Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2

The stem cell-intrinsic model of self-renewal via asymmetric cell division (ACD) posits that fate determinants be partitioned unequally between daughter cells to either activate or suppress the stemness state. ACD is a purported mechanism by which hematopoietic stem cells (HSCs) self-renew, but definitive evidence for this cellular process remains open to conjecture. To address this issue, we chose 73 candidate genes that function within the cell polarity network to identify potential determinants that may concomitantly alter HSC fate while also exhibiting asymmetric segregation at cell division. Initial gene-expression profiles of polarity candidates showed high and differential expression in both HSCs and leukemia stem cells. Altered HSC fate was assessed by our established in vitro to in vivo screen on a subcohort of candidate polarity genes, which revealed 6 novel positive regulators of HSC function: Ap2a2, Gpsm2, Tmod1, Kif3a, Racgap1, and Ccnb1. Interestingly, live-cell videomicroscopy of the endocytic protein AP2A2 shows instances of asymmetric segregation during HSC/progenitor cell cytokinesis. These results contribute further evidence that ACD is functional in HSC self-renewal, suggest a role for Ap2a2 in HSC activity, and provide a unique opportunity to prospectively analyze progeny from HSC asymmetric divisions.     

High Mortality in Late Octogenarians Undergoing Isolated Aortic Valve Replacement for Aortic Valve Stenosis: EuroSCORE Underestimates Mortality in this Cohort

Objectives Considering the expanding technology of catheter-based aortic valve implantation, high-risk patients who would not be suitable for conventional aortic valve replacement (AVR) should be identified.Methods From 1997 to April 2007, 190 patients aged from 80 and 89 years old received isolated AVR. Patients between 80 and 84 years old were categorized as the early octogenarians (n = 148) and patients between 85 and 89 years old were categorized as the late octogenarians (n = 42).Results Thirty days mortality in the early and late octogenarians were 6 and 21%, respectively (p = 0.003). The additive and logistic EuroSCORE were 8.0 ± 2.4 and 8.8 ± 1.8 in the early octogenarians and 13.2 ± 11.8 and 14.6 ± 8.7 in the late octogenarians. Multivariate analysis revealed the late octogenarians (OR 6.7, 95%CL 1.8-24.4, p = 0.004) and poor left ventricular function (OR 8.0, 95%CL 1.2-53.5, p = 0.032) as significant risk factors for 30 days mortality. Early octogenarians showed 1-year, 3-year, 5-year, and 8-year survival of 82.4, 67.6, 54.7, and 33%, respectively. Late octogenarians showed 1-year, 3-year, 5-year, and 8-year survivals of 69.0, 66.2, 41.6, 22.3%, respectively.Conclusions Mortality after AVR in the late octogenarians was very high, and was underestimated by EuroSCORE in this patients group. In late octogenarians, catheter-based aortic valve implantation despite relative low EuroSCORE level could be considered as a reasonable alternative.     

A Case of an Arachnoid Cyst Masquerading as Corticobasal Degeneration

We present an individual, “JD”, a 69-year-old Caucasian, married female with symptoms that included progressive right arm stiffness, tremor, and clumsiness; increasing gait and balance disturbance; increased fatigue and emotionality. Neuropsychological evaluation revealed compromised semantics and language-associated functions; impaired visual constructional ability; markedly reduced cognitive and visuomotor processing speed; low average to average working memory; variable praxis performance; variable abstract reasoning, problem solving, and set shifting; and lower overall intellectual functioning compared to premorbid estimates. Overall, her neuropsychological profile indicated marked compromise of the frontal and left parietal regions. The data coupled with her symptom pattern and demographics partially fit corticobasal degeneration diagnostic criteria. Neuroimaging, however, performed 2 years prior to the assessment and again during the current workup revealed an enlarging arachnoid cyst compressing the left parietal and posterior frontal lobe and a small portion of the right medial frontal-parietal region. We discuss the neuroanatomical substrates involved in her cognitive presentation and how two very distinct pathological processes (corticobasal degeneration, arachnoid cyst) can result in two similar symptom presentations. We summarize how multidisciplinary assessment assists with differential diagnosis and treatment planning.     

