The number of cysteine residues per mole in apolipoprotein E affects systematically synchronous neural interactions in women’s healthy brains

Apolipoprotein E (apoE) is involved in lipid metabolism in the brain, but its effects on brain function are not understood. Three apoE isoforms (E4, E3, and E2) are the result of cysteine–arginine interchanges at two sites: there are zero interchanges in E4, one interchange in E3, and two interchanges in E2. The resulting six apoE genotypes (E4/4, E4/3, E4/2, E3/3, E3/2, E2/2) yield five groups with respect to the number of cysteine residues per mole (CysR/mole), as follows. ApoE4/4 has zero cysteine residues per mole (0-CysR/mole), E4/3 has one (1-CysR/mole), E4/2 and E3/3 each has two (2-CysR/mole), E3/2 has three (3-CysR/mole), and E2/2 has four (4-CysR/mole). The use of the number of CysR/mole to characterize the apoE molecule converts the categorical apoE genotype scale, consisting of 6 distinct genotypes above, to a 5-point continuous scale (0–4 CysR/mole). This allows the use of statistical analyses suitable for continuous variables (e.g. regression) to quantify the relations between various variables and apoE. Using such analyses, here, we show for the first time that apoE affects in a graded and orderly manner neural communication, as assessed by analyzing the relation between the number of CysR/mole and synchronous neural interactions (SNI) measured by magnetoencephalography (MEG) in 130 cognitively healthy women. At the one end of the CysR/mole range, the 4-CysR/mole (E2/2) SNI distribution had the highest mean, lowest variance, lowest range, and lowest coefficient of variation, whereas at the other end, 0-CysR/mole (E4/4) SNI distribution had the lowest mean, highest variance, highest range, and highest coefficient of variation. The special status of the 4-CysR/mole distribution was reinforced by the results of a hierarchical tree analysis where the 4-CysR/mole (E2/2) SNI distribution occupied a separate branch by itself and the remaining CysR/mole SNI distributions were placed at increasing distances from the 4-CysR/mole distribution, according to their number of CysR/mole, with the 0-CysR/mole (E4/4) being farthest away. These findings suggest that the 4-CysR/mole (E2/2) SNI distribution could serve as a reference distribution. When the SNI distributions of individual women were expressed as distances from this reference distribution, there was a substantial overlap among women of various CysR/mole. This refocuses the placement of individual brains along a continuous distance from the 4-CysR/mole SNI distribution, in contrast to the common categorical assignment to a specific apoE genotype. Finally, the orderly variation of SNI with the number of CysR/mole found here is in keeping with recent advances and ideas regarding the molecular mechanisms underlying the differential effects of apoE in the brain which emphasize the healthier stability conferred on the apoE molecule by the increasing number of cysteine–arginine interchanges, with 4-CysR/mole (E2/2) being the best case, as opposed to the instability and increased chance of toxic fragmentation of the apoE molecule with lower number of CysR/mole, with 0-CysR/mole (E4/4) as the worst case (Mahley and Huang in Neuron 76:871–885, 2012a). However, our results also document the appreciable variation of SNI properties within the various CysR/mole groups and individuals which points to the existence and important role of other factors involved in shaping brain function at the network level.     

The role of disease management programs in the health behavior of chronically ill patients

Objective

Investigate the effects of disease management program (DMP) implementation on physical activity, smoking, and physical quality of life among chronically ill patients.

Methods

This study used a mixed-methods approach involving qualitative (35 interviews with project managers) and quantitative (survey of patients from 18 DMPs) data collection. Questionnaire response rates were 51% (2010; 2619/5108) at T0 and 47% (2011; 2191/4693) at T1.

Results

Physical activity and the percentage of smokers improved significantly over time, whereas physical quality of life declined. After adjusting for patients’ physical quality of life at T0, age, educational level, marital status, and gender, physical activity at T0 (p < 0.01), changes in physical activity (p < 0.001), and percentage of smokers at T0 (p < 0.05) predicted physical quality of life at T1. Project managers reported that DMPs improved patient–professional interaction. The ability to set more concrete targets improved patients’ health behaviors.

Conclusions

DMPs appear to improve physical activity among chronically ill patients over time. Furthermore, (changes in) health behavior are important for the physical quality of life of chronically ill patients.

Practice implications

Redesigning care systems and implementing DMPs based on the chronic care model may improve health behavior among chronically ill patients.     

