Description: Background.  Microbial translocation has been implicated in the pathogenesis of liver fibrosis and cirrhosis. We sought to determine whether markers of microbial translocation are associated with liver disease progression during coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Methods.  We measured serial plasma lipopolysaccharide (LPS), endotoxin core antibody, intestinal fatty acid–binding protein (I-FABP), soluble CD14 (sCD14), interleukin 6 (IL-6), interleukin 10, and tumor necrosis factor α (TNF-α) levels over a 5-year period in 44 HIV/HCV-coinfected women, 21 of whom experienced liver disease progression and 23 were nonprogressors. Results.  While LPS levels did not differ significantly over time between progressors and nonprogressors ( P = .60), progressors had significantly higher plasma levels of sCD14, a marker of monocyte activation by LPS, at the first time point measured ( P = .03) and throughout the study period ( P = .001); progressors also had higher IL-6 and I-FABP levels over the 5-year study period ( P = .02 and .03, respectively). The associations between progression and sCD14, I-FABP, and IL-6 levels were unchanged in models controlling for HIV RNA and CD4 + T-cell count. Conclusions.  Although LPS levels did not differ between liver disease progressors and nonprogressors, the association of sCD14, I-FABP, and IL-6 levels with liver disease progression suggests that impairment of gut epithelial integrity and consequent microbial translocation may play a role in the complex interaction of HIV and HCV pathogenesis.

Description: This article reports on an investigation with first year undergraduate Product Design and Management students within a School of Engineering and Applied Science. The students at the time of this investigation had studied fundamental engineering science and mathematics for one semester. The students were given an open ended, ill-formed problem which involved designing a simple bridge to cross a river. They were given a talk on problem solving and given a rubric to follow, if they chose to do so. They were not given any formulae or procedures needed in order to resolve the problem. In theory, they possessed the knowledge to ask the right questions in order to make assumptions but, in practice, it turned out they were unable to link their a priori knowledge to resolve this problem. They were able to solve simple beam problems when given closed questions. The results show they were unable to visualize a simple bridge as an augmented beam problem and ask pertinent questions and hence formulate appropriate assumptions in order to offer resolutions.

Description: Aims Three-dimensional rotational angiography (3DRA) is a relatively new but promising imaging technique in the paediatric catheterization laboratory. However, data on effective dose (ED) of this technique in children are lacking. The purpose of this study is to provide ED of 3DRA and to correlate this with parameters readily available in daily practice. Furthermore, the effect of dose-reducing techniques is evaluated. Methods and results Effective doses were calculated with Monte Carlo PCXMC 2.0 in 14 patients who underwent a total of 17 3DRAs at our paediatric catheterization laboratory. Median age was 5.7 years (range 1 day–16.6 years). Median ED was 1.6 milliSievert (mSv) (range 0.7–4.9). Effective dose did not correlate with age and body surface area but did correlate with dose area product (DAP) and milliGray (mGy) with r 2 of 0.75 and 0.83, respectively. Reduction of the total amount of frames from 248 to 133 per rotation resulted in further dose reduction of over 50% with preserved image quality. Conclusion The median ED of 3DRA in children is 1.6 mSv and correlates with DAP and mGy. This dose can be halved by applying frame reduction. A significant further dose reduction can be achieved by obtaining additional knowledge of the equipment used.

