Chromosomal rearrangements and genetic structure at different evolutionary levels of the Sorex araneus group.

Robertsonian (Rb) fusions received large theoretical support for their role in speciation, but empirical evidence is often lacking. Here, we address the role of Rb rearrangements on the genetic differentiation of the karyotypically diversified group of shrews, Sorex araneus. We compared genetic structure between 'rearranged' and 'common' chromosomes in pairwise comparisons of five karyotypic taxa of the group. Considering all possible comparisons, we found a significantly greater differentiation at rearranged chromosomes, supporting the role of chromosomal rearrangements in the general genetic diversification of this group. Intertaxa structure and distance were larger across rearranged chromosomes for most of the comparisons, although these differences were not significant. This last result could be explained by the large variance observed among microsatellite-based estimates. The differences observed among the pairs of taxa analysed support the role of both the hybrid karyotypic complexity and the level of evolutionary divergence.

Perfusion abnormalities in hemimegalencephaly

INTRODUCTION: Cerebrovascular changes are rarely discussed in patients with hemimegalencephaly. These alterations have previously been associated with epileptical activity. CASE: We report the case of a 36-week gestation neonate presenting with total right hemimegalencephaly, as demonstrated by a magnetic resonance imaging (MRI) performed in the first days of life. Perfusion-weighted imaging displayed a clear hypervascularization of the right hemisphere. Diffusion-tensor imaging showed an arrangement of white matter fibers concentrically around the ventricle on the right hemisphere. AngioMRI showed an obvious asymmetry in the size of the middle cerebral arteries, with the right middle cerebral artery being prominent. The baby was free of clinical seizures during his first week of life. An electroencephalogram at that time displayed an asymmetric background activity, but no electrical seizures. CONCLUSION: Perfusion anomalies in hemimegalencephaly may not necessarily be related to epileptical activity, but may be related to vessel alterations.

Early-onset acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and regressive autistic disorders with epileptic EEG abnormalities: the continuing debate.

Early-onset acquired epileptic aphasia (Landau-Kleffner syndrome) may present as a developmental language disturbance and the affected child may also exhibit autistic features. Landau-Kleffner is now seen as the rare and severe end of a spectrum of cognitive-behavioural symptoms that can be seen in idiopathic (genetic) focal epilepsies of childhood, the benign end being the more frequent typical rolandic epilepsy. Several recent studies show that many children with rolandic epilepsy have minor developmental cognitive and behavioural problems and that some undergo a deterioration (usually temporary) in these domains, the so-called "atypical" forms of the syndrome. The severity and type of deterioration correlate with the site and spread of the epileptic spikes recorded on the electroencephalogram within the perisylvian region, and continuous spike-waves during sleep (CSWS) frequently occur during this period of the epileptic disorder. Some of these children have more severe preexisting communicative and language developmental disorders. If early stagnation or regression occurs in these domains, it presumably reflects epileptic activity in networks outside the perisylvian area, i.e. those involved in social cognition and emotions. Longitudinal studies will be necessary to find out if and how much the bioelectrical abnormalities play a causal role in these subgroup of children with both various degrees of language and autistic regression and features of idiopathic focal epilepsy. One has to remember that it took nearly 40 years to fully acknowledge the epileptic origin of aphasia in Landau-Kleffner syndrome and the milder acquired cognitive problems in rolandic epilepsies.

Language Regression Associated With Autistic Regression and Electroencephalographic (EEG) Abnormalities: A Prospective Study.

We report a boy, referred at 25 months following a dramatic isolated language regression antedating autistic-like symptomatology. His sleep electroencephalogram (EEG) showed persistent focal epileptiform activity over the left parietal and vertex areas never associated with clinical seizures. He was started on adrenocorticotropic hormone (ACTH) with a significant improvement in language, behavior, and in EEG discharges in rapid eye movement (REM) sleep. Later course was characterized by fluctuations/regressions in language and behavior abilities, in phase with recrudescence of EEG abnormalities prompting additional ACTH courses that led to remarkable decrease in EEG abnormalities, improvement in language, and to a lesser degree, in autistic behavior. The timely documentation of regression episodes suggesting an "atypical" autistic regression, striking therapy-induced improvement, fluctuation of symptomatology over time could be ascribed to recurrent and persisting EEG abnormalities.

Abnormalities of fuel utilization as predisposing to the development of obesity in humans.

