Primary Adult-Onset Hemophagocytic Lymphohistiocytosis with Neurologic Presentation.

Hemophagocytic lymphohistiocytosis (HLH) is a rare immune deregulatory disorder that predominantly presents in children. Here we describe three patients with adult-onset primary HLH whose initial presentations were characterized by neurological features, and we review the literature of published cases. These cases ranged in age from 17 to 30 and presented with a variety of neurological symptoms. One of our cases demonstrated numerous microhemorrhages on MR brain. This is the first published case of adult-onset HLH presenting with cerebral microhemorrhages. In addition, literature review identified five additional patients with isolated central nervous system presentation of primary HLH.

Data Harmonization in Aging Research: Not so Fast.

BACKGROUND/STUDY CONTEXT: Harmonizing measures in order to conduct pooled data analyses has become a scientific priority in aging research. Retrospective harmonization where different studies lack common measures of comparable constructs presents a major challenge. This study compared different approaches to harmonization with a crosswalk sample who completed multiple versions of the measures to be harmonized. METHODS: Through online recruitment, 1061 participants aged 30 to 98 answered two different depression scales, and 1065 participants answered multiple measures of subjective health. Rational and configural methods of harmonization were applied, using the crosswalk sample to determine their success; and empirical item response theory (IRT) methods were applied in order empirically to compare items from different measures as answered by the same person. RESULTS: For depression, IRT worked well to provide a conversion table between different measures. The rational method of extracting semantically matched items from each of the two scales proved an acceptable alternative to IRT. For subjective health, only configural harmonization was supported. The subjective health items used in most studies form a single robust factor. CONCLUSION: Caution is required in aging research when pooling data across studies using different measures of the same construct. Of special concern are response scales that vary widely in the number of response options, especially if the anchors are asymmetrical. A crosswalk sample that has completed items from each of the measures being harmonized allows the investigator to use empirical approaches to identify flawed assumptions in rational or configural approaches to harmonizing.

Genome sequences of four bacterial strains isolated from organofluorine enrichment cultures.

Because fluorinated organic compounds are broadly used and highly persistent, microbes isolated from wastewater may be able to degrade these contaminants. Here, we report the genome sequences of Flavobacterium sp. str. WV_118_3, Nocardioides sp. str. WV_118_6, Ochrobactrum anthropi str. WV_118_8, and Sphingomonas sp. str. VL_57B, isolated from wastewater.

Large-scale synthesis of transition-metal-doped TiO2 nanowires with controllable overpotential.

Practical implementation of one-dimensional semiconductors into devices capable of exploiting their novel properties is often hindered by low product yields, poor material quality, high production cost, or overall lack of synthetic control. Here, we show that a molten-salt flux scheme can be used to synthesize large quantities of high-quality, single-crystalline TiO2 nanowires with controllable dimensions. Furthermore, in situ dopant incorporation of various transition metals allows for the tuning of optical, electrical, and catalytic properties. With this combination of control, robustness, and scalability, the molten-salt flux scheme can provide high-quality TiO2 nanowires to satisfy a broad range of application needs from photovoltaics to photocatalysis.

Si/InGaN core/shell hierarchical nanowire arrays and their photoelectrochemical properties.

Three-dimensional hierarchical nanostructures were synthesized by the halide chemical vapor deposition of InGaN nanowires on Si wire arrays. Single phase InGaN nanowires grew vertically on the sidewalls of Si wires and acted as a high surface area photoanode for solar water splitting. Electrochemical measurements showed that the photocurrent density with hierarchical Si/InGaN nanowire arrays increased by 5 times compared to the photocurrent density with InGaN nanowire arrays grown on planar Si (1.23 V vs RHE). High-resolution transmission electron microscopy showed that InGaN nanowires are stable after 15 h of illumination. These measurements show that Si/InGaN hierarchical nanostructures are a viable high surface area electrode geometry for solar water splitting.

Durability of the effects of testosterone and growth hormone supplementation in older community-dwelling men: the HORMA Trial.