Description: Background.  Liver disease is common during human immunodeficiency virus (HIV) infection, but valid serum fibrosis markers are lacking. We hypothesize that HIV monoinfection and HIV/hepatitis C virus (HCV) coinfection is associated with an enhanced liver fibrosis (ELF) score higher than that for uninfected controls and examine whether this association is affected by factors other than liver injury. Methods.  The association of HIV and HIV/HCV coinfection with the ELF score was evaluated using multivariable regression after controlling for transient elastography–measured liver stiffness and traditional and HIV-related factors in a cross-sectional analysis of 297 women. Results.  HIV/HCV-coinfected and HIV-monoinfected women had higher median ELF scores than controls (9.6, 8.5, and 8.2, respectively). After adjustment for demographic, behavioral, and metabolic factors and for inflammatory markers, HIV/HCV coinfection remained associated with a 9% higher ELF score (95% confidence interval [CI], 5%–13%), while the association of HIV monoinfection was substantially attenuated (1% higher ELF score; 95% CI, –2% to 4%). After further adjustment for liver stiffness, HIV/HCV coinfection remained associated with 6% higher levels (95% CI, 3%–10%). In HIV/HCV-coinfected and HIV-monoinfected women, higher liver stiffness values were associated with higher ELF scores, as were older age and a nadir CD4 + T-cell count of 〈200 cells/mm 3 . Conclusions.  Our findings suggest that the ELF score can be used to assess liver fibrosis severity in HIV-infected women. However, higher ELF scores may reflect extrahepatic fibrosis in HIV-infected patients with a history of severe immunosuppression or advanced age.

Description: Background.  Few studies have examined the relationship of human immunodeficiency virus (HIV) monoinfection and its associated perturbations with liver fibrosis. Methods.  Using multivariable linear regression, we examined the demographic, behavioral, metabolic and viral factors associated with transient elastography–measured liver stiffness in 314 participants (165 HIV positive/hepatitis C virus [HCV] negative, 78 HIV positive/HCV positive, 14 HIV negative/HCV positive, 57 HIV negative/HCV negative) in the Women's Interagency HIV Study. Results.  Compared with HIV negative/HCV negative women, HIV positive/HCV positive women had higher median liver stiffness values (7.1 vs 4.4 kPa; P 〈 .001); HIV positive/HCV negative and HIV negative/HCV negative women had similar liver stiffness values (both 4.4 kPa; P = .94). HIV/HCV coinfection remained associated with higher liver stiffness values (74% higher; 95% confidence interval [CI], 49–104) even after multivariable adjustment. Among HCV positive women, waist circumference (per 10-cm increase) was associated with 18% (95% CI, 7.5%–30%) higher liver stiffness values after multivariable adjustment; waist circumference showed little association among HIV positive/HCV negative or HIV negative/HCV negative women. Among HIV positive/HCV negative women, history of AIDS (13%; 95% CI, 4% –27%) and HIV RNA (7.3%; 95% CI, 1.59%–13.3%, per 10-fold increase) were associated with greater liver stiffness. Conclusions.  HCV infection but not HIV infection is associated with greater liver stiffness when infected women are compared with those with neither infection. Our finding that waist circumference, a marker of central obesity, is associated with greater liver stiffness in HIV/HCV-coinfected but not HIV-monoinfected or women with neither infection suggests that in the absence of HCV-associated liver injury the adverse effects of obesity are lessened.

Description: The US Naval Research Laboratory conducted comprehensive high-altitude (7 km above mean sea level) aero-geophysical surveys over Afghanistan in 2006 (Rampant Lion I). The surveys were done in collaboration with the US Geological Survey and upon the request of Islamic Republic of Afghanistan Ministry of Mines. In this study, we show that a best fitting admittance between topography and airborne gravity in western Afghanistan can be used to predict airborne gravity for the no-data area of eastern Afghanistan where the mountains are too high to conduct airborne surveys, due to the threat of ground fire. The differences between the airborne and the predicted gravity along a tie-track through the no-data area were found to be within ±12 mGal range with rms difference 7.3 mGal, while those between the predicted gravity from a simple Airy model (with compensation depth of 32 km and crustal density of 2.67 g cm –3 ) and the airborne gravity were within ±22 mGal range with rms difference 10.3 mGal. A combined airborne free-air anomaly has been constructed by merging the predicted gravity with the airborne data. We also demonstrate that sediment thickness can be estimated for basin areas where surface topography and airborne free-air anomaly profiles do not show a correlation presumably because of thick sediments. In order to estimate sediment thickness, we first determine a simple linear relationship from a scatter plot of the airborne gravity points and the interpolated Shuttle Radar Topography Mission (SRTM) topography along the Rampant Lion I tracks, and computed corresponding quasi-topography tracks by multiplying the linear relationship with the airborne free-air anomalies. We then take the differences between the SRTM and quasi-topography as a first-order estimate of sediment thickness. A global gravity model (GOCO02S), upward continued to the same altitude (7 km above mean sea level) as the data collection, was compared with the low-pass filtered (with cutoff wavelength 132 km which is approximately equivalent to the reported safe degree and order 250 of GOCO02S at 34º N) combined airborne free-air anomalies. The rms difference between the two data sets was 12.4 mGal. The observed admittance in the western Afghanistan mountains appears to be best fit to a theoretical elastic plate compensation model (with an effective elastic thickness of 5 km and crustal thickness of 22 km) where the ratio between surface load and subsurface load is equal.