Does tin pre-treatment enhance the bond strength of adhesive systems to enamel?

Objectives

The study investigated the modification of composite-to-enamel bond strength by pre-treatment of enamel with a concentrated, acidic SnCl₂-solution.

Methods

Six groups of flat human enamel specimens (n = 44 per group) were treated as follows: OB-H: H₃PO₄ etching, Optibond FL application (primer + adhesive; manufacturer's instructions); OB-S: SnCl₂ pre-treatment, Optibond FL application (primer + adhesive); OB-HS: H₃PO₄ etching + SnCl₂ pre-treatment, Optibond FL application (primer + adhesive); CF-N: Clearfil SE application (primer + bond; manufacturer's instructions); CF-H: H₃PO₄ etching, Clearfil SE application (primer + bond); CF-S: SnCl₂ pre-treatment, Clearfil SE application (primer + bond). Enamel specimens were then built up with resin composite (Clearfil Majesty Esthetic) and stored (100% humidity, 37 °C, 1 week). μTBS-measurement and failure mode analysis of one-half of the specimens were performed immediately after storage, while the other half was analysed after a thermocycling procedure (8500 cycles; 5 °C and 55 °C; dwell time 30 s). Additional specimens were prepared for SEM- and EDX-analysis.

Results

Highest values were measured for OB-H before and after thermocycling, lowest values for CF-N. Compared to OB-H treatment, OB-S treatment reduced μTBS before/after thermocycling by 23%/28% and OB-HS treatment by 8%/24% (except for OB-SH before (n.s.), all p ≤ 0.001 compared to OB-H). In the Clearfil SE treated groups pre-treatment increased μTBS significantly compared to CF-N (before/after: CF-H: +46%/+70%; CF-S: +51%/42%; all p ≤ 0.001).

Conclusion

Pre-treatment with H₃PO₄ or SnCl₂ markedly increased the μTBS of Clearfil SE to enamel. However, thermocycling partly reduced the gain in μTBS obtained by SnCl₂ pre-treatment.

Clinical significance

The application of an acidic and highly concentrated SnCl₂ solution is a good option to increase the μTBS between enamel and a resin composite mediated by an adhesive system containing the multifunctional monomer MDP.     

Implementation of HIV early infant diagnosis and HIV type 1 RNA viral load determination on dried blood spots in Cameroon: challenges and propositions

The testing of dried blood spots (DBSs) for human immunodeficiency type 1 (HIV-1) proviral DNA by PCR is a technology that has proven to be particularly valuable in diagnosing exposed infants. We implemented this technology for HIV-1 early infant diagnosis (EID) and HIV-1 RNA viral load determination in infants born of HIV-1-seropositive mothers from remote areas in Cameroon. The samples were collected between December 2007 and September 2010. Fourteen thousand seven hundred and sixty-three (14,763) DBS samples from infants born of HIV-positive mothers in 108 sites nationwide were tested for HIV. Of these, 1452 were positive on first PCR analyses (PCR1), giving an overall infection rate of 12.30%. We received only 475 DBS specimen for a second PCR testing (PCR2); out of these, 145 were positive. The median HIV-1 RNA viral load for 169 infant DBS samples tested was 6.85 log copies/ml, with values ranging from 3.37 to 8 log copies/ml. The determination of the viral load on the same DBS as that used for PCR1 allowed us to bypass the PCR2. The viral load values were high and tend to decrease with age but with a weak slope. The high values of viral load among these infants call for early and effective administration of antiretroviral therapy (ART). The findings from this study indicate that the use of DBS provides a powerful tool for perinatal screening programs, improvement on the testing algorithm, and follow-up during treatment, and thus should be scaled up to the entire nation.     

