Interstitial deletion of 6q25.2�Cq25.3: a novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss

Interstitial deletions of 6q are rare. We report a detailed clinical and molecular characterization of four patients with interstitial deletion involving 6q25. All of our patients presented with microcephaly, developmental delay, dysmorphic features and hearing loss, whereas two of them had agenesis of the corpus callosum. We determined the size, extent and genomic content of the deletions using high-density array-comparative genomic hybridization (a-CGH), and found that a common segment spanning 3.52 Mb within the 6q25.2–q25.3 region was deleted in all four cases. We hypothesize that a subset of genes in the commonly deleted region are dosage sensitive and that haploinsufficieny of these genes impairs normal development of the brain and hearing.     

Trauma-induced dystonia and camptocormia in a child

A 14-year-old male sustained neck trauma during a fight at school. Torticollis developed immediately afterwards, followed by axial dystonia and camptocormia. Thorough evaluation for etiology or background disease, including psychiatric examination, was negative except for the recent trauma. Antidystonia medications, administered after significant worsening of the symptoms, led to improvement. Dystonia and camptocormia resulting from trauma are rare presentations in childhood and adolescence.     

Molecular imaging of neurodegeneration by a novel cross-disease biomarker

Current pre-mortem diagnosis of neurodegenerative disorders such as Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS) is based on clinical assessment of neurological deficits. However, symptoms and signs emerge only late in the disease course, thus indicating an urgent need for novel tools for detection of the underlying neuropathology. NST-729 (MW = 310) is a novel molecular imaging probe, which is a member of the ApoSense family of small molecule detectors of apoptosis. We now report on the ability of NST-729, upon its systemic administration in vivo, to detect characteristic neuropathology in pre-clinical models of AD (Tg2576 transgenic mice) and ALS (transgenic SOD-1 G93A mutation mice). In the AD model, NST-729 clearly and selectively bound and imaged amyloid plaques, in excellent correlation with a typical amyloid ex vivo staining (Congo red). In the ALS model, NST-729 distinctly and selectively imaged multiple degenerating neurons in the motor nuclei in the pons, medulla and spinal cord, manifesting numerous multifocal irregularities and disruptions of neuritic projections, typical of axonal apoptosis. Study results therefore support the potential utility of NST-729 as a cross-disease biomarker for neurodegeneration, and also its potential role as the first molecular probe for ALS. Future radio-labeled NST-729 analogues may assist in the early diagnosis of disease, and in the development of neuroprotective therapies for these severe neurological disorders.     

Home-based motor imagery training for gait rehabilitation of people with chronic poststroke hemiparesis

Dunsky A, Dickstein R, Marcovitz E, Levy S, Deutsch J. Home-based motor imagery training for gait rehabilitation of people with chronic poststroke hemiparesis.

Objective

To test the feasibility and efficacy of a home-based motor imagery gait training program to improve walking performance of individuals with chronic poststroke hemiparesis.

Design

Nonrandomized controlled trial.

Setting

Local facility.

Participants

Participants (N=17) were community-dwelling volunteers with hemiparesis caused by a unilateral stroke that occurred at least 3 months before the study.

Intervention

Participants received 15 minutes of supervised imagery gait training in their homes 3 days a week for 6 weeks. The intervention addressed gait impairments of the affected lower limb and task-specific gait training. Walking ability was evaluated by kinematics and functional scales twice before the intervention, 3 and 6 weeks after the intervention began, and at the 3-week follow-up.

Main Outcome Measures

Spatiotemporal, kinematic, and functional walking measurements.

Results

Walking speed increased significantly by 40% after training, and the gains were largely maintained at the 3-week follow-up. The effect size of the intervention on walking speed was moderate (.64). There were significant increases in stride length, cadence, and single-support time of the affected lower limb, whereas double-support time was decreased. Improvements were also noted on the gait scale of the Tinetti Performance-Oriented Mobility Assessment as well as in functional gait. Sixty-five percent of the participants advanced 1 walking category in the Modified Functional Walking Categories Index.

Conclusions

Although further study is recommended, the findings support the feasibility and justify the incorporation of home-based motor imagery exercises to improve walking skills for poststroke hemiparesis.     

