Spontaneous upper limb monoplegia secondary to probable cerebral amyloid angiopathy

Cerebral amyloid angiopathy is a clinicopathological disorder characterised by vascular amyloid deposition initially in leptomeningeal and neocortical vessels, and later affecting cortical and subcortical regions. The presence of amyloid within the walls of these vessels leads to a propensity for primary intracerebral haemorrhage. We report the unusual case of a 77-year-old female who presented to our emergency department with sudden onset isolated hypoaesthesia and right upper limb monoplegia. A CT scan demonstrated a peripheral acute haematoma involving the left perirolandic cortices. Subsequent magnetic resonance imaging demonstrated previous superficial haemorrhagic events. One week following discharge the patient re-attended with multiple short-lived episodes of aphasia and jerking of the right upper limb. Further imaging demonstrated oedematous changes around the previous haemorrhagic insult. Cerebral amyloid angiopathy is an overlooked cause of intracerebral haemorrhage; the isolated nature of the neurological deficit in this case illustrates the many guises in which it can present

Evidence for predilection of macrophage infiltration patterns in the deeper midline and mesial temporal structures of the brain uniquely in patients with HIV-associated dementia

<p>Abstract</p> <p>Background</p> <p>HIV-1 penetrates the central nervous system, which is vital for HIV-associated dementia (HAD). But the role of cellular infiltration and activation together with HIV in the development of HAD is poorly understood.</p> <p>Methods</p> <p>To study activation and infiltration patterns of macrophages, CD8+ T cells in relation to HIV in diverse CNS areas of patients with and without dementia. 46 brain regions from two rapidly progressing severely demented patients and 53 regions from 4 HIV+ non-dementia patients were analyzed. Macrophage and CD8+ T cell infiltration of the CNS in relation to HIV was assessed using immuno-histochemical analysis with anti-HIV (P24), anti-CD8 and anti-CD68, anti-S-100A8 and granzyme B antibodies (cellular activation). Statistical analysis was performed with SPSS 12.0 with Student's t test and ANOVA.</p> <p>Results</p> <p>Overall, the patterns of infiltration of macrophages and CD8+ T cells were indiscernible between patients with and without dementia, but the co-localization of macrophages and CD8+ T cells along with HIV P24 antigen in the deeper midline and mesial temporal structures of the brain segregated the two groups. This predilection of infected macrophages and CD8+ T cells to the middle part of the brain was unique to both HAD patients, along with unique nature of provirus gag gene sequences derived from macrophages in the midline and mesial temporal structures.</p> <p>Conclusion</p> <p>Strong predilection of infected macrophages and CD8+ T cells was typical of the deeper midline and mesial temporal structures uniquely in HAD patients, which has some influence on neurocognitive impairment during HIV infection.</p

NMDA Receptor Stimulation Induces Reversible Fission of the Neuronal Endoplasmic Reticulum

With few exceptions the endoplasmic reticulum (ER) is considered a continuous system of endomembranes within which proteins and ions can move. We have studied dynamic structural changes of the ER in hippocampal neurons in primary culture and organotypic slices. Fluorescence recovery after photobleaching (FRAP) was used to quantify and model ER structural dynamics. Ultrastructure was assessed by electron microscopy. In live cell imaging experiments we found that, under basal conditions, the ER of neuronal soma and dendrites was continuous. The smooth and uninterrupted appearance of the ER changed dramatically after glutamate stimulation. The ER fragmented into isolated vesicles in a rapid fission reaction that occurred prior to overt signs of neuronal damage. ER fission was found to be independent of ER calcium levels. Apart from glutamate, the calcium ionophore ionomycin was able to induce ER fission. The N-methyl, D-aspartate (NMDA) receptor antagonist MK-801 inhibited ER fission induced by glutamate as well as by ionomycin. Fission was not blocked by either ifenprodil or kinase inhibitors. Interestingly, sub-lethal NMDA receptor stimulation caused rapid ER fission followed by fusion. Hence, ER fission is not strictly associated with cellular damage or death. Our results thus demonstrate that neuronal ER structure is dynamically regulated with important consequences for protein mobility and ER luminal calcium tunneling

Normalisation of cerebrospinal fluid biomarkers parallels improvement of neurological symptoms following HAART in HIV dementia – case report

