Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites.

Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ɛ4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aß1₋42 levels, suggesting a role for the CR1 protein in Aß metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Impact of tongue reduction on overall speech intelligibility, articulation and oromyofunctional behavior in 4 children with Beckwith-Wiedemann syndrome.

OBJECTIVE: The purpose of this study was to determine the impact of partial glossectomy (using the keyhole technique) on speech intelligibility, articulation, resonance and oromyofunctional behavior. PATIENTS AND METHODS: A partial glossectomy was performed in 4 children with Beckwith- Wiedemann syndrome between the ages of 0.5 and 3.1 years. An ENT assessment, a phonetic inventory, a phonemic and phonological analysis and a consensus perceptual evaluation of speech intelligibility, resonance and oromyofunctional behavior were performed. RESULTS: It was not possible in this study to separate the effects of the surgery from the typical developmental progress of speech sound mastery. Improved speech intelligibility, a more complete phonetic inventory, an increase in phonological skills, normal resonance and increased motor-oriented oral behavior were found in the postsurgical condition. The presence of phonetic distortions, lip incompetence and interdental tongue position were still present in the postsurgical condition. CONCLUSION: Speech therapy should be focused on correct phonetic placement and a motor-oriented approach to increase lip competence, and on functional tongue exercises and tongue lifting during the production of alveolars. Detailed analyses in a larger number of subjects with and without Beckwith-Wiedemann syndrome may help further illustrate the long-term impact of partial glossectomy.

The promise of self-determination theory to study the therapist-client relationship in speech-language treatment.

This study aims at examining the therapist-client relationship in speech-language treatment and its relationships with clients' motivation from the perspective of Self-Determination Theory (SDT). It adds to the current literature by relying on observations as well as client perceptions of the therapists' interaction style and by studying three different age groups of adults (>18 years old), adolescents (12-18 years old) as well as children (<12 years). Two convenience samples: 1) 42 Speech Language Therapists (SLPs; 95.2 % female) and 72 individuals with communication disorders (ICDs) (72.2 % female;>12 years old), and 2) 21 SLPs (100 % female) and 44 ICDs (50 % girls; <12 years) were recruited for this cross-sectional study. After engaging in a treatment session, ICDs responded to a set of validated questionnaires measuring the SLPs' motivating style, their need-based experiences and motivation towards the treatment. Moreover, each treatment session was observed. Both client-reported as well as observational measures show that SLPs more strongly evince an autonomy-supportive (i.e. motivating) when compared to a controlling (i.e. demotivating) style to the benefit of their clients' motivation. The display of empathy was the most frequently observed strategy. SLPs regularly provided rationales, choices, and opportunities for clients to experiment. However, these behaviors were more frequent in younger compared to older clients. With the younger clients, SLPs frequently used effort-contingent rewards, which is considered a controlling strategy in SDT. Results showed that motivational benefits may be expected if SLPs rely on an autonomy-supportive rather than a controlling style. This study provides a valuable starting point for an SDT-driven examination of the therapist-client relationship and ICD's motivation in the context of speech-language pathology.

Short-term effect of short, intensive speech therapy on articulation and resonance in Ugandan patients with cleft (lip and) palate.

OBJECTIVES: The purpose of the current study was to assess the short-term effectiveness of short and intensive speech therapy provided to patients with cleft (lip and) palate (C(L)P) in terms of articulation and resonance. METHODS: Five Ugandan patients (age: 7.3-19.6 years) with non-syndromic C(L)P received six hours of individualized speech therapy in three to four days. Speech therapy focused on correct phonetic placement and contrasts between oral and nasal airflow and resonance. Speech evaluations performed before and immediately after speech therapy, including perceptual and instrumental assessment techniques, were compared. RESULTS: Post-therapy, improvement of speech was noted for most of the patients, although to varying degrees. Clinically relevant progress of objective nasalance values and/or articulation was obtained in four patients. Overall, two patients showed normal speech intelligibility, while three patients required additional speech therapy. CONCLUSION: These preliminary short-term results demonstrate that short and intensive speech therapy can be effective for patients with C(L)P in countries with limited access to speech-language therapy. However, further research is needed on the long-term effectiveness and the advantages of applying this treatment protocol in countries with good access to speech therapy. LEARNING OUTCOMES: The reader will be able to (1) list the challenges in resource poor-countries to achieve access to speech-language therapy services, (2) describe when the application of speech therapy is appropriate in patients with C(L)P, (3) describe the speech therapy that can be applied to reduce compensatory articulation and resonance disorders in patients with C(L)P, and (4) list the (possible) advantages of short, intensive speech therapy for both resource-poor and developed countries.

Intrathecal labor analgesia: can we use the same mixture as is used epidurally?