A number of recent investigations in man have demonstrated that a low ratio of fat to carbohydrate oxidation (i.e., a high respiratory quotient or RQ) was associated with actual and/or subsequent body weight gain in obese non-diabetic Pima Indians, in American men of various ages and in post-obese European women investigated shortly after the cessation of a hypocaloric diet. It is well known that numerous exogenous and endogenous factors influence the RQ at rest such as: the level of feeding (positive vs. negative energy balance), the composition of food eaten (high vs. low carbohydrate), the size of the glycogen stores, the amount of adipose tissue as well as genetic factors. It should be stressed that some nutritional situations can co-exist during which a low ratio of fat to carbohydrate is observed (i.e., a high RQ) despite weight loss. Furthermore, in most studies mentioned above, the low fat to carbohydrate oxidation ratio explains less than 10% of the variance in weight gain, suggesting that numerous additional factors also play a substantial role in the onset of weight gain. It is concluded that: 1) a low fat to carbohydrate oxidation ratio or an abnormal fat oxidation is difficult to define quantitatively since it is largely influenced by the energy level and the composition of the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Multimodal Highlighting of Structural Abnormalities in Diabetic Rat and Human Corneas.

PURPOSE: This study aimed to highlight structural corneal changes in a model of type 2 diabetes, using in vivo corneal confocal microscopy (CCM). The abnormalities were also characterized by transmission electron microscopy (TEM) and second harmonic generation (SHG) microscopy in rat and human corneas. METHODS: Goto-Kakizaki (GK) rats were observed at age 12 weeks (n = 3) and 1 year (n = 6), and compared to age-matched controls. After in vivo CCM examination, TEM and SHG microscopy were used to characterize the ultrastructure and the three-dimensional organization of the abnormalities. Human corneas from diabetic (n = 3) and nondiabetic (n = 3) patients were also included in the study. RESULTS: In the basal epithelium of GK rats, CCM revealed focal hyper-reflective areas, and histology showed proliferative cells with irregular basement membrane. In the anterior stroma, extracellular matrix modifications were detected by CCM and confirmed in histology. In the Descemet's membrane periphery of all the diabetic corneas, hyper-reflective deposits were highlighted using CCM and characterized as long-spacing collagen fibrils by TEM. SHG microscopy revealed these deposits with high contrast, allowing specific detection in diabetic human and rat corneas without preparation and characterization of their three-dimensional organization. CONCLUSION: Pathologic findings were observed early in the development of diabetes in GK rats. Similar abnormalities have been found in corneas from diabetic patients. TRANSLATIONAL RELEVANCE: This multidisciplinary study highlights diabetes-induced corneal abnormalities in an animal model, but also in diabetic donors. This could constitute a potential early marker for diagnosis of hyperglycemia-induced tissue changes.

A clonal Plasmodium falciparum population in an isolated outbreak of malaria in the Republic of Cabo Verde

We present the first parasitological, molecular and longitudinal analysis of an isolated outbreak of malaria. This outbreak occurred on Santiago Island (Republic of Cabo Verde), a region where malaria is hypoendemic and controlled, and thus the population is considered non-immune. Blood samples were collected from the inhabitants over 1 month and during cross-sectional surveys in the following year. The presence and nature of the parasites was determined by PCR. Plasmodium falciparum was the only species detected. Genetic analysis revealed that the circulating parasites were genetically homogeneous, and probably clonal. Gametocytes were found throughout this period. Our data suggest that this represented a focal outbreak, resulting in the infection of at least 40% of the villagers with a clonal parasite line. Thus, P. falciparum infections can persist for at least 1 year in a substantial proportion (10%) of the hosts. Implications for malaria control and the interpretation of epidemiological data are discussed.

Case study of intracerebral plasmacytoma as an initial presentation of multiple myeloma.

Cerebral involvement is an uncommon complication of multiple myeloma. We report on a 64-year-old man hospitalized for a partial seizure. MRI showed two intracerebral lesions, which proved to be plasmacytomas. After complete staging, we retained the diagnosis of immunoglobulin G lambda-type multiple myeloma with CNS involvement. Cytogenetic analysis of plasma cells detected a deletion in the p53 gene at 17p13.1. Despite cranial radiotherapy and systemic chemotherapy, the patient's disease progressed rapidly and he died five months after diagnosis. What makes this case unusual is that overt multiple myeloma had been absent before cerebral involvement was discovered. It confirms the extremely poor prognosis of patients with CNS myeloma even in the presence of aggressive treatment. Cytogenetic abnormalities could be a marker of chromosomal and genetic instability, conferring to multiple myeloma a more aggressive profile.

