Cardiac and vascular hypertrophy in Fabry disease: evidence for a new mechanism independent of blood pressure and glycosphingolipid deposition.

OBJECTIVE: Fabry disease is an X-linked disorder resulting from alpha-galactosidase A deficiency. The cardiovascular findings include left ventricular hypertrophy (LVH) and increased intima-media thickness of the common carotid artery (CCA IMT). The current study examined the possible correlation between these parameters. To corroborate these clinical findings in vitro, plasma from Fabry patients was tested for possible proliferative effect on rat vascular smooth muscle cells (vascular smooth muscle cell [VSMC]) and mouse neonatal cardiomyocytes. METHODS AND RESULTS: Thirty male and 38 female patients were enrolled. LVH was found in 60% of men and 39% of women. Increased CCA IMT was equally present in males and females. There was a strong positive correlation between LV mass and CCA IMT (r2=0.27; P<0.0001). VSMC and neonatal cardiomyocyte proliferative response in vitro correlated with CCA IMT (r2=0.39; P<0.0004) and LV mass index (r2=0.19; P=0.028), respectively. CONCLUSIONS: LVH and CCA IMT occur concomitantly in Fabry suggesting common pathogenesis. The underlying cause may be a circulating growth-promoting factor whose presence has been confirmed in vitro.

CD160-Associated CD8 T-Cell Functional Impairment Is Independent of PD-1 Expression.

Expression of co-inhibitory molecules is generally associated with T-cell dysfunction in chronic viral infections such as HIV or HCV. However, their relative contribution in the T-cell impairment remains unclear. In the present study, we have evaluated the impact of the expression of co-inhibitory molecules such as 2B4, PD-1 and CD160 on the functions of CD8 T-cells specific to influenza, EBV and CMV. We show that CD8 T-cell populations expressing CD160, but not PD-1, had reduced proliferation capacity and perforin expression, thus indicating that the functional impairment in CD160+ CD8 T cells may be independent of PD-1 expression. The blockade of CD160/CD160-ligand interaction restored CD8 T-cell proliferation capacity, and the extent of restoration directly correlated with the ex vivo proportion of CD160+ CD8 T cells suggesting that CD160 negatively regulates TCR-mediated signaling. Furthermore, CD160 expression was not up-regulated upon T-cell activation or proliferation as compared to PD-1. Taken together, these results provide evidence that CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression.

Distal locking of femoral nails: evaluation of a new radiation-independent targeting system.

OBJECTIVES: The purpose of this study was to assess the effectiveness of a novel radiation-independent aiming device for distal locking of intramedullary nails in a human cadaver model. METHODS: A new targeting system was used in 25 intact human cadaver femora for the distal locking procedure after insertion of an intramedullary nail. The number of successful screw placements and the time needed for this locking procedure were recorded. The accuracy of the aiming process was evaluated by computed tomography. RESULTS: The duration of the distal locking process was 8.0 ± 1.8 minutes (mean ± SD; range, 4-11 minutes). None of the screw placements required fluoroscopic guidance. Computed tomography revealed high accuracy of the locking process. The incidence angle (α) of the locking screws through the distal locking holes of the nail was 86.8° ± 5.0° (mean ± SD; range, 80°-96°). Targeting failed in 1 static locking screw because of a material defect in the drilling sleeve. CONCLUSIONS: This cadaver study indicated that an aiming arm-based targeting device is highly reliable and accurate. The promising results suggest that it will help to decrease radiation exposure compared with the traditional "free-hand technique."

Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver.

Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. Although such rhythms have been extensively studied at the level of transcription and mRNA accumulation, little is known about the accumulation patterns of proteins. Here, we quantified temporal profiles in the murine hepatic proteome under physiological light-dark conditions using stable isotope labeling by amino acids quantitative MS. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, a group comprising about one-half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or posttranslational diurnal control. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night. Also, these rhythms persisted in clock-deficient animals subjected to rhythmic feeding, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors.