In a randomized double-blind study, three groups of 25 term parturients received one of the following intrathecal drugs or combinations for relief of labor pain: sufentanil 7.5 microg (1.5 ml), sufentanil 5 microg + bupivacaine 1 mg (1.5 ml) or the combination bupivacaine 1.75 mg, sufentanil 1.05 microg and epinephrine 1.75 microg, that is 1.5 ml of our standard epidural mixture. After the intrathecal injection, patients received a peridural catheter for supplementation of analgesia. Onset and duration of the three regimens were similar. Analgesia lasted for approximately 95-115 minutes which was similar to durations obtained with the subsequent epidural top-ups. Pruritus was observed significantly less frequently in the group treated intrathecally with the epidural mixture. The incidence of other maternal side-effects was extremely low and not different among the groups. Instrumental delivery, Apgar scores and umbilical blood gases were identical. More cardiotocographic changes were observed in the plain sufentanil group but this was not related to neonatal outcome. It was concluded that intrathecal injection of the standard epidural mixture offers effective and long-lasting analgesia. This may avoid side-effects and complications, manipulations of drugs with the risk for contamination, spilling of drugs and loss of time.

Target controlled infusion of remifentanil and propofol for cesarean section in a patient with multivalvular disease and severe pulmonary hypertension.

A 36 year old parturient with known valvular heart disease was admitted with respiratory distress and fatigue after 35 weeks of pregnancy. Echocardiography revealed severe tricuspid regurgitation, mitral stenosis and aortic valve insufficiency. Following clinical examination and insertion of a radial and pulmonary artery catheter it was decided to perform a Caesarean Section. The pulmonary artery pressure upon arrival in the operating theatre was 105/50 mm Hg whereas cardiac output was 3.5 l/min. Induction of anesthesia was performed with a target controlled infusion of remifentanil and propofol combined with rocuronium bromide. Haemodynamic variables remained very stable during and after intubation. The lungs of the apnoeic baby were manually ventilated until spontaneous respiration began at 1 minute post delivery. Apgar scores were 3, 7 and 9 after 1, 5 and 10 minutes respectively. Umbilical artery pH was 7.29. The patient's haemodynamic status gradually improved over the following few days. Two months following delivery she underwent unevenful valvular surgery.

Speech characteristics in a Ugandan child with a rare paramedian craniofacial cleft: a case report.

The purpose of this study is to describe the speech characteristics in an English-speaking Ugandan boy of 4.5 years who has a rare paramedian craniofacial cleft (unilateral lip, alveolar, palatal, nasal and maxillary cleft, and associated hypertelorism). Closure of the lip together with the closure of the hard and soft palate (one-stage palatal closure) was performed at the age of 5 months. Objective as well as subjective speech assessment techniques were used. The speech samples were perceptually judged for articulation, intelligibility and nasality. The Nasometer was used for the objective measurement of the nasalance values. The most striking communication problems in this child with the rare craniofacial cleft are an incomplete phonetic inventory, a severely impaired speech intelligibility with the presence of very severe hypernasality, mild nasal emission, phonetic disorders (omission of several consonants, decreased intraoral pressure in explosives, insufficient frication of fricatives and the use of a middorsum palatal stop) and phonological disorders (deletion of initial and final consonants and consonant clusters). The increased objective nasalance values are in agreement with the presence of the audible nasality disorders. The results revealed that several phonetic and phonological articulation disorders together with a decreased speech intelligibility and resonance disorders are present in the child with a rare craniofacial cleft. To what extent a secondary surgery for velopharyngeal insufficiency, combined with speech therapy, will improve speech intelligibility, articulation and resonance characteristics is a subject for further research. The results of such analyses may ultimately serve as a starting point for specific surgical and logopedic treatment that addresses the specific needs of children with rare facial clefts.

Role of the endocardial endothelium in the negative inotropic effects of thiopental.

BACKGROUND: Myocardial function is regulated by endocardial endothelium (EE). Several studies have demonstrated the involvement of vascular endothelium in regulating the vasoactive effects of anesthetic agents. Because vascular endothelium and EE form a contiguous layer, it was postulated that EE might also be involved in regulating the inotropic effects of anesthetics. The effects of thiopental on isolated feline papillary muscle with and without EE were examined. METHODS: The study was performed on isolated cat papillary muscles (n = 48). The effects of increasing doses of thiopental (1.5, 3, 6, 9, 12, and 24 micrograms/ml) on isometric and isotonic muscle contraction parameters were evaluated in three protocols under different experimental conditions. In the first protocol, the effects of thiopental were studied in the muscles with an intact EE (group A, n = 8) and muscles in which the EE was selectively damaged by a 1-s immersion in 0.5% Triton X-100 (group B, n = 8). In the second protocol, cumulative concentration responses for thiopental were obtained in muscles with (group C, n = 8) and without (group D, n = 8) EE, pretreated with 10(-3) M of the blocking NG-nitro-L-arginine methyl ester (L-NAME). In the third protocol, the same cumulative concentration responses were obtained for thiopental in muscles with (group E, n = 8) and without (group F, n = 8) EE after pretreatment with 5 x 10(-4) M L-arginine. RESULTS: In the presence of an intact EE, thiopental induced a dose-dependent decrease in myocardial function. With the EE removed, low doses of thiopental (1.5 to 6 micrograms/ml) no longer altered myocardial function. Pretreatment of the muscles with L-NAME inhibited the negative inotropic effects of low doses of thiopental and mimicked the response obtained after EE was removed. Pretreatment with L-arginine slightly accentuated the negative inotropic effects of low doses of thiopental. CONCLUSIONS: The negative inotropic actions of small doses of thiopental depend on the presence of an intact EE. Pretreatment of the muscles with L-NAME inhibited the negative inotropic effects of low doses of thiopental, suggesting possible involvement of the nitric oxide pathway.