics in our population that aid in the assessment of patients with brachial plexopathies. We advise NCS and EMG be performed in all patients with suspected plexopathy. Imaging studies are useful in selected patients.

A study of idiopathic generalised epilepsy in an Irish population.

UNLABELLED: Idiopathic generalised epilepsy (IGE) is subdivided into syndromes based on clinical and EEG features. PURPOSE: The aim of this study was to characterise all cases of IGE with supportive EEG abnormalities in terms of gender differences, seizure types reported, IGE syndromes, family history of epilepsy and EEG findings. We also calculated the limited duration prevalence of IGE in our cohort. METHODS: Data on abnormal EEGs were collected retrospectively from two EEG databases at two tertiary referral centres for neurology. Clinical information was obtained from EEG request forms, standardised EEG questionnaires and medical notes of patients. RESULTS: two hundred twenty-three patients met our inclusion criteria, 89 (39.9%) male and 134 (60.1%) females. Tonic clonic seizures were the most common seizure type reported, 162 (72.65%) having a generalised tonic clonic seizure (GTCS) at some time. IGE with GTCS only (EGTCSA) was the most common syndrome in our cohort being present in 94 patients (34 male, 60 female), with 42 (15 male, 27 female) patients diagnosed with Juvenile myoclonic epilepsy (JME), 23 (9 male, 14 female) with Juvenile absence epilepsy (JAE) and 20 (9 male, 11 female) with childhood absence epilepsy (CAE). EEG studies in all patients showed generalised epileptiform activity. CONCLUSIONS: More women than men were diagnosed with generalised epilepsy. Tonic clonic seizures were the most common seizure type reported. EGTCSA was the most frequent syndrome seen. Gender differences were evident for JAE and JME as previously reported and for EGTCSA, which was not reported to date, and reached statistical significance for EGTCA and JME.

The role of the standard EEG in clinical psychiatry.

BACKGROUND: The EEG is a commonly requested test on patients attending psychiatric services, predominantly to investigate for a possible organic brain syndrome causing behavioural changes. AIMS: To assess referrals for EEG from psychiatric services in comparison with those from other sources. We determine which clinical factors were associated with an abnormal EEG in patients referred from psychiatric sources. METHODS: A retrospective review of EEG requests in a 1-year period was performed. Analysis of referral reasons for psychiatric patients was undertaken, and outcome of patients referred from psychiatric services post-EEG was reviewed. RESULTS: One thousand four hundred and seventy EEGs were reviewed, of which 91 (6.2%) were referred from psychiatry. Neurology service referrals had detection rates of abnormal EEGs of 27%, with psychiatric referrals having the lowest abnormality detection rate of 17.6% (p < 0.1). In psychiatric-referred patients the only significant predictors found of an abnormal EEG were a known history of epilepsy (p < 0.001), being on clozapine (p < 0.05), and a possible convulsive seizure (RR = 6.51). Follow-up data of 53 patients did not reveal a significant clinical impact of EEG results on patient management. CONCLUSIONS: Many patients are referred for EEG from psychiatric sources despite a relatively low index of suspicion of an organic brain disorders, based on reasons for referral documented, with an unsurprising low clinical yield.

RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages.

Abstract High-mobility group box chromosomal protein 1 (HMGB1) is a protein with both intranuclear functions and extracellular cytokine-like effects. In this report, we study possible candidate receptors for HMGB1 on macrophages (Mphi) and define pathways activated by HMGB1 binding. Bone marrow Mphi were prepared from Dark Agouti (DA) rats and stimulated in vitro with HMGB1. The kinetics of tumour necrosis factor (TNF) production, NO production, activation of p38 mitogen-activated protein kinase (MAPK), p44/42 MAPK- and SAPK/JNK-signalling pathways, nuclear translocation of nuclear factor kappa B (NF-kappaB) and HMGB1-induced upregulation of major histocompatibility complex (MHC) class II and CD86 were analysed. Mphi from interleukin (IL)-1 receptor type I-/-, Toll-like receptor 2 (TLR2-/-) and RAGE-/- mice were used to investigate the role of these receptors in HMGB1 signalling. HMGB1 induced TNF and NO production by Mphi, phosphorylation of all investigated MAP kinase pathways and NF-kappaB translocation, and expression of MHC class II was increased. Mphi from RAGE-/- mice produced significantly lower amounts of TNF, IL-1beta and IL-6, while IL-1RI-/- and TLR2-/- Mphi produced cytokine levels comparable with wildtype controls in response to HMGB1 stimulation. We conclude that HMGB1 has the potential to induce a proinflammatory phenotype in Mphi, with RAGE as the major activation-inducing receptor.

Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1.

The nuclear protein high-mobility group box chromosomal protein 1 (HMGB1) was recently described to act as a pro-inflammatory cytokine and as a late mediator of severe sepsis and septic shock. The protein is released from monocytes in response to endotoxin and activates monocytes and endothelial cells through nuclear factor kappa B. We have previously demonstrated that the B-box of HMGB1 mediates a pro-inflammatory effect on endothelial cells including the upregulation of cell-adhesion molecules and release of interleukin (IL)-8 and granulocyte colony-stimulating factor. Here, we report that HMGB1 is released from human umbilical vein endothelial cells (HUVEC) in response to lipopolysaccharide (LPS) and tumour necrosis factor (TNF)-alpha. A nuclear relocation of HMGB1 to the cytoplasm was seen at 4 h. Subsequently, high amounts of HMGB1 could be seen in the supernatants from stimulated cells after 16 h. It was also observed that the pro-inflammatory activity of HMGB1 is sensitive to dexamethasone. Interestingly, the HMGB1-induced TNF-alpha release from monocytes could be inhibited by either the A-box of the protein or the p38 inhibitor CNI-1493, but neither had any inhibitory effects on the HMGB1-dependent upregulation of cell-adhesion molecules on HUVEC. Altogether, these results suggest that HUVEC may be an important source of HMGB1 secretion in response to systemic infection and that endothelial cells and monocytes may use different signalling pathways.

Surface runoff losses of phosphorus from Virginia soils amended with turkey manure using phytase and high available phosphorus corn diets.

Many states have passed legislation that regulates agricultural P applications based on soil P levels and crop P uptake in an attempt to protect surface waters from nonpoint P inputs. Phytase enzyme and high available phosphorus (HAP) corn supplements to poultry feed are considered potential remedies to this problem because they can reduce total P concentrations in manure. However, less is known about their water solubility of P and potential nonpoint-source P losses when land-applied. This study was conducted to determine the effects of phytase enzyme and HAP corn supplemented diets on runoff P concentrations from pasture soils receiving surface applications of turkey manure. Manure from five poultry diets consisting of various combinations of phytase enzyme, HAP corn, and normal phytic acid (NPA) corn were surface-applied at 60 kg P ha(-1) to runoff boxes containing tall fescue (Festuca arundinacea Schreb.) and placed under a rainfall simulator for runoff collection. The alternative diets caused a decrease in manure total P and water soluble phosphorus (WSP) compared with the standard diet. Runoff dissolved reactive phosphorus (DRP) concentrations were significantly higher from HAP manure-amended soils while DRP losses from other manure treatments were not significantly different from each other. The DRP concentrations in runoff were not directly related to manure WSP. Instead, because the mass of manure applied varied for each treatment causing different amounts of manure particles lost in runoff, the runoff DRP concentrations were influenced by a combination of runoff sediment concentrations and manure WSP.

Interleukin-2, interferon-alpha and 5-fluorouracil immunotherapy for metastatic renal cell carcinoma: the all Ireland experience.

OBJECTIVE: To analyse the long-term efficacy of combined interferon-alpha (IFN-alpha) and interleukin-2 (IL-2) subcutaneously, with 5-fluorouracil (5-FU) intravenously in a general multicentre setting, as treatment for metastatic renal cell carcinoma (RCC). METHODS: Fifty-nine patients with metastatic RCC were scheduled to receive an 8-week cycle of immunotherapy. Karnofsky score ranged from 70 to 100 (median 90). Thirty-one patients at presentation had metastases of which 14 underwent nephrectomy. Metastases occurred in multiple organs (lung 74%, mediastinal lymphadenopathy 22%, bone 21%). Therapeutic response and survival were analysed. RESULTS: Nine patients died from disease progression prior to completion of one full cycle. Six cases (10%) have stable disease at a follow-up of 51 months (range 20-88 months). Currently 11 patients (19%) are alive at a mean follow-up of 45 months (range 18-88 months). Forty-eight patients (81%) died of their disease at a mean follow-up of 10 months (range 0.5-46 months). Survival rate at 1 year was 53%, at 2 years 21%, at 3 years 16% and at 5 years 5%. Overall median survival is 10 months. CONCLUSION: IL-2 and IFN-alpha with 5-FU based immunotherapy achieve durable survival rates at 3 years in a minority of patients. Addition of 5-FU does not increase survival in our group. This study population is very different to other reported series. However it reflects better the entire population with metastatic RCC though results are subsequently poorer. Identifying patients that will respond is paramount.