OBJECTIVES: To determine the durability of anabolic effects and adverse events (AEs) after stopping testosterone and growth hormone supplementation in older men. DESIGN: Secondary analysis of a double-masked, randomized controlled trial of testosterone gel (5 or 10 g/daily) plus rhGH (0, 3 or 5 µg/kg/day) with follow-up of outcomes 3 months later. PARTICIPANTS: A total of 108 community-dwelling 65- to 90-year-old men. MEASUREMENTS: Testosterone and IGF-1 levels, body composition (DEXA), 1-repetition maximum (1-RM) strength, stair-climbing power, quality-of-life (QOL) and activity questionnaires, AEs. RESULTS: Despite improvements in body composition during treatment, residual benefits 3 months later (week 28) were variable. For participants with improvements exceeding their week-17 median changes, benefits were sustained at week 28 for lean body mass (1·45 ± 1·63 kg, 45% of week-17 values, P < 0·0001 vs baseline), appendicular skeletal muscle mass (ASMM, 0·71 ± 1·01 kg, 42%, P < 0·0001), total fat (-1·06 ± 2·18 kg, 40%, P < 0·0001) and trunk fat (-0·89 ± 1·42 kg, 50%, P < 0·0001); retention of ASMM was associated with greater week-16 protein intake (P = 0·01). For 1-RM strength, 39%-43% of week-17 improvements (P ≤ 0·05) were retained and associated with better week-17 strength (P < 0·0001), change in testosterone from week 17-to 28 (P = 0·004) and baseline PASE (P = 0·04). Framingham 10-year cardiovascular risks were low (~14%), did not worsen and improved by week 28 (P = 0·0002). The hypothalamic-pituitary-gonadal axis recovered completely. CONCLUSIONS: Durable improvements in muscle mass, strength and fat mass were retained 3 months after discontinuing hormone supplementation in participants with greater than median body composition changes during treatment, but not in others with smaller gains. AEs largely resolved after intervention discontinuation. Additional strategies may be needed to sustain or augment muscle mass and strength gains achieved during short-term hormone therapy.

JAM-C induces endothelial cell permeability through its association and regulation of {beta}3 integrins.

OBJECTIVE: The molecular mechanisms regulating vascular permeability are only now being elucidated. The junctional adhesion molecule (JAM) JAM-C has been linked to the induction of vascular permeability. We sought to understand the mechanism whereby JAM-C may disrupt junctional integrity in endothelial cells (ECs). METHODS AND RESULTS: We show here that JAM-C alters permeability through modulation of integrin activity. JAM-C overexpression results in an increase in JAM-C at junctions and an increase in permeability. Conversely, knockdown of JAM-C by siRNA results in a reduction in permeability. JAM-C associates with alphavbeta3 integrin and regulates its localization and activity. JAM-C also inhibits the activation state of the beta(1) integrin although it does not associate with this integrin. These changes induced on the integrins are mediated through regulation of the small GTPase, Rap1b but not Rap1a. Thrombin, a powerful inductor of vascular leak, causes localization of JAM-C into the junctions, whereas angiopoietin-1, an inhibitor of permeability, prevents JAM-C translocation. CONCLUSIONS: The regulation of EC junctional integrity involves the coordinated and dynamic modification of localization and activity of junctional stabilizers such as the integrin beta(3) and the destabilizer, JAM-C.

Chronic increases in sphingosine kinase-1 activity induce a pro-inflammatory, pro-angiogenic phenotype in endothelial cells.

