Tropomyosin pseudo-phosphorylation results in dilated cardiomyopathy.

Phosphorylation of cardiac sarcomeric proteins plays a major role in the regulation of the physiological performance of the heart. Phosphorylation of thin filament proteins, such as troponin I and T, dramatically affects calcium sensitivity of the myofiber and systolic and diastolic functions. Phosphorylation of the regulatory protein tropomyosin (Tpm) results in altered biochemical properties of contraction; however, little is known about the physiological effect of Tpm phosphorylation on cardiac function. To address the in vivo significance of Tpm phosphorylation, here we generated transgenic mouse lines having a phosphomimetic substitution in the phosphorylation site of α-Tpm (S283D). High expression of Tpm S283D variant in one transgenic mouse line resulted in an increased heart:body weight ratio, coupled with a severe dilated cardiomyopathic phenotype resulting in death within 1 month of birth. Moderate Tpm S283D mice expression in other lines caused mild myocyte hypertrophy and fibrosis, did not affect lifespan, and was coupled with decreased expression of extracellular signal-regulated kinase 1/2 kinase signaling. Physiological analysis revealed that the transgenic mice exhibit impaired diastolic function, without changes in systolic performance. Surprisingly, we observed no alterations in calcium sensitivity of the myofibers, cooperativity, or calcium-ATPase activity in the myofibers. Our experiments also disclosed that casein kinase 2 plays an integral role in Tpm phosphorylation. In summary, increased expression of pseudo-phosphorylated Tpm impairs diastolic function in the intact heart, without altering calcium sensitivity or cooperativity of myofibers. Our findings provide the first extensive in vivo assessment of Tpm phosphorylation in the heart and its functional role in cardiac performance.

A Novel Approach to Negative Pressure Wound Therapy: Use of High Suction Capillary Device to Improve Wound Healing.

INTRODUCTION: Negative Pressure Wound Therapy (NPWT) is a procedure used for nonhealing wounds. In NPWT, a special sealed dressing of large cell foam (>400 µm) or gauze is connected to a pump. Most commonly, negative pressures between -10 and -125 millimeters of mercury (mm Hg) are used. The mechanism of healing is unknown but maybe attributable to removal of the exudate and bacteria, and the stimulation of tissue repair through microdeformation. Reticulated foams with micron-size open cells, Capillary Suction Devices (CSD; 100 to 5 µm) exert capillary suction between 10 and 70 mm of Hg with a multilayered foam dressing. MATERIALS AND METHODS: Yorkshire pigs received 5 surgical excision wounds, 3 cm2, on each side of the back. The wounds were covered with a NPWT dressing (110 mm Hg negative pressure by a pump), CSD with capillary suctions of 30 mm Hg (CSD-30) and 70 mm Hg (CSD-70), and a conventional gauze dressing. The wounds were measured on day 2, and then every 4-5 days thereafter; the total fluid collected by the various dressing over time. RESULTS: By post-wound day 20, the wounds treated with CSD-70 and NPWT were 100% closed while the wounds treated with CSD-30 and gauze were 65% and 45%, respectively. This indicated comparable wound closure efficacies for CSD-70 and NPWT. The average total fluid uptake measured in grams dry weight were similar for CSD-70 and NPWT, 36 and 38 g, respectively, while the values were 24 g for CSD-30 and 12 g for gauze. However, the maximum fluid uptake observed at day 2 indicated that CSD-70 and CSD 30, 24 and 14 g, respectively, were superior to NPWT and gauze 12 and 7 g, respectively. CONCLUSION: This data indicate comparable wound closure efficacies for CSD-70 and NPWT. It is felt that CSD is an effective, safe, and lower cost alternative to vacuum-assisted NPWT.

Extension of the Contingency Naming Test to adult assessment: psychometric analysis in a college student sample.

The Contingency Naming Test (CNT; Taylor, Albo, Phebus, Sachs, & Bierl, 1987) was initially designed to assess aspects of executive functioning, such as processing speed and response inhibition, in children. The measure has shown initial utility in identifying differences in executive function among child clinical groups; however, there is an absence of adequate psychometric data for use with adults. The current study expanded psychometric data upward for use with a college student sample and explored the measure's test-retest reliability and factor structure. Performance in the adult sample showed continued improvement above child norms, consistent with theories of executive function development. Exploratory factor analysis showed that the CNT is most closely related to measures of processing speed, as well as elements of response inhibition within the latter trials. Overall, results from the current study provide added support for the utility of the CNT as a measure of executive functioning in young adults. However, more research is needed to determine patterns of performance among adult clinical groups, as well as to better understand how performance patterns may change in a broader age range, including middle and older adulthood.

