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Background: Left ventricular (LV) wall stress reduction is a cornerstone in treating heart failure. Large animal models and computer simulations indicate that adding non-contractile material to the damaged LV wall can potentially reduce myofiber stress. We sought to quantify the effects of a novel implantable hydrogel (Algisyl-LVR™) treatment in combination with coronary artery bypass grafting (i.e. Algisyl-LVR™+CABG) on both LV function and wall stress in heart failure patients., Methods and Results: Magnetic resonance images obtained before treatment (n=3), and at 3 months (n=3) and 6 months (n=2) afterwards were used to reconstruct the LV geometry. Cardiac function was quantified using end-diastolic volume (EDV), end-systolic volume (ESV), regional wall thickness, sphericity index and regional myofiber stress computed using validated mathematical modeling. The LV became more ellipsoidal after treatment, and both EDV and ESV decreased substantially 3 months after treatment in all patients; EDV decreased from 264 ± 91 ml to 146 ± 86 ml and ESV decreased from 184 ± 85 ml to 86 ± 76 ml. Ejection fraction increased from 32 ± 8% to 47 ± 18% during that period. Volumetric-averaged wall thickness increased in all patients, from 1.06 ± 0.21 cm (baseline) to 1.3 ± 0.26 cm (3 months). These changes were accompanied by about a 35% decrease in myofiber stress at end-of-diastole and at end-of-systole. Post-treatment myofiber stress became more uniform in the LV., Conclusions: These results support the novel concept that Algisyl-LVR™+CABG treatment leads to decreased myofiber stress, restored LV geometry and improved function., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Existing evidence is controversial regarding the association between BRAF mutation status and aggressive features of papillary thyroid cancer (PTC). Specifically, no study has incorporated multiple surgical practices performing routine central lymph node dissection (CLND) and thus has patients who are truly evaluable for the presence or absence of central lymph node metastases (CLNMs)., Methods: Consecutive patients who underwent total thyroidectomy and routine CLND at 4 tertiary endocrine surgery centers were retrospectively reviewed. Descriptive and bivariable analyses examined demographic, patient, and tumor-related factors. Multivariable analyses examined the odds of CLNM associated with positive BRAF status., Results: In patients with classical variant PTC, bivariate analysis found no significant associations between BRAF mutation and aggressive clinicopathologic features; multivariate analysis demonstrated that BRAF status was not an independent predictor of CLNM. When all patients with PTC were analyzed, including those with aggressive or follicular subtypes, bivariate analysis showed BRAF mutation to be associated with LNM, advanced American Joint Committee on Cancer (AJCC) stage, and histologic subtype. Multivariable analyses showed BRAF, age, size, and extrathyroidal extension to be associated with CLNM., Conclusion: Although BRAF mutation was found to be an independent predictor of central LNM in the overall cohort of patients with PTC, this relationship lost significance when only classical variant PTC was included in the analysis. The usefulness of BRAF in predicting the presence of LNM remains questionable. Prospective studies are needed before BRAF mutation can be considered a reliable factor to guide the treatment of patients with PTC, specifically whether to perform prophylactic CLND.

We developed a novel aerosol-mediated drug delivery system for inner ear therapy by using a silicon-based multiple-Fourier horn nozzle. Intratympanic aerosol (ITA) methylprednisolone (MP) delivery can protect hearing after acoustic trauma. The highest concentration of MP (38.9 ± 5.47 ppm) appeared at 2 h and declined rapidly within 10 h. The concentrations of MP remained at a relatively low level for more than 10 h. Compared to the baseline, the auditory brainstem response (ABR) thresholds shifted markedly at 1 h after noise exposure in all groups (p < 0.05). From the cochleograms, it can be noted that the main lesions encompassed the 2-20 kHz frequency range. Significant differences ( ) were observed for the range between 5 and 8 kHz in the cell loss of outer hair cells (OHCs). The losses for IHCs were lower than for OHCs. The MP movement in the middle ear was simulated by a convection diffusion equation with a relaxation time. The relaxation time was 0.5 h, and the concentration threshold of MP on the round window membrane (RWM) in the middle ear (C T) was 8900 ppm. Using the unit hydrograph (UH) method, we obtained a proper boundary concentration on the RWM at the cochlea, which resulted in a well-fit concentration. Finally, a linking mechanism between the middle ear and the cochlea was established by the RWM. The adjustable permeability and concentration threshold provide the flexibility to match the peak times and peak values of the concentration on the RWM in the middle ear and the cochlea.

Surgical ventricular restoration (SVR) is a procedure designed to treat heart failure by surgically excluding infarcted tissues from the dilated failing left ventricle. To elucidate and predict the effects of geometrical changes from SVR on cardiac function, we created patient-specific mathematical (finite-element) left ventricular models before and after surgery using untagged magnetic resonance images. Our results predict that the postsurgical improvement in systolic function was compromised by a decrease in diastolic distensibility in patients. These two conflicting effects typically manifested as a more depressed Starling relationship (stroke volume vs. end-diastolic pressure) after surgery. By simulating a restoration of the left ventricle back to its measured baseline sphericity, we show that both diastolic and systolic function improved. This result confirms that the increase in left ventricular sphericity commonly observed after SVR (endoventricular circular patch plasty) has a negative impact and contributes partly to the depressed Starling relationship. On the other hand, peak myofiber stress was reduced substantially (by 50%) after SVR, and the resultant left ventricular myofiber stress distribution became more uniform. This significant reduction in myofiber stress after SVR may help reduce adverse remodeling of the left ventricle. These results are consistent with the speculation proposed in the Surgical Treatment for Ischemic Heart Failure trial (20) for the neutral outcome, that "the lack of benefit seen with surgical ventricular reconstruction is that benefits anticipated from surgical reduction of left ventricular volume (reduced wall stress and improvement in systolic function) are counter-balanced by a reduction in diastolic distensibility."

Serotonin, a neurotransmitter found throughout the brain and body, has long been of interest in autism. Repeated findings of elevated platelet serotonin levels in approximately one third of children with autism has led some to believe that dysfunctional serotonin signaling may be a causal mechanism for the disorder. Because serotonin is critical to fetal brain development, concerns have arisen regarding prenatal exposure to substances that manipulate serotonin levels, such as selective serotonin reuptake inhibitors (SSRIs). This review examines evidence regarding the serotonin system and autism spectrum disorders (ASD), as well as what the literature has reported thus far on developmental effects of prenatal exposure to SSRIs. Possible mechanisms by which SSRIs could affect the fetus during pregnancy and clinical implications are also discussed. Though the majority of studies conducted in infants and children suggest prenatal exposure to SSRIs does not affect neurodevelopment, interpretation must be tempered given small sample sizes. The only published study that focused on prenatal SSRI exposure and ASD found an increased risk with exposure to SSRIs, especially during the first trimester. Obstacles that will be faced in future research are isolating medication effects from maternal depression and, given the infrequent occurrence of exposure and outcome, obtaining an adequate sample size. Whether serotonin is an etiologic factor in ASD, and what it points to as a marker for subgrouping, remains unclear. Understanding how the development of ASD might be affected by prenatal factors that influence serotonin levels, such as SSRIs, could identify modifiable targets for prevention., (© 2013 International Society for Autism Research, Wiley Periodicals, Inc.)