Cell directional spread determines accuracy,precision, and length of the neuronal population vector

The neuronal population vector (NPV) for movement direction is the sum of weighted neuronal directional contributions. Based on theoretical considerations, we proposed recently that the sharpness of tuning will impact the directional precision, accuracy, and length of the NPV, such that sharper tuning will yield NPV with higher precision, higher accuracy, and shorter length (Mahan and Georgopoulos in Front Neural Circuits 7:92, 2013). Furthermore, we proposed that controlling the inhibitory drive in a local network could be the mechanism by which the sharpness of directional tuning would be varied, resulting in a continuous specification and control of movement’s directional precision, accuracy, and speed (Mahan and Georgopoulos in Front Neural Circuits 7:92, 2013, Fig. 5). As a first step in testing this idea, here we analyzed data from 899 cells recorded in the motor cortex during performance of a center → out task. There were two major findings. First, directional selectivity varied with cell activity, such that it was higher in cells with lower mean discharge rates. And second, NPVs calculated from subsets of cells with higher directional selectivity (and, correspondingly, lower mean discharge rates) were more accurate (i.e., closer to the movement), precise (i.e., less variable), and shorter (i.e., slower; Schwartz in Science 265:540–542, 1994). These findings confirm our predictions above made from modeling (Mahan and Georgopoulos in Front Neural Circuits 7:92, 2013) and provide a simple mechanism by which desired attributes of the directional motor command can be implemented. We hypothesize that the inhibitory drive in a local network is controlled directly and independently of recurrent collaterals or common excitatory inputs to other cells. This could be achieved by a private excitation/inhibition of key inhibitory interneurons in a way similar to that in operation for Renshaw cells in the spinal cord. The presence of such a private line of inhibitory control remains to be investigated.     

Long-term impact of multifactorial treatment on new-onset diabetes and related cardiovascular events in metabolic syndrome: a post hoc ATTEMPT analysis

This post hoc analysis of the Assessing The Treatment Effect in Metabolic Syndrome Without Perceptible diabeTes (ATTEMPT) study assesses the 3? year incidence of new-onset diabetes (NOD) and related cardiovascular disease (CVD) events in patients with metabolic syndrome (MetS), after multifactorial (lifestyle and drug, including atorvastatin) intervention. Patients were randomized to group A (low-density lipoprotein cholesterol [LDL-C] target < 100 mg/dL) and group B (< 130 mg/dL). The incidence of NOD during the 42-month follow-up was very low, 0.83 to 1.00/100 patient-years in patients with MetS and MetS with impaired fasting glucose, respectively. Older age, increased waist circumference, and persistent MetS were determinants of NOD. One CVD nonfatal event occurred in the 28 patients with NOD. Our findings suggest that treating the characteristics of MetS is achievable and beneficial. New-onset diabetes incidence and CVD events were negligible and not different from what is expected in the general population.     

Incidence,timing, and predictors of valve dislodgment during TAVI with the medtronic corevalve system

Objectives : To determine the incidence, timing and predictors of periprocedural valve dislodgment with the Medtronic Corevalve System (MCS). Background : Periprocedural valve dislodgment may occur during transcatheter aortic valve implantation (TAVI). Methods : Ninety‐eight consecutive patients underwent TAVI with the MCS after a comprehensive baseline assessment including invasive angiography, echocardiography, and Multi‐Slice Computed Tomography (MSCT). The invasive monitoring charts and angiographic studies of all TAVI procedures were reviewed to determine the incidence and timing of valve dislodgment. Results : Valve dislodgment occurred in 18 patients. Patients with valve dislodgment had a larger Aortic Valve Area (0.76 ± 0.25 cm² vs. 0.61 ± 0.19 cm², P = 0.007), lower mean transaortic gradient (37.65 ± 14.62 mm Hg vs. 47.11 ± 16.08 mm Hg, P = 0.03) and significantly less aortic root calcification (Agatston score median 1951 AU (IQR, 799–3103) vs. 3289 AU (IQR 2097–4481), P = 0.016). A lower aortic root calcium score (Agatston score < 2359 AU) was the single independent predictor for valve dislodgment (OR 3.10, 1.09–8.84). After valve dislodgment, the valve could be successfully retrieved and implanted in the proper anatomic location in all cases. Valve dislodgment was associated with a lower incidence of post‐procedural AR ≥ 2 (11.1% vs. 34.6%, P = 0.05). There were no relevant procedural or clinical implications to valve dislodgment. Conclusions : The incidence of periprocedural valve dislodgment was 18% in these series. Less aortic root calcification appeared the single independent predictor. © 2011 Wiley Periodicals, Inc.     