Exploration of malingering indices in the Wechsler Adult Intelligence Scale-Fourth Edition Digit Span subtest.

Prior research shows that Digit Span is a useful embedded measure of malingering. However, the Wechsler Adult Intelligence Scale-IV (Wechsler, 2008) altered Digit Span in meaningful ways, necessitating another look at Digit Span as an embedded measure of malingering. Using a simulated malingerer design, we examined the predictive accuracy of existing Digit Span validity indices and explored whether patterns of performance utilizing the new version would provide additional evidence for malingering. Undergraduates with a history of mild head injury performed with best effort or simulated impaired cognition and were also compared with a large sample of non-head-injured controls. Previously established cutoffs for the age-corrected scaled score and Reliable Digit Span (RDS) performed similarly in the present samples. Patterns of RDS length using all three subscales of the new scale were different in malingerers when compared with both head-injured and non-head-injured controls. Two potential alternative RDS scores were introduced, which showed better sensitivity than the traditional RDS, while retaining specificity to malingering.

The influence of viewpoint and object detail in blind people when matching pictures to complex objects.

We examined haptic viewpoint effects in blindfolded-sighted (BS) and visually impaired subjects: early blind (EB), late blind (LB), and very low vision (VLV). Participants felt complex objects and matched tangible pictures to them. In experiment 1, the EB and BS subjects had similar overall performance. Experiment 2 showed that the presence of a detail on the target object lowered performance in the BS subjects, and that matching accuracy was lower overall for top views for the blind subjects. In experiments 3-5, EB, LB, VLV, and BS subjects made judgments about perspective pictures of a model house with more salient object details. In experiment 3, performance was higher for side views than for corner views. Elevated side views were identified more readily than elevated corner views in experiment 4. Performance for top views was higher than for elevated side views in experiment 5, given the relative simplicity of the top-view depictions and salient details. The EB and BS participants had somewhat lower matching accuracy scores than the other groups. We suggest that visual experience is helpful, but not essential for picture perception. Viewpoint effects may vary with experience and object complexity, but the relevant experience need not be specifically visual in nature.

The effects of curvature on haptic judgments of extent in sighted and blind people.

A series of experiments was carried out to examine the effect of curvature on haptic judgments of extent in sighted and blind individuals. Experiment 1 showed that diameters connecting the endpoints of semicircular lines were underestimated with respect to straight lines, but failed to show an effect of visual experience on length judgments. In experiment 2 we tested are lengths. The effects of curvature on perceived path length were weaker, but were still present in this experiment. Visual experience had no effect on path length judgments. Another experiment was performed to examine the effect of repeated tracing (1, 5, 9, or unlimited number of traces) on judgments of the lengths of straight lines and diameters of semicircles. Judgments of extent were more accurate when subjects engaged in larger numbers of traces. There was no effect of number of traces on curve-height judgments, suggesting that subjects were not using height estimates to judge diameters of semicircles. In a further experiment we tested the effect of number of traces on curves that varied in height. Restricting subjects to a single trace magnified the effect of path length on judgments of the distance between the endpoints of curves. Additional experiments showed that curvature effects on diameter judgments were not eliminated when stimuli were in the frontal plane or when the curves were explored with the use of two hands. Arm support had no effect on judged length in experiment 7. A final experiment showed a robust horizontal vertical illusion in haptic perception of convex curves, with overestimation of the heights of the curves compared with their widths. The practical and theoretical implications of the results are discussed.

Sequential turnover of human immunodeficiency virus type 1 env throughout the course of infection.

We examined the rates of variant population turnover of the V1-V2 and V4-V5 hypervariable domains of the human immunodeficiency virus type 1 (HIV-1) gp120 molecule in longitudinal plasma samples from 14 men with chronic HIV-1 infection using heteroduplex tracking assays (HTA). Six men had high rates of CD4+ T-cell loss, and eight men had low rates of CD4+ T-cell loss over 2.5 to 8 years of infection. We found that V1-V2 and V4-V5 env populations changed dramatically over time in all 14 subjects; the changes in these regions were significantly correlated with each another over time. The subjects with rapid CD4 loss had significantly less change in their env populations than the subjects with slow CD4 loss. The two subjects with rapid CD4 loss and sustained low CD4 counts (<150/microl for at least 2 years) showed stabilization of their V1-V2 and V4-V5 populations as reflected by low levels of total change in HTA pattern and low HTA indices (a novel measure of the emergence of new bands and band distribution); this stabilization was not observed in other subjects. The stabilization of env variant populations at low CD4 counts following periods of rapid viral evolution suggests that selective pressure on env, likely from new immune responses, is minimal when CD4 counts drop dramatically and remain low for extended periods of time.

