Quantitative studies of lower motor neuron degeneration in amyotrophic lateral sclerosis : Evidence for exponential decay of motor unit numbers and greatest rate of loss at the site of onset

Objective: To use our Bayesian method of motor unit number estimation (MUNE) to evaluate lower motor neuron degeneration in ALS. Methods: In subjects with ALS we performed serial MUNE studies. We examined the repeatability of the test and then determined whether the loss of MUs was fitted by an exponential or Weibull distribution. Results: The decline in motor unit (MU) numbers was well-fitted by an exponential decay curve. We calculated the half life of MUs in the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and/or extensor digitorum brevis (EDB) muscles. The mean half life of the MUs of ADM muscle was greater than those of the APB or EDB muscles. The half-life of MUs was less in the ADM muscle of subjects with upper limb than in those with lower limb onset. Conclusions: The rate of loss of lower motor neurons in ALS is exponential, the motor units of the APB decay more quickly than those of the ADM muscle and the rate of loss of motor units is greater at the site of onset of disease. Significance: This shows that the Bayesian MUNE method is useful in following the course and exploring the clinical features of ALS. 2012 International Federation of Clinical Neurophysiology.

A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset : HapMap tag-single-nucleotide polymorphism analysis

Background: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain which is known to be important in the aetiology of schizophrenia. It is therefore not surprising that most antipsychotic medication acts on the Dopamine D2 receptor. DRD2 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. Methods: To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single nucleotide polymorphisms (SNPs) in DRD2 using a multiplex mass spectrometry method. SNPs were chosen using a haplotype block-based gene-tagging approach so the entire DRD2 gene was represented. Results: One polymorphism rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. Individuals carrying the genetic variation were more than twice as likely to have schizophrenia compared to controls. Conclusions: Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor age of onset.

Exploring Genetic Factors Involved in Huntington Disease Age of Onset: E2F2 as a New Potential Modifier Gene

Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample of 35 HD patients from Basque Country Hospitals. We found suggestive association signals between HD eAO and/or mAO and genetic variation within the E2F2, ATF7IP, GRIN2A, GRIN2B, LINC01559, HIP1 and GRIK2 genes. Among them, the most significant was the association between eAO and rs2742976, mapping to the promoter region of E2F2 transcription factor. Furthermore, rs2742976 T allele patient carriers exhibited significantly lower lymphocyte E2F2 gene expression, suggesting a possible implication of E2F2-dependent transcriptional activity in HD pathogenesis. Thus, E2F2 emerges as a new potential HD AO modifier factor.

Estimation of the size of onset of sexual maturity in Nephrops norvegicus (L.).

Size at onset of maturity (SOM) was estimated for both male and female Nephrops from primary sexual characteristics and morphometric traits. SOM estimated from primary sexual characteristics based on histological examination of the gonad ranged from 15.1 mm carapace length (CL) in males to 22.9 mm CL in females. Nephrops morphometric maturity, or change in allometric growth of body parts, was estimated from appendix masculina and cutter claw lengths in males and abdomen width in females from two sites in the Irish Sea. Two regression techniques were used to estimate morphometric maturity. Estimated SOM from morphometric characteristics ranged from 23.2 to 27.6 mm CL in females and from 25.9 to 31.0 mm CL in males. Spatial variation in SOM was observed in Nephrops from different parts of the Irish Sea.

Carriage of apoE epsilon 4 lowers the age of onset of Alzheimer's Disease in Northern Ireland

Alzheimer's disease is the most common neurodegenerative disorder affecting those in mid to late adult life. Carriage of an apolipoprotein E (apoE) epsilon 4 allele has been shown to be associated with an increased risk of developing AD in numerous studies involving populations of various races and ethnic backgrounds. It has also been suggested that carriage of this allele reduces the age of onset of AD. To investigate this, we carried out a genetic association study utilising 108 sporadic late-onset AD patients and age, sex and ethnically-matched controls from Northern Ireland. Findings of this study verified the risk of AD associated with carriage of the apoE epsilon 4 allele in a dose-dependent manner (p

Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests that one modifier may reside in the region close to the HD gene itself. We used data from 535 HD participants of the New England Huntington cohort and the HD MAPS cohort to assess whether AO was influenced by any of the three markers in the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo box 7, HOX7), Delta2642 (within the HD coding sequence), and BJ56 (D4S127). Suggestive evidence for an association was seen between MSX1 alleles and AO, after adjustment for normal CAG repeat, expanded repeat, and their product term (model P value 0.079). Of the variance of AO that was not accounted for by HD and normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals with MSX1 genotype 3/3 tended to have younger AO. No association was found between Delta2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous studies suggesting that there may be a significant genetic modifier for AO in HD in the 4p16 region. Furthermore, the modifier may be present on both HD and normal chromosomes bearing the 3 allele of the MSX1 marker.

How different are the correlates of onset and continuation of civil wars?

It is very common to analyse the factors associated with the onset and continuation of civil wars entirely separately, as if there were likely to be no similarity between them. This is an overstatement of the theoretical position, which has established only that they may be different (i.e. less than perfectly correlated). The hypothesis that the explanatory variables are the same is not theoretically excludable and is empirically testable, both for individual variables and for combinations of them. Starting from this approach yields a rather different picture of the factors associated with the continuation of civil wars, because the relatively small sample size means that confidence intervals on individual coefficients are wide in this case. It is shown here that country size, mountainous terrain and (in most datasets) ethnic diversity seem significant for the continuation of civil wars, starting from the null hypothesis that variables affect onset and continuation probabilities identically, rather than entirely independently. One variable that affects onset and continuation significantly differently is anocracy, which we find to matter only for onset. Civil war is more likely if it occurred two years previously, as well as one year previously, which indicates that wars are more likely to restart after only one year of peace, and also more likely to stop in their first year. The combined model strengthens the result that ethnic diversity matters (it is consistently significant across datasets, whereas it is not when onset is analysed separately), although in the UCD/PRIO dataset it is significant only for onset. By contrast, if continuation is analysed independently, virtually nothing is significant except a pre-1991 dummy and a dummy for civil war two years previously.

Predictors of onset of depression and anxiety in the year after diagnosis of breast cancer

Background Depression and anxiety are common after diagnosis of breast cancer. We examined to what extent these are recurrences of previous disorder and, controlling for this, whether shame, self-blame and low social support after diagnosis predicted onset of depression and anxiety subsequently. Method Women with primary breast cancer who had been treated surgically self-reported shame, self-blame, social support and emotional distress post-operatively. Psychiatric interview 12 months later identified those with adult lifetime episodes of major depression (MD) or generalized anxiety disorder (GAD) before diagnosis and onset over the subsequent year. Statistical analysis examined predictors of each disorder in that year. Results Of the patients, two-thirds with episodes of MD and 40% with episodes of GAD during the year after diagnosis were experiencing recurrence of previous disorder. Although low social support, self-blame and shame were each associated with both MD and GAD after diagnosis, they did not mediate the relationship of disorder after diagnosis with previous disorder. Low social support, but not shame or self-blame, predicted recurrence after controlling for previous disorder. Conclusions Anxiety and depression during the first year after diagnosis of breast cancer are often the recurrence of previous disorder. In predicting disorder following diagnosis, self-blame and shame are merely markers of previous disorder. Low social support is an independent predictor and therefore may have a causal role.

Older age of onset in child L2 acquisition can be facilitative: evidence from the acquisition of English passives by Spanish natives

We report a longitudinal comprehension study of (long) passive constructions in two native-Spanish child groups differing by age of initial exposure to L2 English (young group: 3;0-4;0 years; older group: 6;0-7;0 years); where amount of input, L2 exposure environment, and socio-economic status are controlled. Data from a forced-choice task show that both groups comprehend active sentences, not passives, initially (after 3.6 years of exposure). One year later, both groups improve, but only the older group reaches ceiling on both actives and passives. Two years from initial testing, the younger group catches up. Input alone cannot explain why the younger group takes 5 years to accomplish what the older group does in 4. We claim that some properties take longer to acquire at certain ages because language development is partially constrained by general cognitive and linguistic development (e.g. de Villiers, 2007; Long & Rothman, 2014; Paradis, 2008, 2010, 2011; Tsimpli, 2014).