V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) is a key activator of the ERK pathway and is a target for cross-regulation of this pathway by the cAMP signaling system. The cAMP-activated protein kinase, PKA, inhibits Raf-1 by phosphorylation on S259. Here, we show that the cAMP-degrading phosphodiesterase-8A (PDE8A) associates with Raf-1 to protect it from inhibitory phosphorylation by PKA, thereby enhancing Raf-1's ability to stimulate ERK signaling. PDE8A binds to Raf-1 with high (picomolar) affinity. Mapping of the interaction domain on PDE8A using peptide array technology identified amino acids 454-465 as the main binding site, which could be disrupted by mutation. A cell-permeable peptide corresponding to this region disrupted the PDE8A/Raf-1 interaction in cells, thereby reducing ERK activation and the cellular response to EGF. Overexpression of a catalytically inactive PDE8A in cells displayed a dominant negative phenotype on ERK activation. These effects were recapitulated at the organism level in genetically modified (PDE8A(-/-)) mice. Similarly, PDE8 deletion in Drosophila melanogaster reduced basal ERK activation and sensitized flies to stress-induced death. We propose that PDE8A is a physiological regulator of Raf-1 signaling in some cells.

Injection of Algisyl-LVR, a treatment under clinical development, is intended to treat patients with dilated cardiomyopathy. This treatment was recently used for the first time in patients who had symptomatic heart failure. In all patients, cardiac function of the left ventricle (LV) improved significantly, as manifested by consistent reduction of the LV volume and wall stress. Here we describe this novel treatment procedure and the methods used to quantify its effects on LV wall stress and function. Algisyl-LVR is a biopolymer gel consisting of Na(+)-Alginate and Ca(2+)-Alginate. The treatment procedure was carried out by mixing these two components and then combining them into one syringe for intramyocardial injections. This mixture was injected at 10 to 19 locations mid-way between the base and apex of the LV free wall in patients. Magnetic resonance imaging (MRI), together with mathematical modeling, was used to quantify the effects of this treatment in patients before treatment and at various time points during recovery. The epicardial and endocardial surfaces were first digitized from the MR images to reconstruct the LV geometry at end-systole and at end-diastole. Left ventricular cavity volumes were then measured from these reconstructed surfaces. Mathematical models of the LV were created from these MRI-reconstructed surfaces to calculate regional myofiber stress. Each LV model was constructed so that 1) it deforms according to a previously validated stress-strain relationship of the myocardium, and 2) the predicted LV cavity volume from these models matches the corresponding MRI-measured volume at end-diastole and end-systole. Diastolic filling was simulated by loading the LV endocardial surface with a prescribed end-diastolic pressure. Systolic contraction was simulated by concurrently loading the endocardial surface with a prescribed end-systolic pressure and adding active contraction in the myofiber direction. Regional myofiber stress at end-diastole and end-systole was computed from the deformed LV based on the stress-strain relationship.

Objective: The DSM-IV-TR specifies 12 behavioral features that can occur in hundreds of possible combinations to meet diagnostic criteria for autism spectrum disorder (ASD). This paper describes the frequency and variability with which the 12 behavioral features are documented in a population-based cohort of 8-year-old children under surveillance for ASD, and examines whether documentation of certain features, alone or in combination with other features, is associated with earlier age of community identification of ASD., Method: Statistical analysis of behavioral features documented for a population-based sample of 2,757 children, 8 years old, with ASD in 11 geographically-defined areas in the US participating in the Autism and Developmental Disabilities Monitoring Network in 2006., Results: The median age at ASD identification was inversely associated with the number of documented behavioral features, decreasing from 8.2 years for children with only seven behavioral features to 3.8 years for children with all 12. Documented impairments in nonverbal communication, pretend play, inflexible routines, and repetitive motor behaviors were associated with earlier identification, whereas impairments in peer relations, conversational ability, and idiosyncratic speech were associated with later identification., Conclusions: The age dependence of some of the behavioral features leading to an autism diagnosis, as well as the inverse association between age at identification and number of behavioral features documented, have implications for efforts to improve early identification. Progress in achieving early identification and provision of services for children with autism may be limited for those with fewer ASD behavioral features, as well as features likely to be detected at later ages., (Copyright © 2013 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Introduction: We aimed to evaluate the local incidences of hydronephrosis and renal impairment in the presence of severe uterovaginal or vault prolapse, and determine whether treatment by surgery or ring pessary resulted in the resolution of hydronephrosis in these patients., Methods: This was a retrospective case study of 121 patients who presented with severe uterovaginal or vault prolapse. All patients who had fourth degree uterovaginal or vault prolapse, and underwent renal ultrasonography and renal function blood tests were included in the study. Follow-up imaging for hydronephrosis was performed to determine the outcome after patients received treatment., Results: The mean age of the study population was 66.1 years. The overall incidence of hydronephrosis was 20.6%. The incidence of hydronephrosis in patients with severe vault prolapse was 7.1%, while that in patients with severe uterovaginal prolapse was 22.4%. Of the 25 patients with hydronephrosis, 16 (64.0%) had complete resolution of hydronephrosis after treatment, 5 (20.0%) had residual but smaller degrees of hydronephrosis, and 4 (16.0%) were lost to follow-up. The incidence of renal impairment was 3.3%., Conclusion: The local incidence of hydronephrosis in patients with severe uterovaginal or vault prolapse was 20.6% in our study. We established that 3.3% of women with severe uterovaginal or vault prolapse had mild renal impairment. Treatment by vaginal surgery for severe uterovaginal or vault prolapse appears to result in either complete resolution or improvement of hydronephrosis in the majority of patients.