Sphingosine kinase-1 (SK1) promotes the formation of sphingosine-1-phosphate (S1P), which has potent pro-inflammatory and pro-angiogenic effects. We investigated the effects of raised SK1 levels on endothelial cell function and the possibility that this signaling pathway is activated in rheumatoid arthritis. Human umbilical vein endothelial cells with 3- to 5-fold SK1 (EC(SK)) overexpression were generated by adenoviral and retroviralmediated gene delivery. The activation state of these cells and their ability to undergo angiogenesis was determined. S1P was measured in synovial fluid from patients with RA and OA. EC(SK) showed an enhanced migratory capacity and a stimulated rate of capillary tube formation. The cells showed constitutive activation as evidenced by the induction of basal VCAM-1 expression, and further showed a more augmented VCAM-1 and E selectin response to TNF compared with empty vector control cells (EC(EV)). These changes had functional consequences in terms of enhanced neutrophil binding in the basal and TNFstimulated states in EC(SK). By contrast, over-expression of a dominant-negative SK inhibited the TNF-induced VCAM-1 and E selectin and inhibited PMN adhesion, confirming that the observed effects were specifically mediated by SK. The synovial fluid levels of S1P were significantly higher in patients with RA than in those with OA. Small chronic increases in SK1 activity in the endothelial cells enhance the ability of the cells to support inflammation and undergo angiogenesis, and sensitize the cells to inflammatory cytokines. The SK1 signaling pathway is activated in RA, suggesting that manipulation of SK1 activity in diseases of aberrant inflammation and angiogenesis may be beneficial.

PPARgamma agonists ameliorate endothelial cell activation via inhibition of diacylglycerol-protein kinase C signaling pathway: role of diacylglycerol kinase.

Subject- Peroxisome proliferator-activated receptor (PPAR)-gamma agonists are emerging as potential protectors against inflammatory cardiovascular diseases including atherosclerosis and diabetic complications. However, their molecular mechanism of action within vasculature remains unclear. We report here that PPARgamma agonists, thiazolidinedione class drugs (TZDs), or 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) were capable of activating diacylglycerol (DAG) kinase (DGK), resulting in attenuation of DAG levels and inhibition of protein kinase C (PKC) activation. The PPARgamma agonist-induced DGK was completely blocked by a dominant-negative mutant of PPARgamma, indicating an essential receptor-dependent action. Importantly, the suppression of DAG-PKC signaling pathway was functional linkage to the anti-inflammatory properties of PPARgamma agonists in endothelial cells (EC), characterized by the inhibition of proinflammatory adhesion molecule expression and adherence of monocytes to the activated EC induced by high glucose. These findings thus demonstrate a novel molecular action of PPARgamma agonists to suppress the DAG-PKC signaling pathway via upregulation of an endogenous attenuator, DGK.

Myotonic disorders: A review article.

The myotonic disorders are a heterogeneous group of genetically determined diseases that are unified by the presence of myotonia, which is defined as failure of muscle relaxation after activation. The presentation of these disorders can range from asymptomatic electrical myotonia, as seen in some forms of myotonia congenita (MC), to severe disability with muscle weakness, cardiac conduction defects, and other systemic features as in myotonic dystrophy type I (DM1). In this review, we describe the clinical features and pathophysiology of the different myotonic disorders, their laboratory and electrophysiologic findings and briefly review the currently available treatments.

Photoelectrochemical properties of TiO2 nanowire arrays: a study of the dependence on length and atomic layer deposition coating.

We report that the length and surface properties of TiO(2) nanowires can have a dramatic effect on their photoelectrochemical properties. To study the length dependence, rutile TiO(2) nanowires (0.28-1.8 µm) were grown on FTO substrates with different reaction times (50-180 min) using a hydrothermal method. Nanowires show an increase in photocurrent with length, and a maximum photocurrent of 0.73 mA/cm(2) was measured (1.5 V vs RHE) for 1.8 µm long nanowires under AM 1.5G simulated sunlight illumination. While the incident photon to current conversion efficiency (IPCE) increases linearly with photon absorptance (1-10(-α×length)) with near band gap illumination (λ = 410 nm), it decreases severely at shorter wavelengths of light for longer nanowires due to poor electron mobility. Atomic layer deposition (ALD) was used to deposit an epitaxial rutile TiO(2) shell on nanowire electrodes which enhanced the photocatalytic activity by 1.5 times (1.5 V vs RHE) with 1.8 µm long nanowires, reaching a current density of 1.1 mA/cm(2) (61% of the maximum photocurrent for rutile TiO(2)). Additionally, by fixing the epitaxial rutile shell thickness and studying photoelectrochemical (PEC) properties of different nanowire lengths (0.28-1.8 µm), we found that the enhancement of current increases with length. These results demonstrate that ALD coating improves the charge collection efficiency from TiO(2) nanowires due to the passivation of surface states and an increase in surface area. Therefore, we propose that epitaxial coating on materials is a viable approach to improving their energy conversion efficiency.

Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1-dependent activation of PI-3K/Akt and regulation of Bcl-2 family members.

Sphingosine-1-phosphate (S1P), the bioactive product of sphingosine kinase (SK) activation, is a survival factor for endothelial cells. The mechanism of SK-mediated survival was investigated in endothelial cells with moderately raised intracellular SK activity. Overexpression of SK mediated survival primarily through the activation of the phosphatidyl inositol 3-kinase (PI-3K)/protein kinase B (Akt/PKB) pathway and an associated up-regulation of the antiapoptotic protein B cell lymphoma gene 2 (Bcl-2) and down-regulation of the proapoptotic protein bisindolylmaleimide (Bcl-2 interacting mediator of cell death; Bim). In addition there was an up-regulation and dephosphorylation of the junctional molecule platelet endothelial cell adhesion molecule-1 (PECAM-1), which was obligatory for activation of the PI-3K/Akt pathway, for SK-induced cell survival, and for the changes in the apoptosis-related proteins. Thus, raised intracellular SK activity induced a molecule involved in cell-cell interactions to augment cell survival through a PI-3K/Akt-dependent pathway. This is distinct from the activation of both PI-3K/Akt and mitogen-activated protein kinase (MAPK) pathways seen with exogenously added S1P. Cells overexpressing SK showed enhanced survival under conditions of serum deprivation and absence of attachment to extracellular matrix, suggesting a role for SK in the regulation of vascular phenomena that occur under conditions of stress, such as angiogenesis and survival in unattached states, as would be required for a circulating endothelial cell.

Apolipoprotein E enhances hepatic lipase-mediated hydrolysis of reconstituted high-density lipoprotein phospholipid and triacylglycerol in an isoform-dependent manner.

This study compares the kinetics of hepatic lipase (HL)-mediated phospholipid and triacylglycerol hydrolysis in spherical, reconstituted high-density lipoproteins (rHDL) that contain either apolipoprotein E2 (apoE2), apoE3, apoE4, or apoA-I as the sole apolipoprotein. HL-mediated phospholipid hydrolysis was assessed by incubating various concentrations of rHDL that contained only cholesteryl esters (CE) in their core, (E2/CE)rHDL, (E3/CE)rHDL, (E4/CE)rHDL, and (A-I/CE)rHDL, with a constant amount of HL. The rate of phospholipid hydrolysis was determined as the formation of nonesterified fatty acid mass. HL-mediated triacylglycerol hydrolysis was assessed in rHDL containing CE, unlabeled triacylglycerol, and [(3)H]triacylglycerol in their core, (E2/TG)rHDL, (E3/TG)rHDL, (E4/TG)rHDL, and (A-I/TG)rHDL. Triacylglycerol hydrolysis was determined as the ratio of (3)H-labeled hydrolysis products to (3)H-labeled unhydrolyzed triacylglycerol. The rates of phospholipid hydrolysis in the (E2/CE)rHDL, (E3/CE)rHDL, and (E4/CE)rHDL were significantly greater than that in the (A-I/CE)rHDL. The rates of triacylglycerol hydrolysis were also greater in the (E2/TG)rHDL, (E3/TG)rHDL, and (E4/TG)rHDL compared to the (A-I/TG)rHDL, although to a lesser degree than observed with phospholipid hydrolysis. Furthermore, the rates of both phospholipid and triacylglycerol hydrolyses were greater in the (E2)rHDL than in either the (E3)rHDL or the (E4)rHDL. These results show that apoE increases the rate of HL-mediated phospholipid and triacylglycerol hydrolysis in rHDL and that this influence is isoform dependent.