A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy

Objective

Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted a safety trial of a neutralizing antibody to myostatin, MYO‐029, in adult muscular dystrophies (Becker muscular dystrophy, facioscapulohumeral dystrophy, and limb‐girdle muscular dystrophy).

Methods

This double‐blind, placebo‐controlled, multinational, randomized study included 116 subjects divided into sequential dose‐escalation cohorts, each receiving MYO‐029 or placebo (Cohort 1 at 1mg/kg; Cohort 2 at 3mg/kg; Cohort 3 at 10mg/kg; Cohort 4 at 30mg/kg). Safety and adverse events were assessed by reported signs and symptoms, as well as by physical examinations, laboratory results, echocardiograms, electrocardiograms, and in subjects with facioscapulohumeral dystrophy, funduscopic and audiometry examinations. Biological activity of MYO‐029 was assessed through manual muscle testing, quantitative muscle testing, timed function tests, subject‐reported outcomes, magnetic resonance imaging studies, dual‐energy radiographic absorptiometry studies, and muscle biopsy.

Results

MYO‐029 had good safety and tolerability with the exception of cutaneous hypersensitivity at the 10 and 30mg/kg doses. There were no improvements noted in exploratory end points of muscle strength or function, but the study was not powered to look for efficacy. Importantly, bioactivity of MYO‐029 was supported by a trend in a limited number of subjects toward increased muscle size using dual‐energy radiographic absorptiometry and muscle histology.

Interpretation

This trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate safety margin for clinical studies. Further evaluation of more potent myostatin inhibitors for stimulating muscle growth in muscular dystrophy should be considered. Ann Neurol 2008     

Retinal signs and stroke: revisiting the link between the eye and brain

BACKGROUND AND PURPOSE: The retinal and cerebral vasculature share similar anatomic, physiological, and embryological characteristics. We reviewed the literature, focusing particularly on recent population-based studies, to examine the relationship between retinal signs and stroke. Summary of Review- Hypertensive retinopathy signs (eg, focal retinal arteriolar narrowing, arterio-venous nicking) were associated with prevalent stroke, incident stroke, and stroke mortality, independent of blood pressure and other cerebrovascular risk factors. Diabetic retinopathy signs (eg, microaneurysms, hard exudates) were similarly associated with incident stroke and stroke mortality. Retinal arteriolar emboli were associated with stroke mortality but not incident stroke. There were fewer studies on the association of other retinal signs such as retinal vein occlusion and age-related macular degeneration with stroke, and the results were less consistent. CONCLUSIONS: Many retinal conditions are associated with stroke, reflecting possible concomitant pathophysiological processes affecting both the eye and the brain. However, the incremental value of a retinal examination for prediction of future stroke risk remains to be determined.     

The nature of the self: Neural analyses and heritability estimates of self‐evaluations in middle childhood

How neural correlates of self‐concept are influenced by environmental versus genetic factors is currently not fully understood. We investigated heritability estimates of behavioral and neural correlates of self‐concept in middle childhood since this phase is an important time window for taking on new social roles in academic and social contexts. To do so, a validated self‐concept fMRI task was applied in a twin sample of 345 participants aged between 7 and 9 years. In the self‐concept condition, participants were asked to indicate whether academic and social traits applied to them whereas the control condition required trait categorization. The self‐processing activation analyses (n = 234) revealed stronger medial prefrontal cortex (mPFC) activation for self than for control conditions. This effect was more pronounced for social‐self than academic self‐traits, whereas stronger dorsolateral prefrontal cortex (DLPFC) activation was observed for academic versus social self‐evaluations. Behavioral genetic modeling (166 complete twin pairs) revealed that 25–52% of the variation in academic self‐evaluations was explained by genetic factors, whereas 16–49% of the variation in social self‐evaluations was explained by shared environmental factors. Neural genetic modeling (91 complete twin pairs) for variation in mPFC and anterior prefrontal cortex (PFC) activation for academic self‐evaluations confirmed genetic and unique environmental influences, whereas anterior PFC activation for social self‐evaluations was additionally influenced by shared environmental influences. This indicates that environmental context possibly has a larger impact on the behavioral and neural correlates of social self‐concept at a young age. This is the first study demonstrating in a young twin sample that self‐concept depends on both genetic and environmental factors, depending on the specific domain.     

Differential Disruption of Blood–Brain Barrier in Severe Traumatic Brain Injury

Background

Traumatic brain injury (TBI) is a significant cause of death and disability in young adults, but not much is known about the incidence and characteristics of blood–brain barrier (BBB) dysfunction in this group. In this proof of concept study, we sought to quantify the incidence of BBB dysfunction (defined as a cerebrospinal fluid (CSF)–plasma albumin quotient of ≥0.007) and examine the relationship between plasma and CSF levels of proteins and electrolytes, in patients with severe TBI.

Methods

We recruited 30 patients, all of whom were receiving hypertonic 20 % saline infusion for intracranial hypertension and had external ventricular drains in situ. Simultaneous CSF and blood samples were obtained. Biochemical testing was performed for sodium, osmolality, potassium, glucose, albumin, immunoglobulin-G, and total protein.

Results

Eleven patients (37 %) showed evidence of impairment of passive BBB function, with a CSF–plasma albumin quotient of ≥0.007. There were strong positive correlations seen among CSF–plasma albumin quotient and CSF–plasma immunoglobulin-G quotient and CSF–plasma total protein quotient (r = 0.967, P < 0.001 and r = 0.995, P < 0.001, respectively). We also found a higher maximum intracranial pressure (24 vs. 21 mmHg, P = 0.029) and a trend toward increased mortality (27 vs. 11 %, P = 0.33) in patients with BBB disruption.