BACKGROUND: Since the introduction of HAART the incidence of HIV dementia has declined and HAART seems to improve neurocognitive function in patients with HIV dementia. Currently, HIV dementia develops mainly in patients without effective treatment, though it has also been described in patients on HAART and milder HIV-associated neuropsychological impairment is still frequent among HIV-1 infected patients regardless of HAART. Elevated cerebrospinal fluid (CSF) levels of markers of neural injury and immune activation have been found in HIV dementia, but neither of those, nor CSF HIV-1 RNA levels have been proven useful as diagnostic or prognostic pseudomarkers in HIV dementia. CASE PRESENTATION: We report a case of HIV dementia (MSK stage 3) in a 57 year old antiretroviral naïve man who was introduced on zidovudine, lamivudine and ritonavir boosted indinavir, and followed with consecutive lumbar punctures before and after two and 15 months after initiation of HAART. Improvement of neurocognitive function was paralleled by normalisation of CSF neural markers (NFL, Tau and GFAP) levels and a decline in CSF and serum neopterin and CSF and plasma HIV-1 RNA levels. CONCLUSION: The value of these CSF markers as prognostic pseudomarkers of the effect of HAART on neurocognitive impairment in HIV dementia ought to be evaluated in longitudinal studies

Cellular injury and neuroinflammation in children with chronic intractable epilepsy

<p>Abstract</p> <p>Objective</p> <p>To elucidate the presence and potential involvement of brain inflammation and cell death in neurological morbidity and intractable seizures in childhood epilepsy, we quantified cell death, astrocyte proliferation, microglial activation and cytokine release in brain tissue from patients who underwent epilepsy surgery.</p> <p>Methods</p> <p>Cortical tissue was collected from thirteen patients with intractable epilepsy due to focal cortical dysplasia (6), encephalomalacia (5), Rasmussen's encephalitis (1) or mesial temporal lobe epilepsy (1). Sections were processed for immunohistochemistry using markers for neuron, astrocyte, microglia or cellular injury. Cytokine assay was performed on frozen cortices. Controls were autopsy brains from eight patients without history of neurological diseases.</p> <p>Results</p> <p>Marked activation of microglia and astrocytes and diffuse cell death were observed in epileptogenic tissue. Numerous fibrillary astrocytes and their processes covered the entire cortex and converged on to blood vessels, neurons and microglia. An overwhelming number of neurons and astrocytes showed DNA fragmentation and its magnitude significantly correlated with seizure frequency. Majority of our patients with abundant cell death in the cortex have mental retardation. IL-1beta, IL-8, IL-12p70 and MIP-1beta were significantly increased in the epileptogenic cortex; IL-6 and MCP-1 were significantly higher in patients with family history of epilepsy.</p> <p>Conclusions</p> <p>Our results suggest that active neuroinflammation and marked cellular injury occur in pediatric epilepsy and may play a common pathogenic role or consequences in childhood epilepsy of diverse etiologies. Our findings support the concept that immunomodulation targeting activated microglia and astrocytes may be a novel therapeutic strategy to reduce neurological morbidity and prevent intractable epilepsy.</p

Erythropoietin Amplifies Stroke-Induced Oligodendrogenesis in the Rat

Erythropoietin (EPO), a hematopoietic cytokine, enhances neurogenesis and angiogenesis during stroke recovery. In the present study, we examined the effect of EPO on oligodendrogenesis in a rat model of embolic focal cerebral ischemia.Recombinant human EPO (rhEPO) at a dose of 5,000 U/kg (n = 18) or saline (n = 18) was intraperitoneally administered daily for 7 days starting 24 h after stroke onset. Treatment with rhEPO augmented actively proliferating oligodendrocyte progenitor cells (OPCs) measured by NG2 immunoreactive cells within the peri-infarct white matter and the subventricular zone (SVZ), but did not protect against loss of myelinating oligodendrocytes measured by cyclic nucleotide phosphodiesterase (CNPase) positive cells 7 days after stroke. However, 28 and 42 days after stroke, treatment with rhEPO significantly increased myelinating oligodendrocytes and myelinated axons within the peri-infarct white matter. Using lentivirus to label subventricular zone (SVZ) neural progenitor cells, we found that in addition to the OPCs generated in the peri-infarct white matter, SVZ neural progenitor cells contributed to rhEPO-increased OPCs in the peri-infarct area. Using bromodeoxyuridine (BrdU) for birth-dating cells, we demonstrated that myelinating oligodendrocytes observed 28 days after stroke were derived from OPCs. Furthermore, rhEPO significantly improved neurological outcome 6 weeks after stroke. In vitro, rhEPO increased differentiation of adult SVZ neural progenitor cells into oligodendrocytes and enhanced immature oligodendrocyte cell proliferation.Our in vivo and in vitro data indicate that EPO amplifies stroke-induced oligodendrogenesis that could facilitate axonal re-myelination and lead to functional recovery after stroke