Trends in the prevalence, risk and pregnancy outcome of multiple births with congenital anomaly: a registry-based study in 14 European countries 1984-2007.

OBJECTIVE: To assess the public health consequences of the rise in multiple births with respect to congenital anomalies. DESIGN: Descriptive epidemiological analysis of data from population-based congenital anomaly registries. SETTING: Fourteen European countries. POPULATION: A total of 5.4 million births 1984-2007, of which 3% were multiple births. METHODS: Cases of congenital anomaly included live births, fetal deaths from 20 weeks of gestation and terminations of pregnancy for fetal anomaly. MAIN OUTCOME MEASURES: Prevalence rates per 10,000 births and relative risk of congenital anomaly in multiple versus singleton births (1984-2007); proportion prenatally diagnosed, proportion by pregnancy outcome (2000-07). Proportion of pairs where both co-twins were cases. RESULTS: Prevalence of congenital anomalies from multiple births increased from 5.9 (1984-87) to 10.7 per 10,000 births (2004-07). Relative risk of nonchromosomal anomaly in multiple births was 1.35 (95% CI 1.31-1.39), increasing over time, and of chromosomal anomalies was 0.72 (95% CI 0.65-0.80), decreasing over time. In 11.4% of affected twin pairs both babies had congenital anomalies (2000-07). The prenatal diagnosis rate was similar for multiple and singleton pregnancies. Cases from multiple pregnancies were less likely to be terminations of pregnancy for fetal anomaly, odds ratio 0.41 (95% CI 0.35-0.48) and more likely to be stillbirths and neonatal deaths. CONCLUSIONS: The increase in babies who are both from a multiple pregnancy and affected by a congenital anomaly has implications for prenatal and postnatal service provision. The contribution of assisted reproductive technologies to the increase in risk needs further research. The deficit of chromosomal anomalies among multiple births has relevance for prenatal risk counselling.

Impact of recombination on genetic variability within Staphylococcus aureus clonal complexes.

The population structure of Staphylococcus aureus is generally described as highly clonal and is consequently subdivided into several clonal complexes (CCs). Recent data suggested that recombination might occur more frequently within than among CCs. To test this hypothesis as well as to understand how genetic diversity is created in S. aureus, we analyzed a collection of 182 isolates with MLST and five highly variable core adhesion (ADH) genes. As expected the polymorphism of ADH genes was higher than MLST genes. However both categories of genes showed low within CCs diversity with a dominant haplotype and its single nucleotide variants. Several recombination events were detected but none involved intra-CC recombination. This did not confirm the hypothesis of higher recombination within CCs. Nevertheless, molecular analyses of variance indicated that these few recombination events have a significant impact on the genetic diversity within CCs. In addition, although most ADH genes were under purifying selection, signs of positive selection associated with a recombinant group were detected. These data highlight the importance of recombination on the evolution of the highly clonal S. aureus and suggest that recombination when combined with demographic mechanisms as well as selection might favor the rapid creation of new clonal complexes.

The population genetics of clonal and partially clonal diploids.

The consequences of variable rates of clonal reproduction on the population genetics of neutral markers are explored in diploid organisms within a subdivided population (island model). We use both analytical and stochastic simulation approaches. High rates of clonal reproduction will positively affect heterozygosity. As a consequence, nearly twice as many alleles per locus can be maintained and population differentiation estimated as F(ST) value is strongly decreased in purely clonal populations as compared to purely sexual ones. With increasing clonal reproduction, effective population size first slowly increases and then points toward extreme values when the reproductive system tends toward strict clonality. This reflects the fact that polymorphism is protected within individuals due to fixed heterozygosity. Contrarily, genotypic diversity smoothly decreases with increasing rates of clonal reproduction. Asexual populations thus maintain higher genetic diversity at each single locus but a lower number of different genotypes. Mixed clonal/sexual reproduction is nearly indistinguishable from strict sexual reproduction as long as the proportion of clonal reproduction is not strongly predominant for all quantities investigated, except for genotypic diversities (both at individual loci and over multiple loci).

Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats.

We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.