The cAMP signaling system can trigger precise physiological cellular responses that depend on the fidelity of many protein-protein interactions, which act to bring together signaling intermediates at defined locations within cells. In the heart, cAMP participates in the fine control of excitation-contraction coupling, hence, any disregulation of this signaling cascade can lead to cardiac disease. Due to the ubiquitous nature of the cAMP pathway, general inhibitors of cAMP signaling proteins such as PKA, EPAC and PDEs would act non-specifically and universally, increasing the likelihood of serious 'off target' effects. Recent advances in the discovery of peptides and small molecules that disrupt the protein-protein interactions that underpin cellular targeting of cAMP signaling proteins are described and discussed.

Physical functional ability and nutritional status are two major indicators for predicting the risk of mortality in older adults. The present study examined the complementarity of the Activities of Daily Living (ADL) and the Mini-Nutritional Assessment (MNA) for predicting follow-up 4-year all-cause mortality risk in elderly Taiwanese. We analysed data of the 'Survey of Health and Living Status of the Elderly in Taiwan', a population-based longitudinal cohort study which involved 2872 men and women of ≥ 65 years old at baseline (1999). We rated their functional dependency with the ADL scale and nutritional status with the MNA (both the long form, LF and the short form, SF) at baseline, and analysed the complementarity of the two scales in predicting follow-up 4-year all-cause mortality with Cox regression analysis and the net reclassification improvement (NRI) to quantify the improvement. The results showed that both ADL and MNA offered improvement in predicting follow-up mortality risk beyond that predicted by either one alone according to the Akaike information criterion and the NRI. The MNA-SF was nearly as effective as the MNA-LF in improving the predictive ability of the ADL. The present study suggests that the MNA (especially the SF because of its simplicity and time-saving feature) together with the ADL scale might be of value for predicting the mortality risk of frail elderly living in various settings.

Background: This study aims to improve accuracy of Bioelectrical Impedance Analysis (BIA) prediction equations for estimating fat free mass (FFM) of the elderly by using non-linear Back Propagation Artificial Neural Network (BP-ANN) model and to compare the predictive accuracy with the linear regression model by using energy dual X-ray absorptiometry (DXA) as reference method., Methods: A total of 88 Taiwanese elderly adults were recruited in this study as subjects. Linear regression equations and BP-ANN prediction equation were developed using impedances and other anthropometrics for predicting the reference FFM measured by DXA (FFMDXA) in 36 male and 26 female Taiwanese elderly adults. The FFM estimated by BIA prediction equations using traditional linear regression model (FFMLR) and BP-ANN model (FFMANN) were compared to the FFMDXA. The measuring results of an additional 26 elderly adults were used to validate than accuracy of the predictive models., Results: The results showed the significant predictors were impedance, gender, age, height and weight in developed FFMLR linear model (LR) for predicting FFM (coefficient of determination, r2 = 0.940; standard error of estimate (SEE) = 2.729 kg; root mean square error (RMSE) = 2.571kg, P < 0.001). The above predictors were set as the variables of the input layer by using five neurons in the BP-ANN model (r2 = 0.987 with a SD = 1.192 kg and relatively lower RMSE = 1.183 kg), which had greater (improved) accuracy for estimating FFM when compared with linear model. The results showed a better agreement existed between FFMANN and FFMDXA than that between FFMLR and FFMDXA., Conclusion: When compared the performance of developed prediction equations for estimating reference FFMDXA, the linear model has lower r2 with a larger SD in predictive results than that of BP-ANN model, which indicated ANN model is more suitable for estimating FFM.

Background: Minocycline is a tetracycline derivative that readily crosses the blood brain barrier and appears to have beneficial effects on neuroinflammation, microglial activation and neuroprotection in a variety of neurological disorders. Both microglial activation and neuroinflammation have been reported to be associated with autism. The study was designed to evaluate the effects of minocycline treatment on markers of neuroinflammation and autism symptomatology in children with autism and a history of developmental regression., Methods: Eleven children were enrolled in an open-label trial of six months of minocycline (1.4 mg/kg). Ten children completed the trial. Behavioral measures were collected and cerebrospinal fluid (CSF), serum and plasma were obtained before and at the end of minocycline treatment and were analyzed for markers of neuroinflammation., Results: Clinical improvements were negligible. The laboratory assays demonstrated significant changes in the expression profile of the truncated form of brain derived neurotrophic factor (BDNF) (P = 0.042) and hepatic growth factor (HGF) (P = 0.028) in CSF. In serum, the ratio of the truncated BDNF form and α-2 macroglobulin (α-2 M), was also significantly lower (P = 0.028) while the mature BDNF/α-2 M ratio revealed no difference following treatment. Only the chemokine CXCL8 (IL-8) was significantly different (P = 0.047) in serum while no significant changes were observed in CSF or serum in chemokines such as CCL2 (MCP-1) or cytokines such as TNF-α, CD40L, IL-6, IFN-γ and IL-1β when pre- and post-treatment levels of these proteins were compared. No significant pre- and post-treatment changes were seen in the profiles of plasma metalloproteinases, putative targets of the effects of minocycline., Conclusions: Changes in the pre- and post-treatment profiles of BDNF in CSF and blood, HGF in CSF and CXCL8 (IL-8) in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotrophic growth factors. However, in this small group of children, no clinical improvements were observed during or after the six months of minocycline administration., Trial Registration: NCT00409747.

Purpose: The purpose of this study was to determine the minimum amount of resistance exercise that would stimulate bone formation, via an elevation in bone mineral density (BMD), during the growth period in male rats., Methods: Forty male rats were randomly divided into control group (Con, n = 8), one ladder climb resistance-trained group (1LC, n = 8), two ladder climb resistance-trained group (2LC, n = 8), three ladder climb resistance-trained group (3LC, n = 8), and four ladder climb resistance-trained group (4LC, n = 8). All exercised groups were conditioned to climb a vertical ladder with weights appended to their tail 3 d·wk(-1) for a total of 6 wk., Results: After 6 wk, left tibia BMD (mean ± SE) was significantly greater for 2LC, 3LC, and 4LC (0.233 ± 0.003 g·cm(-2)) when compared with Con (0.218 ± 0.003 g·cm). Left femur BMD was significantly greater for 2LC, 3LC, and 4LC (0.318 ± 0.003 g·cm(-2)) when compared with 1LC (0.299 ± 0.008 g·cm(-2)) and Con (0.289 ± 0.010 g·cm(-2)).There were no significant differences in BMD between 2LC, 3LC, and 4LC groups., Conclusion: The results suggest that during growth, a low amount of resistance exercise was just as effective as high volumes of strength training for stimulating bone modeling.

Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 as well as Huntington's disease are a group of neurodegenerative disorders caused by expanded CAG repeats encoding a long polyglutamine (polyQ) tract in the respective proteins. Evidence has shown that the accumulation of intranuclear and cytoplasmic misfolded polyQ proteins leads to apoptosis and cell death. Thus suppression of aggregate formation is expected to inhibit a wide range of downstream pathogenic events in polyQ diseases. In this study, we established a high-throughput aggregation screening system using 293 ATXN3/Q75-GFP cells and applied this system to test the aqueous extract of Paeonia lactiflora (P. lactiflora) and its constituents. We found that the aggregation can be significantly prohibited by P. lactiflora and its active compound paeoniflorin. Meanwhile, P. lactiflora and paeoniflorin upregulated HSF1 and HSP70 chaperones in the same cell models. Both of them further reduced the aggregation in neuronal differentiated SH-SY5Y ATXN3/Q75-GFP cells. Our results demonstrate how P. lactiflora and paeoniflorin are likely to work on polyQ-aggregation reduction and provide insight into the possible working mechanism of P. lactiflora in SCA3. We anticipate our paper to be a starting point for screening more potential herbs for the treatment of SCA3 and other polyQ diseases.

Background: Controversy exists regarding the optimal management of incidentally discovered, small pancreatic neuroendocrine tumors (PNETs). Our aim was to review the outcomes of patients who underwent nonoperative and operative management., Methods: We retrospectively reviewed patients with nonfunctioning PNETs at our institution from January 1, 2000 to June 30, 2011. Patients were included if the tumor was sporadic and <4 cm without radiographic evidence of local invasion or metastases., Results: Nonoperative patients (n = 77, median age, 67 years; range, 31-94) had a median tumor size of 1.0 cm (range, 0.3-3.2). Mean follow-up (F/U) was 45 months (max. 153 months). Median tumor size did not change throughout F/U; there was no disease progression or disease specific mortality. In the operative group (n = 56, median age, 60 years; range, 27-82), median neoplasm size was 1.8 cm (range, 0.5-3.6). Mean F/U was 52 months (max. 138 months). A total of 46% of the operative patients had some type of complication, more than half due to a clinically significant pancreatic leak. No recurrence or disease specific mortality was seen in the operative group, including 5 patients with positive lymph nodes., Conclusion: Small nonfunctioning PNETs usually exhibit minimal or no growth over many years. Nonoperative management may be advocated when serial imaging demonstrates minimal or no growth without suspicious features., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: The presence of ischemic mitral regurgitation (IMR) after ST-segment elevation myocardial infarction (STEMI) portends a poorer prognosis. The possible influence of reperfusion therapy in restoring mitral valve competence in inferoposterior STEMI has not been well elucidated., Methods and Results: We studied 423 consecutive patients with a first inferoposterior STEMI and determined the presence of IMR in patients treated with reperfusion therapy versus medical therapy. A primary percutaneous coronary intervention (PCI) was performed in 186 patients; 74 patients underwent thrombolysis, 63 patients had rescue PCI whereas 54 patients were treated medically. The mean time interval between STEMI presentation and echocardiography was 14 ± 27 days. Patients receiving reperfusion therapy had less moderate or severe IMR (2.5 vs. 11.1%, P=0.001). The presence of IMR between the primary PCI and the thrombolytic groups was similar (52.2 vs. 60.8%, P=NS). Left ventricular ejection fraction (47.7 ± 10.3 vs. 53.1 ± 11.4%, P<0.001) and infarct size (mean CK-MB) (271 ± 168 vs. 222 ± 151 U/l, P<0.001) were significantly worse in patients with IMR. Dominance of the coronary artery system, involvement of the right or the left coronary arteries, and the presence of triple-vessel disease did not correlate with the presence of IMR. After adjustment for age and left ventricular ejection fraction, there was a trend toward poorer survival and recurrent admission for heart failure at 1 year in patients with IMR (hazard ratio=2.4, 95% confidence interval 0.91-6.2, P=0.08)., Conclusion: Both thrombolytic therapy and primary PCI were associated with decreased incidences of IMR following inferoposterior STEMI.

Background: Patients with diabetes mellitus have worse long-term outcomes after acute myocardial infarction (AMI) than non-diabetics. This may be related to differential contribution of neutrophil and lymphocyte to inflammation during AMI in diabetics vs. non-diabetics. We aim to determine the predictive value of neutrophil-to-lymphocyte ratio (NLR) for major adverse events post-AMI in Type 2 diabetics vs. non-diabetics., Methods and Results: A total of 2559 consecutive patients admitted for AMI (61 ± 14 years, 73% male and 43% diabetic) were analyzed. A complete blood count was obtained and the NLR computed for each patient on admission. Across the cohort, the 1-year reinfarction rate was 8.4% (n = 214) and 1-year mortality was 14.5% (n = 370). Univariate determinants of the composite endpoint included age, hypertension, hyperlipidemia, smoking, revascularization and NLR (P < 0.001 for all). The cohort was divided into NLR quartiles. Admission NLR was significantly higher in the diabetic group, 5.2 ± 5.8 vs. 4.6 ± 5.4 (P = 0.007). A step-wise increase in the incidence of the composite endpoint was noted across NLR quartiles for diabetic subjects; hazard ratio (HR) was 2.41 for fourth vs. first quartile (95% confidence interval = 1.63-3.53, P < 0.001). Multivariate analysis of the diabetic group showed that NLR remains as an independent predictor of the composite endpoint (adjusted HR = 1.53, 95% confidence interval = 1.00-2.33, P = 0.048). However, in non-diabetics, HR for NLR was not significant (P = 0.35)., Conclusion: Increased NLR post-AMI is an independent predictor of major adverse cardiac events in diabetics. Monitoring this easily obtainable new index allows prognostication and risk stratification.

The cross-cultural validity of the Mandarin-adaptation of the social responsiveness scale (SRS) was examined in a sample of N = 307 participants in Taiwan, 140 typically developing and 167 with clinically-diagnosed developmental disorders. This scale is an autism assessment tool that provides a quantitative rather than categorical measure of social impairment in the general population. SRS total and subscale scores distinguished significantly between autism spectrum disorder and other developmental disorders (p < 0.01). Total SRS scores and sensitivity and specificity of the scale for diagnosing developmental disorders in the Taiwan study were similar to those observed in Western studies. These findings support the cross-cultural validity of the SRS scale for detecting autistic traits and for distinguishing between autism and other neuropsychiatric conditions.