Location-independent and location-linked representations of sound objects.

For the recognition of sounds to benefit perception and action, their neural representations should also encode their current spatial position and their changes in position over time. The dual-stream model of auditory processing postulates separate (albeit interacting) processing streams for sound meaning and for sound location. Using a repetition priming paradigm in conjunction with distributed source modeling of auditory evoked potentials, we determined how individual sound objects are represented within these streams. Changes in perceived location were induced by interaural intensity differences, and sound location was either held constant or shifted across initial and repeated presentations (from one hemispace to the other in the main experiment or between locations within the right hemispace in a follow-up experiment). Location-linked representations were characterized by differences in priming effects between pairs presented to the same vs. different simulated lateralizations. These effects were significant at 20-39 ms post-stimulus onset within a cluster on the posterior part of the left superior and middle temporal gyri; and at 143-162 ms within a cluster on the left inferior and middle frontal gyri. Location-independent representations were characterized by a difference between initial and repeated presentations, independently of whether or not their simulated lateralization was held constant across repetitions. This effect was significant at 42-63 ms within three clusters on the right temporo-frontal region; and at 165-215 ms in a large cluster on the left temporo-parietal convexity. Our results reveal two varieties of representations of sound objects within the ventral/What stream: one location-independent, as initially postulated in the dual-stream model, and the other location-linked.

Actin cables and the exocyst form two independent morphogenesis pathways in the fission yeast.

Cell morphogenesis depends on polarized exocytosis. One widely held model posits that long-range transport and exocyst-dependent tethering of exocytic vesicles at the plasma membrane sequentially drive this process. Here, we describe that disruption of either actin-based long-range transport and microtubules or the exocyst did not abolish polarized growth in rod-shaped fission yeast cells. However, disruption of both actin cables and exocyst led to isotropic growth. Exocytic vesicles localized to cell tips in single mutants but were dispersed in double mutants. In contrast, a marker for active Cdc42, a major polarity landmark, localized to discreet cortical sites even in double mutants. Localization and photobleaching studies show that the exocyst subunits Sec6 and Sec8 localize to cell tips largely independently of the actin cytoskeleton, but in a cdc42 and phospholipid phosphatidylinositol 4,5-bisphosphate (PIP₂)-dependent manner. Thus in fission yeast long-range cytoskeletal transport and PIP₂-dependent exocyst represent parallel morphogenetic modules downstream of Cdc42, raising the possibility of similar mechanisms in other cell types.

Independent relations of left ventricular structure with the 24-h urinary excretion of sodium and aldosterone

Objective: Previous studies reported on the association of left ventricular mass index (LVMI) with urinary sodium or with circulating or urinary aldosterone.We investigated the independent associations of LVMI with the urinary excretion of both sodium and aldosterone. Design and method: We randomly recruited 317 untreated subjects from a White population (45.1%women; mean age 48.2 years).Measurements included echocardiographic left ventricular (LV) properties, the 24 h urinary excretion of sodium and aldosterone, plasma renin activity (PRA), and proximal (RNaprox) and distal (RNadist) renal sodium reabsorption, assessed fromthe endogenous lithium clearance. Inmultivariable-adjusted models,we expressed changes in LVMI per 1 SD increase in the explanatory variables, while accounting for sex, age, systolic blood pressure and the waist-to-hip ratio. Results: LVMI increased independentlywith the urinary excretion of both sodium (+2.48 g/m2; P=0.005) and aldosterone (+2.63 g/m2; P=0.004). Higher sodium excretion was associated with increased mean wall thickness (MWT: +0.126 mm, P=0.054), but with no change in LV end-diastolic diameter (LVID: +0.12mm, P=0.64). In contrast, higher aldosterone excretion was associated with higher LVID (+0.54 mm; P=0.017), but with no change in MWT (+0.070mm; P=0.28).Higher RNadistwas associatedwith lower relativewall thickness (−0.81×10−2, P=0.017), because of opposite trends in LVID(+0.33 mm; P=0.13) and MWT (−0.130mm; P=0.040). LVMI was not associated with PRA or RNaprox. Conclusions: LVMI independently increased with both urinary sodium and aldosterone excretion. IncreasedMWT explained the association of LVMI with urinary sodium and increased LVID the association of LVMI with urinary aldosterone.