Description: Reduced expression of SMN protein causes spinal muscular atrophy (SMA), a neurodegenerative disorder leading to motor neuron dysfunction and loss. However, the molecular mechanisms by which SMN regulates neuronal dysfunction are not fully understood. Here, we report that reduced SMN protein level alters miRNA expression and distribution in neurons. In particular, miR-183 levels are increased in neurites of SMN-deficient neurons. We demonstrate that miR-183 regulates translation of mTor via direct binding to its 3' UTR. Interestingly, local axonal translation of mTor is reduced in SMN-deficient neurons, and this can be recovered by miR-183 inhibition. Finally, inhibition of miR-183 expression in the spinal cord of an SMA mouse model prolongs survival and improves motor function of Smn -mutant mice. Together, these observations suggest that axonal miRNAs and the mTOR pathway are previously unidentified molecular mechanisms contributing to SMA pathology.

Description: Interferon lambda 4 protein can be generated in IFNL4 -G carriers but not IFNL4 -TT homozygotes. We studied 890 anti–hepatitis C virus (HCV)–positive participants in the Women's Interagency HIV Study. Among blacks (n = 555), HCV was more often cleared for those with genotype IFNL4 -TT/TT (32.6%; odds ratio [OR], 3.59; P = 3.3 x 10 –5 ) than IFNL4 -TT/G (11.3%; OR, 0.95; P = .86) or IFNL4 -G/G (11.9%; referent). Pooling these data with published results in blacks (n = 1678), ORs were 3.84 ( P = 8.6 x 10 –14 ) for IFNL4 -TT/TT and 1.44 ( P = .03) IFNL4 -TT/G, and the area under the curve was 0.64 for IFNL4 -G genotype and 0.61 for rs12979860 ( IL28B ). IFNL4 -G is strongly associated with impaired spontaneous HCV clearance.

Description: F-actin bundling plastin 3 (PLS3) is a fully protective modifier of the neuromuscular disease spinal muscular atrophy (SMA), the most common genetic cause of infant death. The generation of a conditional PLS3 -over-expressing mouse and its breeding into an SMA background allowed us to decipher the exact biological mechanism underlying PLS3-mediated SMA protection. We show that PLS3 is a key regulator that restores main processes depending on actin dynamics in SMA motor neurons (MNs). MN soma size significantly increased and a higher number of afferent proprioceptive inputs were counted in SMA PLS3 compared with SMA mice. PLS3 increased presynaptic F-actin amount, rescued synaptic vesicle and active zones content, restored the organization of readily releasable pool of vesicles and increased the quantal content of the neuromuscular junctions (NMJs). Most remarkably, PLS3 over-expression led to a stabilization of axons which, in turn, resulted in a significant delay of axon pruning, counteracting poor axonal connectivity at SMA NMJs. These findings together with the observation of increased endplate and muscle fiber size upon MN-specific PLS3 over-expression suggest that PLS3 significantly improves neuromuscular transmission. Indeed, ubiquitous over-expression moderately improved survival and motor function in SMA mice. As PLS3 seems to act independently of Smn, PLS3 might be a potential therapeutic target not only in SMA but also in other MN diseases.