OBJECTIVE:

Several groups have reported apparent association between month of birth and multiple sclerosis. We sought to test the extent to which such studies might be confounded by extraneous variables such as year and place of birth.

METHODS:

Using national birth statistics from two continents, we assessed the evidence for seasonal variations in birth rate and tested the extent to which these are subject to regional and temporal variation. We then established the age and regional origin distribution for a typical multiple sclerosis case collection and determined the false positive rate expected when comparing such a collection with birth rates estimated by averaging population specific national statistics.

RESULTS:

We confirm that seasonality in birth rate is ubiquitous and subject to highly significant regional and temporal variations. In the context of this variation we show that birth rates observed in typical case collections are highly likely to deviate significantly from those obtained by the simple un-weighted averaging of national statistics. The significant correlations between birth rates and both place (latitude) and time (year of birth) that characterise the general population, indicate that the apparent seasonal patterns for month of birth suggested to be specific for multiple sclerosis (increased in the spring and reduced in the winter) are expected by chance alone.

INTERPRETATION:

In the absence of adequate control for confounding factors, such as year and place of birth, our analyses indicate that the previous claims for association of multiple sclerosis with month of birth are probably false positives. ANN NEUROL 2013. © 2013 American Neurological Association.

Background:

Controversy surrounds the safety of intravenous (IV) tissue plasminogen activator (tPA) in ischemic stroke patients treated with warfarin. The European tPA license precludes its use in anticoagulated patients altogether. American guidelines accept IV tPA use with an international normalized ratio (INR) ≤1.7. The influence of warfarin on symptomatic intracerebral hemorrhage (SICH), arterial recanalization and long-term functional outcome in stroke thrombolysis remains unclear.

Methods:

We analysed data from 45074 patients treated with IV tPA enrolled in the SITS International Stroke Thrombolysis Register. 768 patients had baseline warfarin treatment with INR≤1.7. Outcome measures were SICH, arterial recanalization, mortality and functional independence at 3 months.

Results:

Patients on warfarin with INR≤1.7 were older, had more co-morbidities, and more severe strokes compared to patients without warfarin. There were no significant differences between patients with and without warfarin in SICH rates (adjusted odds ratio (aOR) 1.23 (95% CI 0.72-2.11) per SITS-MOST, 1.26 (0.82-1.70)) per ECASS II after adjustment for age, stroke severity and co-morbidities. Neither did warfarin independently influence mortality, aOR 1.05 (0.83-1.35), nor functional independence at 3 months, aOR 1.01 (0.81-1.24). Arterial recanalization by CT/MR angiography trended higher in warfarin patients, 62% (37/59) vs. 55% (776/1475), p=0.066. Recanalization approximated by disappearance at 22-36 hours of a baseline hyperdense middle cerebral artery sign was increased 63% (124/196) vs 55% (3901/7099), p=0.022. Interpretation: Warfarin treatment with INR≤1.7 did not increase the risk for SICH or death, and had no impact on long-term functional outcome in patients treated with intravenous tPA for acute ischemic stroke. ANN NEUROL 2013. © 2013 American Neurological Association.

Approximately 700,000 people in the United States have an ischemic stroke annually. Substantial research has tested therapies for the very early treatment of ischemic stroke but, to date, only intravenous thrombolysis and intra-arterial measures to restore perfusion have shown success. Despite a 15-year effort to increase the use of these therapies, only approximately 5% of patients with stroke are currently being treated. Although most patients with stroke have some neurological recovery, more than half of stroke survivors have residual impairments that lead to disability or long-term institutionalized care. Laboratory research has demonstrated several mechanisms that help the brain to recover after a stroke. New pharmacological and cell-based approaches that are known to promote brain plasticity are emerging from laboratory studies and may soon expand the window for stroke treatment to restore function. It is time to build on this knowledge and to translate the understanding of recovery after stroke into the clinical setting. Measures that might augment recovery should become a major focus of clinical research in stroke in the 21(st) century. ANN NEUROL 2013. © 2013 American Neurological Association.

Objective:

Genetic epilepsies and many other human genetic diseases display phenotypic heterogeneity, often for unknown reasons. Disease severity associated with nonsense mutations is dependent partially on mutation gene location and resulting efficiency of nonsense mediated mRNA decay (NMD) to eliminate potentially toxic proteins. Nonsense mutations in the last exon do not activate NMD, thus producing truncated proteins. We compared the protein metabolism and the impact on channel biogenesis, function and cellular homeostasis of truncated γ2 subunits produced by GABRG2 nonsense mutations associated with epilepsy of different severities and by a nonsense mutation in the last exon unassociated with epilepsy.

Methods:

GABAA receptor subunits were coexpressed in nonneuronal cells and neurons. NMD was studied using minigenes that support NMD. Protein degradation rates were determined using (35) S radiolabeling pulse chase. Channel function was determined by whole cell recordings while subunits trafficking and cellular toxicity were determined using flow cytometry, immunoblotting and immunohistochemistry.

Results:

Although all GABRG2 nonsense mutations resulted in loss of γ2 subunit surface expression, the truncated subunits had different degradation rates and stabilities, suppression of wildtype subunit biogenesis and function, amounts of conjugation with polyubiquitin and endoplasmic reticulum stress levels. Interpretation: We compared molecular phenotypes of GABRG2 nonsense mutations. The findings suggest that despite the common loss of mutant allele function, each mutation produced different intracellular levels of trafficking-deficient subunits. The concentration-dependent suppression of wildtype channel function and cellular disturbance resulting from differences in mutant subunit metabolism may contribute to associated epilepsy severities and by implication to phenotypic heterogeneity in many inherited human diseases. ANN NEUROL 2013. © 2013 American Neurological Association.

OBJECTIVE:

To define the role that repeat expansions of a GGGGCC hexanucleotide sequence of the C9orf72 gene play in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A genetic model for ALS was developed to determine whether loss of function of the zebrafish orthologue of C9orf72 (zC9orf72) leads to abnormalities in neuronal development.

METHODS:

C9orf72 mRNA levels were quantified in brain and lymphoblasts derived from FTLD and ALS/FTLD patients and in zebrafish. Knockdown of the zC9orf72 was performed using 2 specific antisense morpholino oligonucleotides to block transcription. Quantifications of spontaneous swimming and tactile escape response, as well as measurements of axonal projections from the spinal cord, were performed.

RESULTS:

Significantly decreased expression of C9orf72 transcripts in brain and lymphoblasts was found in sporadic FTLD and ALS/FTLD patients with normal-size or expanded hexanucleotide repeats. The zC9orf72 is selectively expressed in the developing nervous system at developmental stages. Loss of function of the zC9orf72 transcripts causes both behavioral and cellular deficits related to locomotion without major morphological abnormalities. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts.

INTERPRETATION:

Our results indicate C9orf72 haploinsufficiency could be a contributing factor in the spectrum of ALS/FTLD neurodegenerative disorders. Loss of function of the zebrafish orthologue of zC9orf72 expression in zebrafish is associated with axonal degeneration of motor neurons that can be rescued by expressing human C9orf72 mRNA, highlighting the specificity of the induced phenotype. These results reveal a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease.