Action performance and action-word understanding: evidence of double dissociations in left-damaged patients

It has been proposed that language and action representational systems overlap when the tasks used to assess them involve the same stimuli and require abilities acquired at similarly early developmental stage. We matched variables at task and stimulus level to test this hypothesis in a group of 12 left-damaged patients (and 17 controls). At the patients' group level, we replicated previously reported correlations between linguistic and nonlinguistic tasks. When performances were analysed individually, however, double dissociations were observed between the ability to imitate pantomimes and the ability to produce and comprehend the corresponding action verbs, as well as between the ability to use tools and the ability to comprehend the corresponding tool nouns. These findings suggest that processing action words is independent of the ability to produce the associated object-directed actions. Double dissociations were also found between the ability to comprehend action verbs and the ability to comprehend tool nouns. Moreover, action and tool naming showed differential effects of age of acquisition, suggesting that the two word categories meet the lexical organization by word class (nouns and verbs), even when related to identical action concept. Dissociations at behavioural level are supported by anatomical dissociations shown in the analysis of patients' lesions.     

Streptococcus pyogenes Isolates Causing Severe Infections in Norway in 2006 to 2007: emm Types,Multilocus Sequence Types,and Superantigen Profiles

To investigate the epidemiological patterns and genetic characteristics of disease caused by group A Streptococcus (GAS), all available isolates from invasive cases in Norway during 2006 to 2007 (262 isolates) were subjected to antimicrobial susceptibility testing, T serotyping, emm typing, and multilocus sequence typing and screened for known streptococcal pyrogenic exotoxin (Spe) genes, smeZ, and ssa. The average incidence rate was 3.1 cases per 100,000 individuals. The most prevalent sequence types (STs) were STs 52, 28, and 334. In association with emm types 28, 77, and 87, the serotype T-28 comprised 24.8% of the strains. emm types 28, 1, and 82 were dominating. In 2007, a sharp increase in the number of emm-6 strains was noted. All strains were sensitive to penicillin and quinupristin-dalfopristin, while 3.4% and 6.1% of the strains were resistant to macrolides and tetracycline, respectively. Furthermore, the emm-6 strains had intermediate susceptibility to ofloxacin. Isolates displayed a wide variety of gene profiles, as shown by the presence or absence of the Spe genes, smeZ, and ssa, but 48% of the isolates fell into one of three profiles. In most cases, an emm type was restricted to one gene profile. Although the incidence decreased during this study, invasive GAS disease still has a high endemic rate, with involvement of both established and emerging emm types displaying variability in virulence gene profiles as well as differences in gender and age group preferences.Group A streptococcus (GAS), Streptococcus pyogenes, is a highly prevalent Gram-positive human pathogen with a worldwide distribution. Most often, it causes superficial infections of the upper respiratory tract and of the skin, leading to pharyngitis and impetigo, respectively. Invasive GAS infections, on the other hand, can be life-threatening due to conditions such as bacteremia, cellulitis, erysipelas, meningitis, and pneumonia, including the severe manifestations of necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS) (8). In a historical perspective, GAS has been associated with high fatality rates due to severe scarlet fever, puerperal sepsis, and systemic disease (24). With the introduction of antibiotics in the 1940s, incidence rates of severe GAS infections dropped in developed countries and stayed low until the 1980s. Increased virulence and invasiveness then resulted in an increased number of reported septicemia, NF, and STSS cases in previously healthy children and adults in the United States and Europe (14, 33, 49).S. pyogenes harbors a large number of virulence factors that contribute to its complex pathogenicity (7, 12). One of the major virulence factors, the M protein, encoded by the emm gene, confers antiphagocytic properties and induces a type-specific host immune response. Another important group of virulence factors, targeted by anti-T sera, are the pilin proteins, producing pilus-like structures (40) involved in adhesion and invasion of eukaryotic cells and in biofilm formation (1, 31). The streptococcal pyrogenic exotoxins (Spe proteins), a family of bacterial superantigens, are potent immunostimulators associated with disease conditions such as acute rheumatic fever, scarlet fever, and STSS (12, 54). In total, 11 superantigens have been identified in GAS to date, including SpeA, SpeC, SpeG to -M, streptococcal mitogenic exotoxin Z (SmeZ), and streptococcal superantigen (SSA). Because of an issue with the naming of some of the more recently discovered superantigens and for the sake of simplicity, SpeK/L (4, 21, 45), SpeL/M (45, 52), and SpeM (52) are here referred to as SpeK, SpeL, and SpeM, respectively. The proteins SpeB, a cysteine protease, and SpeF, a DNase, were previously considered to be superantigens due to contamination with the potent SmeZ protein (7, 44). Except for speG, speJ, and smeZ, most genes encoding superantigens are associated with bacteriophages (4, 17, 18). Phages are believed to be the major contributors to genetic variation in GAS, both between strains and within strains of the same type (2, 4). Isolates of the same emm type usually share a superantigen profile. Variants differing by the presence or absence of one or a few genes may occur, however, and geographic and temporal differences in the superantigen content of strains of a given emm type have been reported (11).The M protein has traditionally been targeted for serotyping of GAS strains because of its importance as a virulence determinant. However, sequencing of the emm gene (3) is now becoming the standard method, and to date, more than 150 emm types have been described (36). Another method, which has been used for the last 50 years and is still an important alternative to serological M typing, is T typing using slide agglutination tests (39). Multilocus sequence typing (MLST), a widely used method for genetic characterization of organisms of a bacterial species, which is based on the nucleotide sequence variation in seven housekeeping genes, provides unambiguous results that are easily comparable between laboratories (15). Although geographical and temporal variation has been described for GAS populations (15, 35, 47), strains with the same emm type isolated as much as 50 years apart may harbor identical allelic profiles (15) and share the same T type (23). Due to the clonal population structure of S. pyogenes strains, results obtained by T typing, emm typing, and MLST correlate with each other (15, 23, 53).Norway experienced relatively low incidence rates of severe GAS disease after the introduction of antibiotics, but in the mid-1980s there was an increased occurrence of severe invasive disease, especially in otherwise healthy young adults, largely caused by M-1 strains (9, 33). Thereafter, until the early 2000s, there was a significant decrease in the frequency of emm-1 strains and, at the same time, an increase in diversity among the Norwegian GAS strains (37). Antibiotic resistance levels were generally very low in Norway during this period (37).In more recent reports from the United States (2000 to 2004) and the United Kingdom (2003 to 2004), emm-1 and emm-3 strains were still among the most frequent strains found in invasive GAS disease (29, 43). The overall distributions of the most prevalent emm types in Europe and the United States during this period were in congruence, but there were marked differences in the emm type distributions between countries such as Norway''s neighbors, Denmark, Finland, and Sweden (29). The most prominent difference was seen in Finland, where 45% of the strains were emm-28 strains (29). Recently, Finland also reported a rapid change in genotype prevalence caused by the previously uncommon emm type 84 during 2005 to 2007 (50).The distribution of GAS strains and the virulence factors associated with the different strains are not stable over time. Therefore, epidemiological studies targeting genetic types, important virulence factors, and the antimicrobial susceptibility status of these microorganisms are of basic importance for detection of new emerging clones, determination of their potential to cause disease, and development and refinement of vaccines. To provide better insight into the current epidemiological situation for severe GAS infections in Norway, we characterized all available isolates from invasive GAS disease obtained in 2006 to 2007, using emm typing, MLST, spe gene profiling, including smeZ and ssa, and antibiotic resistance screening using selected antibiotics.     

Lonomia obliqua (Lepidoptera, Saturniidae) caterpillar bristle extract induces direct lysis by cleaving erythrocyte membrane glycoproteins

Lonomia obliqua caterpillar bristle extract induces hemolysis in vitro on washed human and rat erythrocytes, in either the absence or presence of exogenous lecithin. In the former condition, phospholipases A₂ are key enzymes involved in hemolysis. However, the mechanism whereby this extract causes direct hemolysis is not known. Thus, the aim of this study was to investigate the hemolytic mechanism of the crude extract of the caterpillar L. obliqua on human erythrocytes in the absence of lecithin. The extract significantly increased the erythrocyte osmotic fragility and promoted the removal of glycophorins A and C, and band 3 from the erythrocyte membrane. The use of Ca²⁺ and Mg²⁺ ions significantly potentiated glycoprotein removal, remarkably of erythrocyte band 3. The composition of fatty acids was analyzed by HPLC in both L. obliqua caterpillar bristle extract and human erythrocyte membranes incubated with the extract. The levels of unsaturated fatty acids were remarkably augmented in erythrocytes incubated with the extract than in control erythrocytes, modifying thereby the saturated/unsaturated fatty acid ratio. Altogether, evidence is provided here that the interplay of at least three mechanisms of action accounts for the direct activity of the bristle extract on erythrocyte membrane, leading to hemolysis: the removal of glycoproteins and band 3; the insertion of fatty acids; and the action of phospholipases. Such mechanisms might affect erythrocyte flexibility and deformability, which may induce hemolysis by increasing erythrocyte fragility. However, whether the direct hemolytic activity of L. obliqua caterpillar is the major cause of intravascular hemolysis during envenomation still needs further investigation.     