Targeting cell death in vivo in experimental traumatic brain injury by a novel molecular probe

Traumatic brain injury (TBI) remains a frequent and major challenge in neurological and neurosurgical practice. Apoptosis may play a role in cerebral tissue damage induced by the traumatic insult, and thus its detection and inhibition may advance patient care. DDC (N,N'-didansyl-L-cystine) is a novel fluorescent probe for detection of apoptotic cells. We now report on the performance of DDC in experimental TBI. Closed head injury was induced in mice by weight-drop. DDC was administered intravenously in vivo. Two hours later, animals were sacrificed, and brain tissue was subjected to fluorescent microcopy, for assessment of DDC uptake, in correlation with histopathological assessment of apoptosis by TUNEL and caspase substrates, and also in correlation with the neurological deficits, as assessed by Neurological Severity Score (NSS). Selective uptake of DDC was observed at the primary site of injury, and also at remote sites. Uptake was at the cellular level, with accumulation of DDC in the cytoplasm. Cells manifesting DDC uptake were confirmed as apoptotic cells by detection of the characteristic apoptotic DNA fragmentation (positive TUNEL staining) and detection of activated caspases. The damaged region stained by DDC fluorescence correlated with the severity of neuronal deficits. Our study confirms the role of apoptosis in TBI, and proposes DDC as a useful tool for its selective targeting and detection in vivo. Such imaging of apoptosis, following future radiolabeling of DDC, may advance care for patients with head injury, by allowing real-time evaluation of the extent of tissue damage, assessment of novel therapeutic strategies, and optimization of treatment for the individual patient.     

Youth Exposed to Terrorism: the Moderating Role of Ideology

The present review examines the moderating role of ideology on the effects of war, armed conflict, and terrorism on youth. Ideology is an important factor given the central role played by religio-political ideology and nationalism in present-day conflicts. Ideologies or worldviews represent cognitive frameworks that imbue the traumatic situation with meaning and order. Analysis of the pool of studies identified three categories of ideologically based moderating factors, each representing an aspect of social construction of traumatic events, namely, religion, political ideology, and self-concept. The two closely related categories of religion and politico-religious beliefs showed both positive and negative effects on psychological and psychiatric outcomes among youth. The third category of different aspects of self-concept yielded consistently positive moderating effects. The mechanisms by which each category of ideology moderates effects of exposure to war, armed conflict, and terrorism are discussed, and research and clinical implications are presented.     

The elephant in the room: talking race in medical education

The deaths of black men and women while in police custody, rising anti-immigrant sentiment and rhetoric in high-income countries, and the continued health disparities experienced by Indigenous communities globally have brought race and racism to the forefront of public discourse in recent years. In a context where academic health science centres are increasingly called to be “socially accountable,” ignoring the larger social context of race and racism is something that medical education institutions can little afford to do. However, many such institutions have largely remained silent on the issue of race and racism, both within and outside of healthcare. Most medical education continues to emphasize a primarily biological understanding of race. We argue that a different approach is needed. Highlighting the social construction of race is an essential starting point for educators and trainees to tackle racialized health disparities in our clinics and to challenge racism in our classrooms, educational and research institutions, and communities.     

Novel immunotherapy for malignant melanoma with a monoclonal antibody that blocks CEACAM1 homophilic interactions

CEACAM1 (biliary glycoprotein-1, CD66a) was reported as a strong clinical predictor of poor prognosis in melanoma. We have previously identified CEACAM1 as a tumor escape mechanism from cytotoxic lymphocytes. Here, we present substantial evidence in vitro and in vivo that blocking of CEACAM1 function with a novel monoclonal antibody (MRG1) is a promising strategy for cancer immunotherapy. MRG1, a murine IgG1 monoclonal antibody, was raised against human CEACAM1. It recognizes the CEACAM1-specific N-domain with high affinity (K(D) ~ 2 nmol/L). Furthermore, MRG1 is a potent inhibitor of CEACAM1 homophilic binding and does not induce any agonistic effect. We show using cytotoxicity assays that MRG1 renders multiple melanoma cell lines more vulnerable to T cells in a dose-dependent manner, only following antigen-restricted recognition. Accordingly, MRG1 significantly enhances the antitumor effect of adoptively transferred, melanoma-reactive human lymphocytes using human melanoma xenograft models in severe combined immunodeficient/nonobese diabetic (SCID/NOD) mice. A significant antibody-dependent cell cytotoxicity response was excluded. It is shown that MRG1 reaches the tumor and is cleared within a week. Importantly, approximately 90% of melanoma specimens are CEACAM1(+), implying that the majority of patients with melanoma could be amenable to MRG1-based therapy. Normal human tissue microarray displays limited binding to luminal epithelial cells on some secretory ducts, which was weaker than the broad normal cell binding of other anticancer antibodies in clinical use. Importantly, MRG1 does not directly affect CEACAM1(+) cells. CEACAM1 blockade is different from other immunomodulatory approaches, as MRG1 targets inhibitory interactions between tumor cells and late effector lymphocytes, which is thus a more specific and compartmentalized immune stimulation with potentially superior safety profile.