Viewpoint and orientation influence picture recognition in the blind.

In the first three experiments, subjects felt solid geometrical forms and matched raised-line pictures to the objects. Performance was best in experiment 1 for top views, with shorter response latencies than for side views, front views, or 3-D views with foreshortening. In a second experiment with blind participants, matching accuracy was not significantly affected by prior visual experience, but speed advantages were found for top views, with 3-D views also yielding better matching accuracy than side views. There were no performance advantages for pictures of objects with a constant cross section in the vertical axis. The early-blind participants had lower performance for side and frontal views. The objects were rotated to oblique orientations in experiment 3. Early-blind subjects performed worse than the other subjects given object rotation. Visual experience with pictures of objects at many angles could facilitate identification at oblique orientations. In experiment 5 with blindfolded sighted subjects, tangible pictures were used as targets and as choices. The results yielded superior overall performance for 3-D views (mean, M = 74% correct) and much lower matching accuracy for top views as targets (M = 58% correct). Performance was highest when the target and matching viewpoint were identical, but 3-D views (M = 96% correct) were still far better than top views. The accuracy advantage of the top views also disappeared when more complex objects were tested in experiment 6. Alternative theoretical implications of the results are discussed.

Leptin replacement therapy but not dietary polyunsaturated fatty acid alleviates HIV protease inhibitor-induced dyslipidemia and lipodystrophy in mice.

A major complication associated with the use of protease inhibitors (PIs) in treatment of HIV-infected patients is lipid abnormalities including dyslipidemia, lipodystrophy, and liver steatosis. Previous studies revealed that these abnormalities are associated with PI-induced accumulation of activated sterol regulatory element binding proteins (SREBPs) in the nucleus of liver and adipose tissues, resulting in constitutive activation of lipid metabolism genes. This study used the mouse model to determine the potential of polyunsaturated fatty acid (PUFA) diet or leptin replacement therapy to alleviate these PI-induced metabolic abnormalities. Results showed that feeding C57BL/6 mice with a PUFA-rich diet failed to normalize plasma cholesterol and triglyceride levels in ritonavir-treated mice. The PUFA-rich diet also had no effect on ritonavir-induced interscapular fat accumulation and liver steatosis. In contrast, daily administration of leptin significantly reversed the elevated plasma cholesterol level induced by ritonavir. Leptin replacement therapy also significantly reduced the ritonavir-induced interscapular fat mass and improved liver steatosis. Taken together, these data suggest that PI-induced lipid abnormalities, especially dyslipidemia, lipodystrophy, and liver steatosis, may be reduced with leptin replacement therapy.

The HIV protease inhibitor ritonavir increases lipoprotein production and has no effect on lipoprotein clearance in mice.

This study examined the effect of human immunodeficiency virus (HIV) protease inhibitor therapy on lipoprotein production and catabolism in vivo. The HIV protease inhibitor ritonavir was given to C57BL/6 mice fed either a basal low-fat diet or a Western type high-fat diet. Fasted mice were injected with Triton WR1339 followed by hourly blood collection to monitor lipoprotein production. Results showed that ritonavir increased VLDL triglyceride production by 30% over a 4 h period when mice were fed the low-fat basal diet. The ritonavir effect was more pronounced under high-fat feeding conditions, with a 2-fold increase in VLDL triglyceride production rate. Ritonavir did not alter hepatic expression levels of diacylglycerol acyltransferase or microsomal triglyceride transfer protein, but increased hepatic apolipoprotein B (apoB) secretion rates under both low- and high-fat dietary conditions. In contrast to its effect on lipoprotein production, ritonavir did not alter triglyceride-rich lipoprotein clearance from circulation under either dietary condition. Taken together, these results indicate that the hyperlipidemic effect of HIV protease inhibitors is a direct result of increased hepatic lipoprotein production. The mechanism appears to be related to their role in preventing proteasome-mediated degradation of apoB and activated sterol regulatory element binding proteins in the liver.