Introduction: This retrospective study assessed the surgical outcomes of patients for whom the transobturator polypropylene mesh kit was used for the management of pelvic organ prolapse (Gynecare Prolift) in a tertiary urogynaecological centre in Singapore from January 1, 2006 to December 31, 2007., Methods: 169 patients (2006 n = 95; 2007 n = 74) with total (n = 76), anterior (n = 82) and posterior (n = 11) Prolifts were followed up for two years post-surgery., Results: Intraoperatively, the incidence of haematoma, blood loss > 1,000 mL and blood transfusion was lower in 2007 than in 2006, although the difference was not statistically significant. One (1.4%) patient had rectal perforation in 2007. The mesh erosion rates were similar for all Prolift types (total 17.2%; posterior 14.5%; anterior 18.2%). Two patients, who had total Prolift in 2006, required mesh excision under anaesthesia for mesh extrusion. 138 (81.7%) patients were available for review at two years - nine (6.5%) patients had recurrent cystourethrocoeles and two (1.4%) had recurrent vault prolapse. Of the nine patients who had total Prolift with uterine conservation, two (1.4%) had recurrent uterine descent. The subjective cure rates two years after Prolift surgery were 98.7% for patients from 2006 and 100% for patients from 2007. The objective cure rates were 89.6% for patients from 2006 and 91.8% for patients from 2007., Conclusion: Prolift mesh surgery appears to have a very high success rate for pelvic reconstructive surgery. The learning curve of the surgeon may, however, be a factor determining surgical outcome in these patients.

The Study to Explore Early Development (SEED), a multisite investigation addressing knowledge gaps in autism phenotype and etiology, aims to: (1) characterize the autism behavioral phenotype and associated developmental, medical, and behavioral conditions and (2) investigate genetic and environmental risks with emphasis on immunologic, hormonal, gastrointestinal, and sociodemographic characteristics. SEED uses a case-control design with population-based ascertainment of children aged 2-5 years with an autism spectrum disorder (ASD) and children in two control groups-one from the general population and one with non-ASD developmental problems. Data from parent-completed questionnaires, interviews, clinical evaluations, biospecimen sampling, and medical record abstraction focus on the prenatal and early postnatal periods. SEED is a valuable resource for testing hypotheses regarding ASD characteristics and causes.

Objective: General surgery (GS) and otolaryngology (OTO) do not require a minimum number of thyroidectomies to qualify for board certification. No standardized criteria exist for declaring competence in this procedure. A survey was created to assess GS and OTO resident perspectives on becoming competent in thyroid surgery., Design: A survey was electronically mailed to all GS and OTO residents assessing their competence in thyroid surgery., Setting: National survey of general surgery and otolaryngology residents., Participants: National general surgery and otolaryngology residents., Results: A convenience sample of 526 residents responded (246/280 = GS/OTO). The mean clinical year of training was 3.3 (3.1/3.5). Most residents (50%/41%) performed between 1 and 10 thyroid operations. Residents believed 13 and 25 (GS/OTO) thyroidectomies were required by their respective Boards. Both groups felt that 30 (27/33) thyroid operations were necessary to obtain competence (p < 0.01). The most important feature was operative volume with graduated responsibility, followed by guidance under an expert mentor. Analysis of residents PGY4 and greater showed no significant differences., Conclusions: While residents of both specialties generally agree on learning methods, the perception of readiness to perform thyroid surgery after training is variable. A disconnect is present between the number of cases required for Board certification, the number of cases residents believe are required, and the number of cases residents believe it takes to achieve competency., (Copyright © 2012 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Reported associations between gestational tobacco exposure and autism spectrum disorders (ASDs) have been inconsistent., Objective: We estimated the association between maternal smoking during pregnancy and ASDs among children 8 years of age., Methods: This population-based case-cohort study included 633,989 children, identified using publicly available birth certificate data, born in 1992, 1994, 1996, and 1998 from parts of 11 U.S. states subsequently under ASD surveillance. Of these children, 3,315 were identified as having an ASD by the active, records-based surveillance of the Autism and Developmental Disabilities Monitoring Network. We estimated prevalence ratios (PRs) of maternal smoking from birth certificate report and ASDs using logistic regression, adjusting for maternal education, race/ethnicity, marital status, and maternal age; separately examining higher- and lower-functioning case subgroups; and correcting for assumed under-ascertainment of autism by level of maternal education., Results: About 13% of the source population and 11% of children with an ASD had a report of maternal smoking in pregnancy: adjusted PR (95% confidence interval) of 0.90 (0.80, 1.01). The association for the case subgroup autistic disorder (1,310 cases) was similar: 0.88 (0.72, 1.08), whereas that for ASD not otherwise specified (ASD-NOS) (375 cases) was positive, albeit including the null: 1.26 (0.91, 1.75). Unadjusted associations corrected for assumed under-ascertainment were 1.06 (0.98, 1.14) for all ASDs, 1.12 (0.97, 1.30) for autistic disorder, and 1.63 (1.30, 2.04) for ASD-NOS., Conclusions: After accounting for the potential of under-ascertainment bias, we found a null association between maternal smoking in pregnancy and ASDs, generally. The possibility of an association with a higher-functioning ASD subgroup was suggested, and warrants further study.

The cyclic AMP-specific phosphodiesterase PDE8 has been shown to play a pivotal role in important processes such as steroidogenesis, T cell adhesion, regulation of heart beat and chemotaxis. However, no information exists on how the activity of this enzyme is regulated. We show that under elevated cAMP conditions, PKA acts to phosphorylate PDE8A on serine 359 and this action serves to enhance the activity of the enzyme. This is the first indication that PDE8 activity can be modulated by a kinase, and we propose that this mechanism forms a feedback loop that results in the restoration of basal cAMP levels., (Copyright © 2012. Published by Elsevier B.V.)

