Novel roles of amyloid-beta precursor protein metabolites in fragile X syndrome and autism.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is associated with up to 5% of autism cases. Several promising drugs are in preclinical testing for FXS; however, bench-to-bedside plans for the clinic are severely limited due to lack of validated biomarkers and outcome measures. Published work from our laboratories has demonstrated altered levels of amyloid-beta (Aß) precursor protein (APP) and its metabolites in FXS and idiopathic autism. Westmark and colleagues have focused on ß-secretase (amyloidogenic) processing and the accumulation of Aß peptides in adult FXS models, whereas Lahiri and Sokol have studied α-secretase (non-amyloidogenic or anabolic) processing and altered levels of sAPPα and Aß in pediatric autism and FXS. Thus, our groups have hypothesized a pivotal role for these Alzheimer's disease (AD)-related proteins in the neurodevelopmental disorders of FXS and autism. In this review, we discuss the contribution of APP metabolites to FXS and autism pathogenesis as well as the potential use of these metabolites as blood-based biomarkers and therapeutic targets. Our future focus is to identify key underlying mechanisms through which APP metabolites contribute to FXS and autism condition-to-disease pathology. Positive outcomes will support utilizing APP metabolites as blood-based biomarkers in clinical trials as well as testing drugs that modulate APP processing as potential disease therapeutics. Our studies to understand the role of APP metabolites in developmental conditions such as FXS and autism are a quantum leap for the neuroscience field, which has traditionally restricted any role of APP to AD and aging.

Neurenteric cyst in an adult: a diagnosis in a quinquagenarian.

Neurenteric cysts are congenital lesions of the spine usually diagnosed in children. There are few reports of diagnosis in adults. The abnormality is thought to arise during embryonic life and can be associated with other congenital deformities. We describe a case where the diagnosis occurred in a 54-year-old woman, whose symptoms improved following surgical excision of the cyst. We postulate that the cyst contributed to symptoms of cord tethering rather than cord compression and that the lateness of presentation was due to age-related spinal degeneration.

Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links.

The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-ß peptide (Aß), Aß precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted α form of the amyloid-ß precursor protein (sAPPα) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPα levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPα level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPα and production of insoluble Aß would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism.

Consultation activities of clinical ethics committees in the United Kingdom: an empirical study and wake-up call.

OBJECTIVE: To identify the consultation activities of clinical ethics committees (CECs) in the UK and the views of CEC chairpersons regarding such activities. METHODS: An anonymous, password-protected online questionnaire was sent by e-mail to 70 CEC chairpersons. The questionnaire contained 14 items. RESULTS: Of the 70 CECs contacted, 30 responded (a response rate of 43%). There has been an almost fourfold increase in the number of CECs in the past 7 years. Over half of the CECs that responded had considered three or fewer active cases and three or fewer retrospective cases in the preceding year. Eighty percent of chairpersons felt that the number of active cases considered by their committee was too low. Seventy percent of CECs had rapid response teams. Aside from low consultation caseloads, chairpersons identified a number of concerns, including education and training of members, composition of CECs, low profile and lack of funding and support. Although most respondents believed there is a need for clinical ethics support in the NHS, many noted the limited use of the services, even after efforts to increase the visibility of their CEC. CONCLUSION: Despite a sharp increase in the absolute numbers of CECs across the UK, the number of cases considered by the majority of CECs is low. The findings presented here suggest we must reflect on the reasons for such low caseloads and pause to consider whether the committee model is most appropriate for the UK context.

Lives on the line? Ethics and practicalities of duty of care in pandemics and disasters.

Pandemics and acute emergencies raise pressing medical, ethical and organisational challenges. These include global governance, priority setting, triaging of patients, allocation of scarce resources and restricting individual liberty in the interests of public health. We will focus particularly on an issue of direct relevance to all respiratory team members, i.e. what is the duty of the healthcare worker to continue working in the face of personal risk, and draw lessons from guidelines, ethical considerations, past pandemics and evolving experience with H1N1 swine influenza.

The "four quadrants" approach to clinical ethics case analysis; an application and review.

In 1982, Jonsen, Siegler and Winslade published Clinical Ethics, in which they described the "four quadrants" approach, a new method of analysing clinical ethics cases. Although the book is now in its 6th edition, a literature search has revealed only one academic paper demonstrating the method at work. This paper is an attempt to start filling this gap. As a way of describing and testing the approach, I apply the four quadrants method to a detailed clinical ethics case. The analysis is interspersed with reflections on the method itself. It is hoped that this experiment will encourage ethicists and clinicians to devote more attention to this neglected approach.

Patient confidentiality and telephone consultations: time for a password.

UNLABELLED: Although telephone consultations are widely used in the delivery of healthcare, they are vulnerable to breaches of patient confidentiality. Current guidelines on telephone consultations do not address adequately the issue of confidentiality. In this paper, we propose a solution to the PROBLEM: a password system to control access to patient information. Authorised persons will be offered the option of selecting a password which they will use to validate their request for information over the telephone. This simple yet stringent method of access control should improve security while allowing the continuing evolution of telephone consultations.

Reversible posterior leukoencephalopathy syndrome associated with left ventricular assist device.