Conclusions

In summary, passive BBB dysfunction is common in patients with severe TBI, and may have important implications for effectiveness of osmotherapy and long-term outcomes. Also, our results suggest that the CSF–plasma total protein quotient, a measurement which is readily available, can be used instead of the CSF–plasma albumin quotient for evaluating BBB dysfunction.     

Women with intellectual disability: Their sexual lives in the 21st century

Abstract

Background The aim of this paper was to give an overview of, and a commentary on, research demonstrating what women with intellectual disability are saying about their intimate relationships and sexual lives in the 21st century.

Method A literature search was undertaken for qualitative studies, published in English since 2011, in which the authors spoke directly and at length to women with intellectual disability. The method was based on the Critical Appraisal Skills Programme (http://www.casp-uk.net).

Results Five studies, from the UK, USA, and Australia, were found to fit the criteria. The numbers of participants in the studies ranged from 9 to 17. All involved women with mild to moderate intellectual disability.

Discussion Though not universal, it is negative perceptions, negative experiences, thwarted ambitions, and abuse that dominate the narratives of the women with intellectual disability when they are asked about their sexual lives.

Conclusion Women with intellectual disability need help in developing their self-esteem, sex education that emphasises female sexual pleasure and assessing risk, as well as peer support. Wider structural, social, and service-level changes are also needed, and these are discussed, along with suggestions for enhancing women's ability to exercise a greater degree of control over their sexual lives.     

Attitudes to people with mental disorders: a mental health literacy survey in a rural area of Maharashtra,India

Introduction  

People with mental disorders experience discrimination as a consequence of stigmatising attitudes that are largely socio-culturally constructed. Thus, there is a need to understand local contexts in order to develop effective programs to change such attitudes. We undertook a mental health literacy survey in rural Maharashtra, India, prior to developing a mental health training program for village health workers (VHWs) in a primary health care setting.     

Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy

Neuronal accumulation of oligomeric amyloid-β (Αβ) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Aβ stress to neurons by immigration into the brain and phagocytosis of Αβ. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Αβ by AD and normal subjects’ macrophages. Both AD and normal macrophages were inhibited in Αβ export across the blood-brain barrier due to adherence of Aβ-engorged macrophages to the endothelial layer. In comparison to normal subjects’ macrophages, AD macrophages ingested and cleared less Αβ, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar Αβ. Confocal microscopy of stained AD brain sections revealed oligomeric Aβ in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar Aβ in plaques and microvessel walls. After incubation with AD brain sections, normal subjects’ monocytes intruded into neurons and uploaded oligomeric Aβ. In conclusion, in patients with AD, macrophages appear to shuttle Aβ from neurons to vessels where their apoptosis may release fibrillar Aβ, contributing to cerebral amyloid angiopathy. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. J. Zaghi and B. Goldenson contributed equally.     

Gene expression analyses of neurons,astrocytes, and oligodendrocytes isolated by laser capture microdissection from human brain: Detrimental effects of laboratory humidity

Laser capture microdissection (LCM) is a versatile computer‐assisted dissection method that permits collection of tissue samples with a remarkable level of anatomical resolution. LCM's application to the study of human brain pathology is growing, although it is still relatively underutilized, compared with other areas of research. The present study examined factors that affect the utility of LCM, as performed with an Arcturus Veritas, in the study of gene expression in the human brain using frozen tissue sections. LCM performance was ascertained by determining cell capture efficiency and the quality of RNA extracted from human brain tissue under varying conditions. Among these, the relative humidity of the laboratory where tissue sections are stained, handled, and submitted to LCM had a profound effect on the performance of the instrument and on the quality of RNA extracted from tissue sections. Low relative humidity in the laboratory, i.e., 6–23%, was conducive to little or no degradation of RNA extracted from tissue following staining and fixation and to high capture efficiency by the LCM instrument. LCM settings were optimized as described herein to permit the selective capture of astrocytes, oligodendrocytes, and noradrenergic neurons from tissue sections containing the human locus coeruleus, as determined by the gene expression of cell‐specific markers. With due regard for specific limitations, LCM can be used to evaluate the molecular pathology of individual cell types in post‐mortem human brain. © 2009 Wiley‐Liss, Inc.     

Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder

The NF1 tumor suppressor gene encodes a guanosine triphosphotase (GTPase)-activating protein that negatively regulates Ras signaling and is inactivated in a subset of juvenile myelomonocytic leukemias (JMMLs). Adoptive transfer of fetal liver cells from Nf1 mutant mice models JMML; however, this system has important limitations as a platform for performing biologic and preclinical studies. We have exploited the interferon-inducible Mx1-Cre transgene to ablate a conditional mutant Nf1 allele in hematopoietic cells. Somatic inactivation of Nf1 induces a myeloproliferative disorder with 100% penetrance that is associated with a sub-acute clinical course, tissue infiltration by myeloid cells, hypersensitivity to granulocyte-macrophage colony stimulating factor, hyperproliferation, and resistance to apoptosis. These Mx1-Cre, Nf1(flox/flox) mice establish a tractable experimental model for testing therapeutics and for identifying mutations that cooperate with hyperactive Ras in myeloid leukemogenesis.