La clause de limitation des bénéfices dans la convention de double imposition entre la Suisse et les Etats-Unis

AVANT PROPOS L'abus des conventions de double imposition (treaty shopping) est une des problématiques les plus riches de la fiscalité internationale contemporaine. L'utilisation d'une telle convention (ci-après : CDI) par des personnes ne résidant effectivement dans aucun des Etats contractants à la convention constitue pour une majorité de la doctrine internationale un abus de droit. La problématique de l'abus des CDI a été identifiée de longue date en Suisse. Elle a suivi une évolution partiellement différente aux Etats-Unis. Les deux approches se sont rencontrées une première fois lors de la conclusion de la CDI CH-US de 1951 (art. XI). Longtemps évoquée, la révision de cette convention a été finalisée en 1996. Cette deuxième rencontre a fait entrer dans l'ordre juridique suisse une disposition d'un type complètement nouveau, qui aura des répercussions jusque dans la pratique anti-abus au plan interne en Suisse. La présente étude s'attachera à examiner l'évolution comparée de la lutte contre l'abus des CDI en Suisse tout d'abord (première partie), et aux Etats-Unis ensuite (IIe partie), ainsi que les relations entre les normes internes anti-abus et celles découlant d'une convention dans chacun des deux Etats. La clause spécifique de limitation des avantages de la Convention actuelle (art. 22 CDI-US) sera analysée dans la IIIe partie. La dernière partie (IVe partie) sera consacrée à une comparaison entre cette disposition et les mesures anti-abus contenues dans le Modèle de convention de l'OCDE afin de déterminer si cette clause constitue réellement l'instrument optimal pour lutter contre l'utilisation indue des conventions de double imposition.

The T309G Murine Double Minute 2 Gene Polymorphism Is an Independent Prognostic Factor for Patients with Renal Cell Carcinoma.

The purpose of this study was to evaluate the association of the T309G MDM2 gene polymorphism with renal cell carcinoma (RCC) risk, pathology, and cancer-specific survival (CSS). T309G MDM2 was genotyped in 449 Caucasians, including 240 with RCC and 209 cancer-free controls. The T309G MDM2 genotype was TT in 174 (38.8%), GT in 214 (47.7%), and GG in 61 (13.6%) subjects, without any significant differences between cases and controls on both univariable (p=0.58) and multivariable logistic regression (each p>0.25). Furthermore, T309G MDM2 was not linked with T stage (p=0.75), N stage (p=0.37), M stage (p=0.94), grade (p=0.21), and subtype (p=0.55). There was, however, a statistically significant association of T309G MDM2 with CSS (p=0.022): patients with TT had significantly worse survival than GG/GT (p=0.009), while those with GT and GG had similar outcomes (p=0.92). The 5-year survival rate for patients with TT, GT, and GG was 69.5%, 84.5%, and 89.7%, respectively. On the multivariable analysis, T309G was identified as an independent prognostic factor. The T309G MDM2 polymorphism is an independent prognostic factor for patients with RCC, with the TT genotype being associated with worse prognosis. In this study, there were no significant associations with RCC risk and pathology.

Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system.

Cardiac hypertrophy is frequent in chronic hypertension. The renin-angiotensin system, via its effector angiotensin II (Ang II), regulates blood pressure and participates in sustaining hypertension. In addition, a growing body of evidence indicates that Ang II acts also as a growth factor. However, it is still a matter of debate whether the trophic effect of Ang II can trigger cardiac hypertrophy in the absence of elevated blood pressure. To address this question, transgenic mice overexpressing the rat angiotensinogen gene, specifically in the heart, were generated to increase the local activity of the renin-angiotensin system and therefore Ang II production. These mice develop myocardial hypertrophy without signs of fibrosis independently from the presence of hypertension, demonstrating that local Ang II production is important in mediating the hypertrophic response in vivo.