Reversible posterior leukoencephalopathy syndrome (RPLES), previously known as posterior reversible encephalopathy syndrome (PRES), is characterized by the presence of bilateral lesions located within the posterior border zones of the cerebral hemisphere and cerebellum. This condition commonly presents with headache, nausea, vomiting, decreased vision and level of consciousness, and seizures. RPLES has been associated with hypertensive encephalopathy, eclampsia, renal failure, and immunosuppressive therapy following transplant. We report the development of RPLES in a boy following implantation of a left ventricular assist device (LVAD). To our knowledge, this is the first report of RPLES in association with the use of LVAD.

Testing for antiphospholipid antibody (aPL) specificities in retrospective "normal" cerebral spinal fluid (CSF).

Antiphospholipid antibodies (aPL) have been found in the blood of patients with systemic and neurological disease. The rare reports of aPL in cerebral spinal fluid (CSF) have been limited mostly to IgG and IgM anticardiolipin (aCL). Our published finding of IgA aPE in the CSF of a young stroke victim prompted us to establish "normal" CSF aPL values for a panel of aPL, which included aCL, antiphosphatidylserine (aPS), antiphosphatidylethanolamine (aPE) and antiphosphatidylcholine (aPC). CSF samples were tested by ELISA for IgG, IgM and IgA aPL. In addition, the CSF samples were tested for activity in the presence and absence of phospholipid (PL) binding plasma-proteins. A total of 24 data points were obtained for each CSF sample. We tested 59 CSF samples obtained from 59 patients who were undergoing evaluation for systemic or neurologic diseases. All CSF samples had normal protein, glucose and cell counts. Ten of the 59 CSF samples (17%) had elevated aPL optical density (OD) values an order of magnitude higher than the other 49 CSF samples for one or more aPL specificity and/or isotype. One CSF sample had both PL-binding protein dependent and independent IgG aPE activity. Another CSF sample showed both IgG aPE and aPC reactivity. The remaining eight CSF samples showed single aPL findings; IgG aPE (5), IgG aPC (1), IgG aCL (1) and IgM aPC (1). Seven of 10 patients with elevated CSF values were females. As expected, most "normal" aPL OD values were substantially lower in CSF than those we have reported in blood samples from volunteer blood donors.

LaCrosse viral encephalitis mimics herpes simplex viral encephalitis.

Temporal lobe abnormalities, findings commonly associated with herpes simplex virus encephalitis, were observed in a male 10 years of age found to have LaCrosse virus encephalitis. Diagnostic features included magnetic resonance imaging revealing abnormal signal intensity in the bilateral frontotemporal regions, and left-sided periodic lateralizing epileptiform discharges. LaCrosse virus encephalitis should be included in the differential diagnosis of viral encephalitis associated with structural and electrographic temporal lobe lesions, represented by periodic lateralizing epileptiform discharges. The recently developed LaCrosse RNA polymerase chain reaction for cerebrospinal fluid may enable rapid diagnosis, prevent the need for treatment with acyclovir, and give parents an encouraging prognosis.

Henoch-Schönlein purpura and stroke: antiphosphatidylethanolamine antibody in CSF and serum.

A 15-year-old girl with features of Henoch-Schönlein purpura and brain infarct had a transient IgA antiphosphatidylethanolamine antibody (aPE) in her serum and CSF that disappeared 5 months after presentation. Serum aPE is known to be associated with thrombotic events. The authors found no aPE in the CSF of two control individuals or in the serum of two patients with active Henoch-Schönlein purpura without neurologic involvement. The patient may represent a variant of antiphospholipid antibody syndrome.

Near infrared spectroscopy (NIRS) distinguishes seizure types.

Near infrared spectroscopy (NIRS) is a noninvasive method for bedside measurement of cerebral oxygenation (SaO(2)). The purpose of this study was to establish differences in SaO(2)for complex partial seizures (CPS) and rapidly secondarily generalized CPS (RCPS). We studied eight adults with medically refractory epilepsy undergoing evaluation for temporal lobectomy. We continually measured cerebral SaO(2)via a Somanetic Invos 3100a cerebral oximeter, pre-ictal (5 minutes), ictal, immediate (30 seconds) post-ictal, and late post-ictal (5 minutes after ictus). Seventeen seizures (12 CPS, four RCPS and one subclinical) were recorded in eight patients. The percentage change in cerebral SaO(2)from pre-ictal to ictal periods was derived. Cerebral SaO(2)increased (percentage change, mean: 16.6, SD: 13.9) for CPS and decreased (percentage change, mean: 51.1, SD: 18.1) for RCPS. No change in cerebral oximetry was recorded for the subclinical seizure. Post-ictal (immediate and late) increase in cerebral SaO(2)was seen for 11 of the 17 seizures (nine CPS and two RCPS). Peripheral SaO(2)rose greater than 93% for all CPS and the subclinical seizure, but decreased between 78 and 84% during RCPS. These results suggest NIRS distinguishes cerebral SaO(2)patterns between CPS and RCPS. The decrease in peripheral SaO(2), however, may account for the decrease in cerebral SaO(2)seen in generalized seizures.