Macrophages in Alzheimer’s disease: the blood-borne identity

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder clinically characterized by cognitive decline involving loss of memory, reasoning and linguistic ability. The amyloid cascade hypothesis holds that mismetabolism and aggregation of neurotoxic amyloid-β (Aβ) peptides, which are deposited as amyloid plaques, are the central etiological events in AD. Recent evidence from AD mouse models suggests that blood-borne mononuclear phagocytes are capable of infiltrating the brain and restricting β-amyloid plaques, thereby limiting disease progression. These observations raise at least three key questions: (1) what is the cell of origin for macrophages in the AD brain, (2) do blood-borne macrophages impact the pathophysiology of AD and (3) could these enigmatic cells be therapeutically targeted to curb cerebral amyloidosis and thereby slow disease progression? This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology

A user-centred approach to developing bWell, a mobile app for arm and shoulder exercises after breast cancer treatment

Purpose: The study aim was to develop a mobile application (app) supported by user preferences to optimise self-management of arm and shoulder exercises for upper-limb dysfunction (ULD) after breast cancer treatment. Methods: Focus groups with breast cancer patients were held to identify user needs and requirements. Behaviour change techniques were explored by researchers and discussed during the focus groups. Concepts for content were identified by thematic analysis. A rapid review was conducted to inform the exercise programme. Preliminary testing was carried out to obtain user feedback from breast cancer patients who used the app for 8 weeks post-surgery. Results: Breast cancer patients’ experiences with ULD and exercise advice and routines varied widely. They identified and prioritised several app features: tailored information, video demonstrations of the exercises, push notifications, and tracking and progress features. An evidence-based programme was developed with a physiotherapist with progressive exercises for passive and active mobilisation, stretching and strengthening. The exercise demonstration videos were filmed with a breast cancer patient. Early user testing demonstrated ease of use, and clear and motivating app content. Conclusions: bWell, a novel app for arm and shoulder exercises was developed by breast cancer patients, health care professionals and academics. Further research is warranted to confirm its clinical effectiveness. Implications for Cancer Survivors: Mobile health has great potential to provide patients with information specific to their needs. bWell is a promising way to support breast cancer patients with exercise routines after treatment and may improve future self-management of clinical care

HIV-1 Nef increases astrocyte sensitivity towards exogenous hydrogen peroxide

<p>Abstract</p> <p>Background</p> <p>HIV-1 infected individuals are under chronic exposure to reactive oxygen species (ROS) considered to be instrumental in the progression of AIDS and the development of HIV-1 associated dementia (HAD). Astrocytes support neuronal function and protect them against cytotoxic substances including ROS. The protein HIV-1 Nef, a progression factor in AIDS pathology is abundantly expressed in astrocytes in patients with HAD, and thus may influence its functions.</p> <p>Results</p> <p>Endogenous expressed HIV-1 Nef leads to increased sensitivity of human astrocytes towards exogenous hydrogen peroxide but not towards TNF-alpha. Cell death of <it>nef</it>-expressing astrocytes exposed to 10 μM hydrogen peroxide for 30 min occurred within 4 h.</p> <p>Conclusion</p> <p>HIV-1 Nef may contribute to neuronal dysfunction and the development of HAD by causing death of astrocytes through decreasing their tolerance for hydrogen peroxide.</p

Athlome Project Consortium: a concerted effort to discover genomic and other "omic" markers of athletic performance.

Despite numerous attempts to discover genetic variants associated with elite athletic performance, injury predisposition, and elite/world-class athletic status, there has been limited progress to date. Past reliance on candidate gene studies predominantly focusing on genotyping a limited number of single nucleotide polymorphisms or the insertion/deletion variants in small, often heterogeneous cohorts (i.e., made up of athletes of quite different sport specialties) have not generated the kind of results that could offer solid opportunities to bridge the gap between basic research in exercise sciences and deliverables in biomedicine. A retrospective view of genetic association studies with complex disease traits indicates that transition to hypothesis-free genome-wide approaches will be more fruitful. In studies of complex disease, it is well recognized that the magnitude of genetic association is often smaller than initially anticipated, and, as such, large sample sizes are required to identify the gene effects robustly. A symposium was held in Athens and on the Greek island of Santorini from 14-17 May 2015 to review the main findings in exercise genetics and genomics and to explore promising trends and possibilities. The symposium also offered a forum for the development of a position stand (the Santorini Declaration). Among the participants, many were involved in ongoing collaborative studies (e.g., ELITE, GAMES, Gene SMART, GENESIS, and POWERGENE). A consensus emerged among participants that it would be advantageous to bring together all current studies and those recently launched into one new large collaborative initiative, which was subsequently named the Athlome Project Consortium