Sensitivity of Spring Phenology to Warming Across Temporal and Spatial Climate Gradients in Two Independent Databases

Disparate ecological datasets are often organized into databases post hoc and then analyzed and interpreted in ways that may diverge from the purposes of the original data collections. Few studies, however, have attempted to quantify how biases inherent in these data (for example, species richness, replication, climate) affect their suitability for addressing broad scientific questions, especially in under-represented systems (for example, deserts, tropical forests) and wild communities. Here, we quantitatively compare the sensitivity of species first flowering and leafing dates to spring warmth in two phenological databases from the Northern Hemisphere. One-PEP725-has high replication within and across sites, but has low species diversity and spans a limited climate gradient. The other-NECTAR-includes many more species and a wider range of climates, but has fewer sites and low replication of species across sites. PEP725, despite low species diversity and relatively low seasonality, accurately captures the magnitude and seasonality of warming responses at climatically similar NECTAR sites, with most species showing earlier phenological events in response to warming. In NECTAR, the prevalence of temperature responders significantly declines with increasing mean annual temperature, a pattern that cannot be detected across the limited climate gradient spanned by the PEP725 flowering and leafing data. Our results showcase broad areas of agreement between the two databases, despite significant differences in species richness and geographic coverage, while also noting areas where including data across broader climate gradients may provide added value. Such comparisons help to identify gaps in our observations and knowledge base that can be addressed by ongoing monitoring and research efforts. Resolving these issues will be critical for improving predictions in understudied and under-sampled systems outside of the temperature seasonal mid-latitudes.

Adiponectin and heme oxygenase-1 suppress TLR4/MyD88-independent signaling in rat Kupffer cells and in mice after chronic ethanol exposure.

Alcoholic liver disease is mediated via activation of TLR4 signaling; MyD88-dependent and -independent signals are important contributors to injury in mouse models. Adiponectin, an anti-inflammatory adipokine, suppresses TLR4/MyD88-dependent responses via induction of heme oxygenase-1 (HO-1). Here we investigated the interactions between chronic ethanol, adiponectin, and HO-1 in regulation of TLR4/MyD88-independent signaling in macrophages and an in vivo mouse model. After chronic ethanol feeding, LPS-stimulated expression of IFN-β and CXCL10 mRNA was increased in primary cultures of Kupffer cells compared with pair-fed control mice. Treatment of Kupffer cells with globular adiponectin (gAcrp) normalized this response. LPS-stimulated IFN-β/CXCL10 mRNA and CXCL10 protein was also reduced in RAW 264.7 macrophages treated with gAcrp or full-length adiponectin. gAcrp and full-length adiponectin acted via adiponectin receptors 1 and 2, respectively. gAcrp decreased TLR4 expression in both Kupffer cells and RAW 264.7 macrophages. Small interfering RNA knockdown of HO-1 or inhibition of HO-1 activity with zinc protoporphyrin blocked these effects of gAcrp. C57BL/6 mice were exposed to chronic ethanol feeding, with or without treatment with cobalt protoporphyrin, to induce HO-1. After chronic ethanol feeding, mice were sensitized to in vivo challenge with LPS, expressing increased IFN-β/CXCL10 mRNA and CXCL10 protein in liver compared with control mice. Pretreatment with cobalt protoporphyrin 24 h before LPS challenge normalized this effect of ethanol. Adiponectin and induction of HO-1 potently suppressed TLR4-dependent/MyD88-independent cytokine expression in primary Kupffer cells from rats and in mouse liver after chronic ethanol exposure. These data suggest that induction of HO-1 may be a useful therapeutic strategy in alcoholic liver disease.