Background: We sought to determine regional myofiber stress after Coapsys device (Myocor, Inc, Maple Grove, MN) implantation using a finite element model of the left ventricle (LV). Chronic ischemic mitral regurgitation is caused by LV remodeling after posterolateral myocardial infarction. The Coapsys device consists of a single trans-LV chord placed below the mitral valve such that when tensioned it alters LV shape and decreases chronic ischemic mitral regurgitation., Methods: Finite element models of the LV were based on magnetic resonance images obtained before (preoperatively) and after (postoperatively) coronary artery bypass grafting with Coapsys implantation in a single patient. To determine the effect of Coapsys and LV before stress, virtual Coapsys was performed on the preoperative model. Diastolic and systolic material variables in the preoperative, postoperative, and virtual Coapsys models were adjusted so that model LV volume agreed with magnetic resonance imaging data. Chronic ischemic mitral regurgitation was abolished in the postoperative models. In each case, myofiber stress and pump function were calculated., Results: Both postoperative and virtual Coapsys models shifted end-systolic and end-diastolic pressure-volume relationships to the left. As a consequence and because chronic ischemic mitral regurgitation was reduced after Coapsys, pump function was unchanged. Coapsys decreased myofiber stress at end-diastole and end-systole in both the remote and infarct regions of the myocardium. However, knowledge of Coapsys and LV prestress was necessary for accurate calculation of LV myofiber stress, especially in the remote zone., Conclusions: Coapsys decreases myofiber stress at end-diastole and end-systole. The improvement in myofiber stress may contribute to the long-term effect of Coapsys on LV remodeling., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Although hyperbaric oxygen therapy has not been accepted as a standard therapy for traumatic brain injuries, it has been used, along with rehabilitative exercises, for traumatic brain injuries, and the standard protocol has a low risk of complications. We report a case of chronic traumatic brain injury that progressed to tension pneumocephalus after hyperbaric oxygen therapy. The patient was a 25-yr-old man who presented with left occipital bone fracture and subarachnoid and subdural hemorrhage after being hit by a car. He underwent craniectomy to remove the hematoma and cerebrospinal fluid diversion with a ventriculoperitoneal shunt for the treatment of hydrocephalus. Fifteen months after the trauma, the patient received hyperbaric oxygen therapy to promote functional recovery. Tension pneumocephalus developed after the first session of hyperbaric oxygen therapy, and immediate burr hole drainage followed by ligation of the ventriculoperitoneal shunt was performed. The patient's consciousness recovered gradually, and he was discharged home. We suggest that patients with unrepaired skull base fracture and cerebrospinal fluid diversion should be carefully evaluated before receiving hyperbaric oxygen therapy.

Nutrition is a key element in geriatric health and is important for functional ability. The present study examined the functional status-predictive ability of the Mini-Nutritional Assessment (MNA). We analysed the dataset of the 'Survey of Health and Living Status of the Elderly in Taiwan', a population-based study conducted by the Bureau of Health Promotion of Taiwan. Study subjects (≥65 years old) who completed both the 1999 and 2003 surveys were rated with the long form and short form of the MNA at baseline and with the Activities of Daily Living (ADL) and the Instrument Activities of Daily Living (IADL) scales 4 years later (end-point). The ability of the MNA to predict ADL or IADL dependency was evaluated with logistic regression models. The results showed that the elderly who were rated malnourished or at risk of malnutrition at baseline generally had significantly higher ADL or IADL scores 4 years later. Lower baseline MNA scores also predicted a greater risk of ADL or IADL dependency. These associations exist even among the elderly who were free of ADL or IADL dependency at baseline. The results clearly indicate that the MNA is able to predict ADL and IADL dependency (in addition to rating current nutritional status) of the elderly. The MNA, especially the short form, should be a valuable tool for identifying elderly at risk of functional decline and/or malnutrition in clinical practice or community programmes.

Cardiac growth and remodeling in the form of chamber dilation and wall thinning are typical hallmarks of infarct-induced heart failure. Over time, the infarct region stiffens, the remaining muscle takes over function, and the chamber weakens and dilates. Current therapies seek to attenuate these effects by removing the infarct region or by providing structural support to the ventricular wall. However, the underlying mechanisms of these therapies are unclear, and the results remain suboptimal. Here we show that myocardial infarction induces pronounced regional and transmural variations in cardiac form. We introduce a mechanistic growth model capable of predicting structural alterations in response to mechanical overload. Under a uniform loading, this model predicts non-uniform growth. Using this model, we simulate growth in a patient-specific left ventricle. We compare two cases, growth in an infarcted heart, pre-operative, and growth in the same heart, after the infarct was surgically excluded, post-operative. Our results suggest that removing the infarct and creating a left ventricle with homogeneous mechanical properties does not necessarily reduce the driving forces for growth and remodeling. These preliminary findings agree conceptually with clinical observations.

Objective: Past research is inconsistent in the stability of autism spectrum disorder (ASD) diagnoses. The authors therefore sought to examine the proportion of children identified from a population-based surveillance system that had a change in classification from ASD to non-ASD and factors associated with such changes., Methods: Children with a documented age of first ASD diagnosis noted in surveillance records by a community professional (n = 1392) were identified from the Autism and Developmental Disabilities Monitoring Network. Children were considered to have a change in classification if an ASD was excluded after the age of first recorded ASD diagnosis. Child and surveillance factors were entered into a multivariable regression model to determine factors associated with diagnostic change., Results: Only 4% of our sample had a change in classification from ASD to non-ASD noted in evaluation records. Factors associated with change in classification from ASD to non-ASD were timing of first ASD diagnosis at 30 months or younger, onset other than developmental regression, presence of specific developmental delays, and participation in a special needs classroom other than autism at 8 years of age., Conclusions: Our results found that children with ASDs are likely to retain an ASD diagnosis, which underscores the need for continued services. Children diagnosed at 30 months or younger are more likely to experience a change in classification from ASD to non-ASD than children diagnosed at 31 months or older, suggesting earlier identification of ASD symptoms may be associated with response to intervention efforts or increased likelihood for overdiagnosis.

Longitudinally extensive transverse myelitis (LETM) is usually associated with neuromyelitis optica and other autoimmune and inflammatory disorders but this is the first report linking it with dengue fever. Dengue infection can cause a variety of neurological complications which may result in poor recovery and long-term disability. The authors report here a patient who developed LETM in the para-infectious stage of dengue fever. The patient had a complicated clinical course resulting in severe paraparesis and urinary retention. Treatment with immunoglobulins and antiviral agents supported by a spell of early intensive rehabilitation programme produced excellent results in terms of recovery.

Background: In clinical heart failure (HF), inefficient propagation of blood through the left ventricle (LV) may result from suboptimal vortex formation (VF) ability of the LV during early diastole. We aim to (i) validate echocardiographic-derived vortex formation time (adapted) (VFTa) in control subjects and (ii) examine its utility in both systolic and diastolic HF., Methods: Transthoracic echocardiography was performed in 32 normal subjects and in 130 patients who were hospitalized with HF [91, reduced ejection fraction (rEF) and 39, preserved ejection fraction (pEF)]. In addition to biplane left ventricular ejection fraction (LVEF) and conventional parameters, the Tei index and tissue Doppler (TD) indices were measured. VFTa was obtained using the formula: 4 × (1 - β)/π × α³ × LVEF, where β is the fraction of total transmitral diastolic stroke volume contributed by atrial contraction (assessed by time velocity integral of the mitral E- and A-waves) and α is the biplane end-diastolic volume (EDV)(1/3) divided by mitral annular diameter during early diastole. VFTa was correlated with demographic, cardiac parameters, and a composite clinical endpoint comprising cardiac death and repeat hospitalization for HF., Results: Mean VFTa was 2.67 ± 0.8 in control subjects; reduced in HF, preserved EF HF, 2.21 ± 0.8; HF with reduced EF, 1.25 ± 0.6 (P< 0.001). It was not affected by age, gender, body surface area but was correlated positively with TD early diastolic myocardial velocities (E', septal, r = 0.46; lateral, r = 0.43), systolic myocardial velocities (S', septal, r = 0.47; lateral, r = 0.41), and inversely with the Tei index (r = -0.41); all Ps < 0.001. Sixty-two HF patients (49%) met the composite endpoint. VFTa of <1.32 was associated with significantly reduced event-free survival (Kaplan Meier log rank = 16.3, P= 0.0001) and predicted the endpoint with a sensitivity and specificity of 65 and 72%, respectively., Conclusion: VFTa, a dimensionless index, incorporating LV geometry, systolic and diastolic parameters, may be useful in the diagnosis and prognosis of HF.