High risk of non-sentinel node metastases in a group of breast cancer patients with micrometastases in the sentinel node

Axillary lymph node dissection (ALND) in breast cancer patients with positive sentinel nodes is under debate. We aimed to establish two models to predict non-sentinel node (NSN) metastases in patients with micrometastases or isolated tumor cells (ITC) in sentinel nodes, to guide the decision for ALND. A total of 1,577 breast cancer patients with micrometastases and 304 with ITC in sentinel nodes, treated by sentinel lymph node dissection and ALND in 2002-2008 were identified in the Danish Breast Cancer Cooperative Group database. Risk of NSN metastases was calculated according to clinicopathological variables in a logistic regression analysis. We identified tumor size, proportion of positive sentinel nodes, lymphovascular invasion, hormone receptor status and location of tumor in upper lateral quadrant of the breast as risk factors for NSN metastases in patients with micrometastases. A model based on these risk factors identified 5% of patients with a risk of NSN metastases on nearly 40%. The model was however unable to identify a subgroup of patients with a very low risk of NSN metastases. Among patients with ITC, we identified tumor size, age and proportion of positive sentinel nodes as risk factors. A model based on these risk factors identified 32% of patients with risk of NSN metastases on only 2%. Omission of ALND would be acceptable in this group of patients. In contrast, ALND may still be beneficial in the subgroup of patients with micrometastases and a high risk of NSN metastases.     

MDM2 309 polymorphism predicts outcome in platinum-treated locally advanced head and neck cancer

Chemo-radiotherapy (CRT) with cisplatin-based regimens is curative in a subset of patients with locally advanced (stage III and IV) squamous carcinomas of the head and neck (LAHNSCC), but causes considerable toxicity. To seek predictive biomarkers, we analysed single nucleotide polymorphisms (SNPs) in the p53 and MDM2 genes in LAHNSCC patients treated with cisplatin-based CRT. We analysed germ-line p53 72 Arg/Pro (R/P) and MDM2 309 SNPs and somatic p53 mutational status in 140 LAHNSCC and determined their utility as predictive biomarkers. In cases with wild-type p53, overall survival (OS) was longest in 72RR (median OS=60.8 months) and less favourable in 72PP (median OS=6.7 months, p<0.0001). OS in individuals with 72RP was intermediate between 72RR and 72PP, while in patients with missense p53 mutations, median OS did not reach statistical significance. Median OS was significantly shorter in patients with MDM2 309 SNP genotypes GG or GT, compared to TT (15 vs. 86 months; p<0.0001). The predictive effect of the G allele was maintained independent of age, gender, stage, primary site, nodal status, performance status, EGFR grade, HPV status, p53 mutation and p53 SNP (HR for death 3.241; 95% CI 1.90-5.52, p<0.001). The predictive utility of the MDM2 germ-line 309 SNP, which can be easily determined from peripheral blood, implies that it may be of value in the objective selection of patients for radical CRT. In contrast, the predictive utility of the 72 Arg/Pro SNP in p53 requires mutational analysis of p53, limiting its routine clinical use.     

Porokeratosis of Mibelli: Successful treatment with 5 percent topical imiquimod and topical 5 percent 5-fluorouracil

Porokeratosis of Mibelli (PM) is a clonal disorder of keratinization. It clinically presents with one or more annular plaques with central atrophy and elevated keratotic borders. With a 7.5 percent risk of malignancy, PM should be treated to prevent transformation into squamous cell carcinoma, Bowen disease, or basal cell carcinoma. Multiple treatment options are available, however, there is not one universally effective treatment. We describe the successful treatment of porokeratosis of Mibelli of the left calf in an 83-year-old man with topical 5 percent imiquimod and topical 5 percent 5-fluorouracil.     

Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake

BACKGROUND:

The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring.

METHODS:

The authors used a case‐control study design to examine the association between retinoblastoma risk and maternal variations in the folate‐metabolizing genes methylenetetrahydrofolate reductase (MTHFR) (a cytosine‐to‐thymine substitution at nucleotide 677 [MTHFR677C→T]; reference single nucleotide polymorphism rs1801133) and dihydrofolate reductase (DHFR) (a 19‐base‐pair deletion of intron 1a [DHFR19bpdel]; rs70991108). In central Mexico, 103 mothers of children with newly diagnosed unilateral retinoblastoma were enrolled in an institutional review board‐approved study along with a control group of 97 mothers who had healthy children. Mothers were interviewed regarding perinatal characteristics, including use of prenatal vitamin supplements, and gave peripheral blood samples, which were used for polymerase chain reaction‐based genotyping of rs1801133 and rs70991108.

RESULTS:

The risk of having a child with unilateral retinoblastoma was associated with maternal homozygosity for DHFR19bpdel (odds ratio, 3.78; 95% confidence interval, 1.89‐7.55; P = .0002), even after controlling for the child's DHFR19bpdel genotype (odds ratio, 2.81; 95% confidence interval, 1.32‐5.99; P = .0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel‐associated risk was elevated significantly only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to the risk of having a child with retinoblastoma.

CONCLUSIONS:

Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biologic folate was associated with an increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population. Cancer 2012. © 2012 American Cancer Society.