An exploratory, placebo-controlled, dose–response study of the efficacy and safety of onabotulinumtoxinA in spinal cord injury patients with urinary incontinence due to neurogenic detrusor overactivity

Purpose

To explore the dose response to onabotulinumtoxinA 50, 100, and 200 U in patients with spinal cord injury (SCI) with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO).

Methods

Patients (N = 73) with SCI (level T1 or lower) with NDO and UI (≥14 UI episodes/week) received 30 intradetrusor injections of onabotulinumtoxinA (50 U [n = 19], 100 U [n = 21], or 200 U [n = 17]) or placebo (n = 16) via cystoscopy, avoiding the trigone. Changes from baseline in UI episodes/week, volume voided/micturition, maximum cystometric capacity, and maximum detrusor pressure (MDP) during first involuntary detrusor contraction (IDC) were evaluated. Adverse events (AEs) were assessed.

Results

A significant linear dose response for UI episodes/week was identified at weeks 18, 30, 36, 42, and 54 (P < 0.05) with a similar trend (P = 0.092) at week 6 (primary time point). A significant linear dose response was observed in volume/void at all post-treatment time points up to week 54 (P < 0.05) and in MDP during first IDC at week 6 (P = 0.034). The proportion of patients who achieved continence at week 6 was highest in the 200 U group. Duration of effect was longest with the 200 U dose, compared with other treatment groups. The AEs were comparable across groups; urinary tract infection was the most common AE across all treatment groups.

Conclusions

In this exploratory dose–response study of SCI patients with UI due to NDO, onabotulinumtoxinA 200 U was the most effective dose. The AE profile was comparable across all groups.     

Complex calcaneal defect reconstruction with osteotomized free fibula–flexor hallucis longus osteomuscular flap

Complex calcaneal defects represent a reconstructive challenge since calcaneous plays a key role in standing and gait. We report the case of a 35‐year‐old patient with a complex calcaneal defect due to chronic osteomyelitis after a high energy Gustillo type IIIB calcaneal fracture that was reconstructed with a free fibula–flexor hallucis longus osteomuscular flap. The fibula was osteotomized into two segments, which were used to reconstruct the bone defect, and the muscular component of the flap was used for coverage of the reconstructed calcaneal skeleton. Fifteen days later permanent skin coverage was ensured with a local random pattern rhomboid skin flap. Early and late postoperative periods were uneventful. Bone maturation was radiographically evident at a follow up of 12 weeks, and complete bone incorporation at 3 years. Full weight bearing was possible at 6 months postop. Final follow up, at 3 years postop, verified a very good functional and aesthetic outcome. © 2012 Wiley Periodicals, Inc. Microsurgery, 2013.     

Subcutaneous drain insertion in patients with post-operative extensive subcutaneous surgical emphysema: a single centre experience

Objective

Extensive surgical subcutaneous emphysema (ESE) albeit a benign condition could cause patients distress and in many cases temporary vision impairment. We describe the role and value of early subcutaneous drain insertion (SCD) in the management of ESE and patients’ experience in this cohort study.

Methods

Extensive surgical subcutaneous emphysema is that which extends to the neck and/or the peri-orbital region. A cohort study of a prospectively collected data was conducted between December 2009 and January 2012. All patients with extensive post-operative surgical emphysema who had SCD (size ≥24 French gauge) were included.

Results

1069 thoracic procedures were performed. 21 patients (1.96 %) were diagnosed with extensive surgical emphysema, there were 16 males, median age was 65 (54–82 years). There were 16 VATS and 5 open procedures. All patients had chest surgical emphysema, 16 patients had peri-orbital and neck swelling and 5 had neck swelling. Surgical emphysema occurred within a median of 3 days post-operatively. 14 (67 %) patients had 1 subcutaneous drain inserted, and 7 (33 %) had bilateral SCD insertion (1 drain each side). 19 (90 %) patients experienced improvement of their symptoms with resolution of neck and peri-orbital swelling within 1 day of SCD insertion, 2 patients had their symptoms improved within 2 days. All patients were satisfied with the outcome following insertion of SCD.

Conclusions

ESE should always be investigated and treated promptly. Early SCD insertion has a valuable role in the management of ESE with improvement of patients’ experience.