Nutritional status and functional ability are mutually dependent especially in the elderly. This study examined the functional status-predictive ability of the MNA in a cross-sectional study. We analyzed the dataset of the "Survey of Health and Living Status of the Elderly in Taiwan" (SHLSET). Subjects were 2948≥65 year-old persons who were rated with the long-form (LF) and short-form (SF) MNA with or without BMI for the risk of malnutrition, and with the Activities of Daily Living (ADL) and the Instrument Activities of Daily Living (IADL) for functional status. The ADL and IADL scores were calculated according to rated nutritional status. Receiver Operating Characteristic (ROC) curves were generated for ADL and IADL status predicted by the MNA. Logistic regression was performed to evaluate the association of rated MNA scores with ADL or IADL status. Results showed that both SF and LF of MNA-T1 and T2 were able to predict ADL and IADL disabilities. Those who were rated malnourished or at risk of malnutrition had drastically higher risk of ADL or IADL dependency compared to those who were rated normal. The SF versions performed well in rating nutritional status and predicting ADL and IADL status. Overall, MNA-T2-SF performed at least equally well as MNA-T1-SF in rating functional decline. These results suggest the MNA is able to predict functional decline of the elderly. MNA-T2, especially the SF, a version without BMI should be particularly useful in clinical, long-term care and community settings., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Using a quarterly (3-mo) monitoring and bait-replenishment interval, 122 subterranean termite colonies throughout the United States were baited with a refined cellulose bait matrix containing 0.5% noviflumuron. All colonies were eliminated in less than 1 yr after initiation of baiting as determined by long-term monitoring and genetic markers. Sixty-three percent of the colonies were eliminated during the first quarter after the initiation of baiting and 77% of colonies were eliminated after consuming two bait tubes or less. This suggests that a single baiting cycle and bait installed in response to a single active monitoring device were sufficient to eliminate the majority of colonies. Although termites temporarily abandoned stations after depleting bait, workers resumed feeding when baits were replenished. Colonies that consumed large amounts of bait before elimination foraged into multiple stations, thus allowing adequate amounts of bait to sustain feeding. The time to eliminate termite colonies with bait replenished quarterly was similar to that previously reported for laminated cellulose bait replenished monthly. Our data support the conclusion that extending the bait replenishment interval from monthly to quarterly for bait tubes with refined cellulose containing 0.5% noviflumuron did not adversely impact colony elimination.

Objective: : Cognitive dysfunction is common in patients with advanced, life-threatening illness and can be attributed to a variety of factors (e.g., advanced age, opiate medication). Such dysfunction likely affects decisional capacity, which is a crucial consideration as the end-of-life approaches and patients face multiple choices regarding treatment, family, and estate planning. This study examined the prevalence of cognitive impairment and its impact on decision-making abilities among hospice patients with neither a chart diagnosis of a cognitive disorder nor clinically apparent cognitive impairment (e.g., delirium, unresponsiveness)., Design: : A total of 110 participants receiving hospice services completed a 1-hour neuropsychological battery, a measure of decisional capacity, and accompanying interviews., Results: : In general, participants were mildly impaired on measures of verbal learning, verbal memory, and verbal fluency; 54% of the sample was classified as having significant, previously undetected cognitive impairment. These individuals performed significantly worse than the other participants on all neuropsychological and decisional capacity measures, with effect sizes ranging from medium to very large (0.43-2.70). A number of verbal abilities as well as global cognitive functioning significantly predicted decision-making capacity., Conclusion: : Despite an absence of documented or clinically obvious impairment, more than half of the sample had significant cognitive impairments. Assessment of cognition in hospice patients is warranted, including assessment of verbal abilities that may interfere with understanding or reasoning related to treatment decisions. Identification of patients at risk for impaired cognition and decision making may lead to effective interventions to improve decision making and honor the wishes of patients and families.

Background: The temporal progression in extent and severity of regional myofiber contractile dysfunction in normally perfused border zone (BZ) myocardium adjacent to a myocardial infarction (MI) has been shown to be an important pathophysiologic feature of the adverse remodeling process in large animal models. We sought, for the first time, to document the presence of impaired contractility of the myofibers in the human BZ myocardium., Methods: A 62-year-old man who experienced an MI in 1985 and had recently had complete revascularization was studied. Myofiber systolic contractile stress developed in the normally perfused BZ adjacent to the MI (T(max&#95;B)) and that developed in regions remote from the MI (T(max&#95;R)) were quantified using cardiac catheterization, magnetic resonance imaging, and mathematical modeling., Results: The resulting finite element model of the patient's beating left ventricle was able to simulate the reduced systolic strains measured using magnetic resonance imaging at matching left ventricular pressures and volumes. The T(max&#95;B) (73.1 kPa) was found to be greatly reduced relative to T(max&#95;R) (109.5 kPa). These results were found to be independent of assumptions relating to BZ myofiber orientation., Conclusions: The results of this study document the presence of impaired contractility of the myofibers in the BZ myocardium and support its role in the post-MI remodeling process in patients. To fully establish this important conclusion serial evaluations beginning at the time of the index MI will need to be performed in a cohort of patients. The current study supports the importance and demonstrates the feasibility of larger and longer-term studies., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction and Hypothesis: We aim to report the 3-year outcome and complications of the tension-free vaginal tape obturator (TVT-O) in treating female stress urinary incontinence (SUI)., Methods: Retrospective analysis for complications and outcome of surgery was performed in 419 women undergoing the TVT-O from 2004 to 2006., Results: Three patients (0.8%) with an isolated TVT-O had a blood loss of more than 200 ml. Two patients (0.5%) had bladder perforation. Out of 11 readmitted patients (2.6%), 10 were due to voiding difficulty. Six patients (1.4%) required tape loosening or division. Persistent pain occurred in 3.6% and erosion in 2.4% of patients. One hundred eighty-five patients (44.2%) came for follow-up at 3 years. The actual subjective and objective success rates were 89.7% and 99.9% at 3 years follow-up, respectively. With imputation, the 3-year subjective and objective success rates were 86.9% and 97.4%, respectively., Conclusions: The TVT-O is effective in treating female SUI with minimal complications.

