Influence of surface treatment and curing mode of resin composite cements on fibroblast behavior.

BACKGROUND: Human gingival fibroblast (HGF-1) cells in the connective tissue provide an effective barrier between the alveolar bone and the oral environment. Cement margins of restorations with intrasulcular preparation or cemented implant restorations are in contact with HGF cells. However, it is unknown to what extend the cement surface finish affects the behavior of HGF cells. The purpose of this study was to compare the behavior of HGF-1 cells in contact with two different resin composite cements with three different surface treatments after light-curing and autopolymerization, respectively. METHODS: Disks of one adhesive (Multilink Automix, Ivoclar Vivadent [MLA]) and one self-adhesive (RelyX Unicem 2 Automix, 3 M [RUN]) resin composite cement were either light-cured or autopolymerized. Specimen surfaces were prepared with the oxygen inhibition layer intact, polished with P2500-grit silicon carbide paper or treated with a scaler. Cells were cultivated on the specimens for 24 h. Viability assay was performed, and cell morphology was examined with scanning electron microscopy. Additionally, roughness parameters of the specimen were analyzed with a 3D laser scanning microscope. Three-way ANOVA was applied to determine the effect of cement material, curing mode and surface treatment (a = 0.05). RESULTS: Overall, cement material (p = 0.031), curing mode (p = 0.001), and surface treatment (p < 0.001) significantly affected relative cell viability of HGF. The autopolymerized specimen with the oxygen inhibition layer left intact displayed the lowest relative cell viability (MLA 25.7%, RUN 46.6%). Removal of the oxygen inhibition layer with a scaler increased cell viability but also resulted in higher surface roughness values. CONCLUSIONS: HGF cell viability is affected by the surface treatment and the curing mode. The oxygen inhibition layer is an inhibitory factor for the viability of HGF cells. Autopolymerization enhances the cytotoxic potential of the oxygen inhibition layer.

A comprehensive in vitro study on the performance of two different strategies to simplify adhesive bonding.

OBJECTIVE: The purpose of this study is to compare the bonding performance and mechanical properties of two different resin composite cements using simplified adhesive bonding strategies. MATERIALS AND METHODS: Shear bond strength of two resin composite cements (an adhesive cement: Panavia V5 [PV5] and a self-adhesive cement: RelyX Universal [RUV]) to human enamel, dentin, and a variety of restorative materials (microfilled composite, composite, polymer-infiltrated ceramic, feldspar ceramic, lithium disilicate and zirconia) was measured. Thermocycle aging was performed with selected material combinations. RESULTS: For both cements, the highest shear bond strength to dentin was achieved when using a primer (PV5: 18.0 ± 4.2 MPa, RUV: 18.2 ± 3.3 MPa). Additional etching of dentin reduced bond strength for RUV (12.5 ± 4.9 MPa). On enamel, PV5 achieved the highest bond strength when the primer was used (18.0 ± 3.1 MPa), while for RUV etching of enamel and priming provided best results (21.2 ± 6.6 MPa). Shear bond strength of RUV to restorative materials was superior to PV5. Bonding to resin-based materials was predominantly observed for RUV. CONCLUSIONS: While use of RUV with the selective-etch technique is slightly more labor intensive than PV5, RUV (with its universal primer) displayed a high-bonding potential to all tested restorative materials, especially to resin. CLINICAL SIGNIFICANCE: For a strong adhesion to the tooth substrate, PV5 (with its tooth primer) is to be preferred because etching with phosphoric acid is not required. However, when using a wide range of varying restorative materials, RUV with its universal primer seems to be an adequate option.

Fabrication and Characterization of PCL/HA Filament as a 3D Printing Material Using Thermal Extrusion Technology for Bone Tissue Engineering.

The most common three-dimensional (3D) printing method is material extrusion, where a pre-made filament is deposited layer-by-layer. In recent years, low-cost polycaprolactone (PCL) material has increasingly been used in 3D printing, exhibiting a sufficiently high quality for consideration in cranio-maxillofacial reconstructions. To increase osteoconductivity, prefabricated filaments for bone repair based on PCL can be supplemented with hydroxyapatite (HA). However, few reports on PCL/HA composite filaments for material extrusion applications have been documented. In this study, solvent-free fabrication for PCL/HA composite filaments (HA 0%, 5%, 10%, 15%, 20%, and 25% weight/weight PCL) was addressed, and parameters for scaffold fabrication in a desktop 3D printer were confirmed. Filaments and scaffold fabrication temperatures rose with increased HA content. The pore size and porosity of the six groups' scaffolds were similar to each other, and all had highly interconnected structures. Six groups' scaffolds were evaluated by measuring the compressive strength, elastic modulus, water contact angle, and morphology. A higher amount of HA increased surface roughness and hydrophilicity compared to PCL scaffolds. The increase in HA content improved the compressive strength and elastic modulus. The obtained data provide the basis for the biological evaluation and future clinical applications of PCL/HA material.

Myelinating Schwann cells and Netrin-1 control intra-nervous vascularization of the developing mouse sciatic nerve.

Peripheral nerves are vascularized by a dense network of blood vessels to guarantee their complex function. Despite the crucial role of vascularization to ensure nerve homeostasis and regeneration, the mechanisms governing nerve invasion by blood vessels remain poorly understood. We found, in mice, that the sciatic nerve invasion by blood vessels begins around embryonic day 16 and continues until birth. Interestingly, intra-nervous blood vessel density significantly decreases during post-natal period, starting from P10. We show that, while the axon guidance molecule Netrin-1 promotes nerve invasion by blood vessels via the endothelial receptor UNC5B during embryogenesis, myelinated Schwann cells negatively control intra-nervous vascularization during post-natal period.

Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit.

Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare type of leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation that lead to ataxia, spasticity, and cognitive decline. During postnatal development (from P5 to P15 in the mouse), MLC1 forms a membrane complex with GlialCAM (another astrocytic transmembrane protein) at the junctions between perivascular astrocytic processes. Perivascular astrocytic processes along with blood vessels form the gliovascular unit. It was not previously known how MLC1 influences the physiology of the gliovascular unit. Here, using the Mlc1 knock-out mouse model of MLC, we demonstrated that MLC1 controls the postnatal development and organization of perivascular astrocytic processes, vascular smooth muscle cell contractility, neurovascular coupling, and intraparenchymal interstitial fluid clearance. Our data suggest that MLC is a developmental disorder of the gliovascular unit, and perivascular astrocytic processes and vascular smooth muscle cell maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.

Thresholds of Endoglin Expression in Endothelial Cells Explains Vascular Etiology in Hereditary Hemorrhagic Telangiectasia Type 1.

Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-ß/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.

In Vitro Investigations in a Biomimetic Approach to Restore One-Piece Zirconia Implants.

The objective of this study was to evaluate the fracture load and retention force of different bonding systems while restoring one-piece zirconia implants with a novel cementation approach using a mesostructure. Polymer-infiltrated ceramic mesostructures (n = 112) were therefore designed as caps on the implant abutment, and a molar feldspathic ceramic crown was constructed on top of it as a suprastructure. For cementation, different bonding systems were used. Fracture load and retention force were measured immediately after storage in water at 37 °C for 24 h (n = 8) as well as after artificial aging in a chewing simulator and subsequent thermal cycling (n = 8). Combined restorations showed higher fracture load compared to monolithic restorations of polymer-infiltrated ceramic (n = 8) or feldspathic ceramic (n = 8) identical in shape. However, the fracture load of the combined restorations was significantly affected by aging, independent of the primers and cements used. Restorations cemented with primers containing methyl methacrylate and 10-methacryloyloxydecyl dihydrogen phosphate exhibited the highest retention force values. Aging did not affect the retention force significantly. Similar fracture load values can be expected from combination restorations when compared with monolithic crowns.

Fracture load of zirconia implant supported CAD/CAM resin crowns and mechanical properties of restorative material and cement.