Genetic variation in the neuropeptide y gene promoter is associated with increased risk of tobacco smoking

Background: Neuropeptide Y (NPY) is a strong candidate gene regarding the pathophysiology of tobacco dependence. It has been associated with various addictive and psychiatric disorders, and closely interacts with the brain reward system. The aim of the present study was to test for association between a functional genetic variant in the NP-Y promoter gene (SNP rs16147) and tobacco smoking. Methods: In a population-based case-control multicenter study designed for tobacco addiction research, a total of 550 Caucasian current smokers, and 544 never-smokers were genotyped for SNP rs16147 and behaviorally characterized with the State-Trait Anxiety Inventory (STAI). Results: Subjects with TT genotype of the SNP rs16147 were significantly more frequently smokers than never-smokers (p = 0.046). In addition, TT genotype exhibited increased state anxiety scores compared to carriers of the C allele (p = 0.037). Conclusions: Our results provide evidence for an involvement of the functionally relevant SNP rs16147 in the pathophysiology of tobacco dependence. Further studies are needed to confirm our findings.     

The relationship of input and output phonological processing: An evaluation of models and evidence to support them

In this paper, we review studies of the relationship between input and output phonological processing and discuss the means by which an interactive activation model that assumes a single phonological network or functionally connected input and output phonological networks could account for apparent dissociations of these two pathways. Following this, we report data from 24 aphasic subjects with word processing deficits that indicate associations between input and output phonological processing. Input phonological measures correlated with output phonological measures, but not with output lexical-semantic measures. Input lexical-semantic measures did not significantly correlate with any of the output measures. We identified one subject, EF, who did not show this overall pattern. She performed well on two measures of phonological input processing (discrimination and rhyme judgements), but produced a high rate of phonological errors in picture naming. On an auditory lexical decision task, however, EF produced a high rate of false alarm errors (misperception of nonwords as words). False alarm errors have been attributed to a disturbance in input phonological processing. Consistent with this hypothesis, the rates of false alarm errors made by this group of subjects on the same auditory lexical decision task correlated with (1) input tasks that require maintaining activation of phonological representations and (2) a measure of output phonological processing (rates of phonologically related nonword errors in picture naming). These results are discussed with reference to current approaches to the study of input and output phonological processing and possible future investigations of this question.     

Immediate and short‐term effects of contextual priming on word retrieval in aphasia

Background: Many therapy techniques for word retrieval disorders use some form of priming to improve access to words. Priming can facilitate or interfere with naming under different circumstances. We examined effects of priming when combined with semantic or phonological context (training words in groups that are semantically or phonologically related) and how these effects interact with the type of naming impairment (semantically or phonologically based). Aims: We addressed three questions (1) Are word retrieval impairments differentially sensitive to priming with semantic or phonological contexts? (2) Would such differences be systematically related to deficits of semantic versus phonological processing? (3) Do effects of priming evolve from immediate interference to short‐term facilitation, as predicted by an interactive activation model of word retrieval? Methods & Procedures: A total of 11 chronic English‐speaking aphasic subjects with varied types of aphasia participated in this experiment. Background measures of semantic and phonological processing ability were administered to determine the nature of each subject's naming impairment. The experiment involved one‐session facilitation treatments for each of three context conditions (semantic, phonological, and unrelated), plus three replications (nine subjects) or one replication (two subjects). Ten pictures in each condition were tested before and after treatment. Five pictures were trained and five served as controls. Participants repeated the name of each picture four times (repetition priming) and then attempted to name each picture individually (naming probe). Repetition priming and naming probes were repeated eight times. We used McNemar tests to compare rates of correct responses before and after priming, and chi square analyses of correct responses and contextual errors on naming probes obtained during the priming sessions. Outcome & results: Our predictions were borne out in the data. Participants varied in their sensitivity to the semantic and phonological contexts. The error data suggest that interference during training is more likely when the context (semantic or phonological) and underlying source of the word processing impairment (semantic or phonological) match. Additionally, we found two sequential effects of contextual priming: immediate interference followed short‐term facilitation. Conclusions: These data have theoretical implications regarding the time course of priming effects, but also have important clinical implications. The present contextual priming procedure is relatively short and could be used as a predictor of performance patterns in a long‐term treatment protocol that uses this approach or other tasks that employ priming.