A 13-month-old alpaca (Vicugna pacos) was presented for mandibular masses and weight loss. Histopathology of biopsy tissue was consistent with lymphoma. The alpaca was euthanized and necropsy revealed lymphoma masses in multiple organs. Immunohistochemistry for T- and B-cell typing was inconclusive. Serology and in-situ polymerase chain reaction hybridization were positive for bovine leukemia virus.

The apnea-hypopnea index (AHI) is a widely accepted measure for the severity of obstructive sleep apnea (OSA). Current methods to determine AHI fail to provide anatomic information for treatment decisions. In this report, we studied three-dimensional models of upper airways acquired by computed tomographic scanning with geometric measurements and computational fluid dynamics (CFD) analysis and evaluated the correlations with AHI.Participants had CT scans of their upper airways after standard polysomnography studies. Three-dimensional surface models of upper airways were generated for cross-sectional area measurements of the choanae (ACH) and the smallest cross-sectional area (Amin). Computational fluid dynamic analysis was then performed by using this three-dimensional model. Pressure differences required to set tidal volume during inspiration (ΔPmin-INSP) and expiration (ΔPmax-EXP) and minimum negative pressure produced in the level of ACH (Pmin-INSP at ACH) and Amin (Pmin-INSP at Amin) were calculated. Correlations of these parameters and the body mass index with AHI were analyzed. Statistical differences between groups of different AHI ranges were also compared.The pressure distribution simulated by CFD demonstrated abrupt pressure drops in Amin level, and this phenomenon was more significant in severe OSA. All parameters except ACH and Pmin-INSP at Amin significantly correlated with the AHI, and there were significant statistical differences between the OSA groups and the normal group. The results indicate that, in our study group, the geometry of pharyngeal airway and its CFD simulation correlate well with AHI. This model may be further applied for clinical evaluation.

Cross-linking of the reverse micelles (RMs) of a triallylammonium surfactant afforded organic nanoparticles with introverted cationic groups. The cross-linked reverse micelles catalyzed size-selective biphasic reaction between sodium azide and alkyl bromides. Size selectivity of up to 9:1 was obtained for alkyl bromides with similar structures. The selectivity was influenced strongly by the size of the water pool and proposed to happen as a result of the "sieving" effect of the alkyl corona., (© 2012 American Chemical Society)

Objective: This study aimed to investigate descriptive characteristics and co-occurring neurodevelopmental and psychiatric conditions in young children, children, and adolescents with a current and consistent or past but not current (PBNC) diagnosis of autism spectrum disorder (ASD) and how such characteristics and conditions may engender a change in diagnosis of an ASD., Methods: Cross-sectional data of 1366 children with a parent-reported current or PBNC ASD diagnosis were obtained from the National Survey of Children's Health 2007 data set across 3 developmental stages: young children (aged 3-5 years), children (aged 6-11 years), and adolescents (aged 12-17 years). Multinomial logistic regression was used to examine demographic characteristics and co-occurring conditions that differentiate the groups with a current ASD from groups with a PBNC ASD., Results: Results indicated the co-occurring conditions that distinguish groups currently diagnosed with an ASD from groups with a PBNC ASD diagnosis. In young children, current moderate/severe learning disability, and current moderate/severe developmental delay; in children, past speech problem, current moderate/severe anxiety, and past hearing problem; and in adolescents, current moderate/severe speech problem, current mild seizure/epilepsy, and past hearing problem., Conclusions: These findings suggest that the presence of co-occurring psychiatric and neurodevelopmental conditions are associated with a change in ASD diagnosis. Questions remain as to whether changes in diagnosis of an ASD are due to true etiologic differences or shifts in diagnostic determination.

Spinocerebellar ataxia 17 (SCA17) is caused by expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) that is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The precise pathogenic mechanism in SCA17 remains unclear. Previously proteomics study using a cellular model of SCA17 has revealed reduced expression of heat shock 70 kDa protein 5 (HSPA5) and heat shock 70 kDa protein 8 (HSPA8), suggesting that impaired protein folding may contribute to the cell dysfunction of SCA17 (Lee et al., 2009). In lymphoblastoid cells, HSPA5 and HSPA8 expression levels in cells with mutant TBP were also significantly lower than that of the control cells (Chen et al., 2010). As nuclear transcription factor Y (NFY) has been reported to regulate HSPA5 transcription, we focused on if NFY activity and HSPA5 expression in SCA17 cells are altered. Here, we show that TBP interacts with NFY subunit A (NFYA) in HEK-293 cells and NFYA incorporated into mutant TBP aggregates. In both HEK-293 and SH-SY5Y cells expressing TBP/Q(61~79), the level of soluble NFYA was significantly reduced. In vitro binding assay revealed that the interaction between TBP and NFYA is direct. HSPA5 luciferase reporter assay and endogenous HSPA5 expression analysis in NFYA cDNA and siRNA transfection cells further clarified the important role of NFYA in regulating HSPA5 transcription. In SCA17 cells, HSPA5 promoter activity was activated as a compensatory response before aggregate formation. NFYA dysfunction was indicated in SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate formation. Because essential roles of HSPA5 in protection from neuronal apoptosis have been shown in a mouse model, NFYA could be a target of mutant TBP in SCA17.

Deep brain stimulation (DBS) of the subthalamic nucleus improves the motor symptoms of Parkinson's disease, but may produce a worsening of speech and language performance at rates and amplitudes typically selected in clinical practice. The possibility that these dissociated effects might be modulated by selective stimulation of left and right STN has never been systematically investigated. To address this issue, we analyzed motor, speech and language functions of 12 patients implanted with bilateral stimulators configured for optimal motor responses. Behavioral responses were quantified under four stimulator conditions: bilateral DBS, right-only DBS, left-only DBS and no DBS. Under bilateral and left-only DBS conditions, our results exhibited a significant improvement in motor symptoms but worsening of speech and language. These findings contribute to the growing body of literature demonstrating that bilateral STN DBS compromises speech and language function and suggests that these negative effects may be principally due to left-sided stimulation. These findings may have practical clinical consequences, suggesting that clinicians might optimize motor, speech and language functions by carefully adjusting left- and right-sided stimulation parameters.