Purpose To test if resin CAD/CAM materials should be considered for zirconia implants and how their mechanical properties affect the fracture load.Methods Fracture load of molar crowns of CAD/CAM materials (VITA CAD-Temp [CT], Cerasmart [CS], Lava Ultimate [LU], Pekkton Ivory [PK]) on zirconia implants (ceramic.implant, 4.0 mm) fixed either with no cement, temporary cement (Harvard Implant semi-permanent [HIS]), self-adhesive (VITA Adiva S-Cem [VAS]) or either one of two adhesive cements (Multilink Automix [MLA], VITA Adiva F-Cem [VAF]) was analyzed. The restorative materials were characterized by their flexural strength, fracture toughness, elemental composition and organic/inorganic ratio while compressive strength of the cements was measured.Results For the fracture load significantly highest mean values were found overall for PK (2921 ±300 N) > LU (2017 ±499 N) > CS (1463 ±367 N) = CT (1451 ±327 N) (p > 0.05). When analyzing the effect of the cement on the fracture load the overall ranking was VAF (2245 ±650 N) ≥ MLA (2188 ±708 N) ≥ VAS (2017 ±563 N) > HIS (1757 ±668 N) = no cement (1595 ±757 N) (p <0.05), meaning fracture load increased with the compressive strength of the cements. Additionally, a linear trend was found between the fracture load and the fracture toughness of the restorative materials.Conclusions All restorative materials exhibited fracture load values similar or higher than lithium disilicate tested previously. Fracture load of CT, CS and LU can be significantly increased when an adhesive cement with a high compressive strength is used.

Chewing simulation of zirconia implant supported restorations.

PURPOSE: To test three potential prosthetic material options for zirconia implants in regard to their mechanical properties, loading and retention capacity as well as to record abrasion after chewing simulation followed by thermocyclic aging. METHODS: Molar crowns (n = 96) of three different computer-aided design/computer-aided manufacturing (CAD/CAM) materials were produced and cemented on zirconia implants (ceramic.implant, Vita) with a diameter of 4.5 mm. Monolithic zirconia (Vita YZ [YZ] with RelyX Unicem 2 Automix [RUN], polymer-infiltrated ceramic (Vita Enamic [VE]) with Vita Adiva F-Cem [VAF] and acrylate polymer (CAD Temp [CT]) with RelyX Ultimate [RUL]. Fracture load and retentive force of the crowns were measured after 24 h water storage at 37 °C and after a chewing simulation followed by thermocyclic aging. Abrasion was recorded by matching stereolithography-data of the crowns obtained before and after chewing simulation. Additionally, the mechanical properties and bonding capabilities of the crown and cement materials were assessed. RESULTS: Fracture load values were significantly highest for YZ > VE = CT. Retention force values did not differ significantly between the materials. The aging procedure did not affect the fracture load values nor the retention force significantly. Abrasion depth of the crowns was lowest for YZ followed by VE and CT. On unpolished crowns, abrasion of YZ and VE tended to be higher than on polished specimens. CONCLUSIONS: Based on the obtained in-vitro results, all tested materials can be recommended for the use on zirconia implants, although CT is only approved for temporary crowns. The loading and retention capacity of the materials were not significantly affected by aging.

Loading capacity of CAD/CAM-fabricated anterior feldspathic ceramic crowns bonded to one-piece zirconia implants with different cements.

OBJECTIVE: This study evaluated the loading capacity of CAD/CAM-fabricated anterior feldspathic ceramic crowns bonded to one-piece zirconia implants with different cements. MATERIAL AND METHODS: Fifty one-piece zirconia implants were embedded in epoxy resin. The abutment aspect of one implant was optically scanned and a standardized upper canine was designed with CAD-software. Fifty feldspathic ceramic crowns were milled, polished, and mounted on the implants either without any cement, with a temporary cement or with three different composite resin cements after surface pretreatment as recommended by the manufacturers (n = 10). After storage in distilled water at 37°C for 24 hr, specimens were loaded until fracture on the palatal surface of the crown at an angle of 45° to the long axis of the implant and loads until fracture were detected and compared. Compressive strength of the investigated cement materials was determined. Statistical analyses were done with One-way ANOVA followed by post hoc Fisher LSD test (α = 0.05). RESULTS: The cements revealed significantly different compressive strength values (temporary cement: 37.1 ± 7.0 MPa; composite resin cements: 185.8 ± 21.3, 277.9 ± 22.1, and 389.0 ± 13.6 MPa, respectively). Load-at-fracture values had an overall mean value of 237.1 ± 58.2 N with no significant difference among the composite resin cements (p > 0.05). Fracture load values with the temporary cement or without cement were significantly lower (p < 0.002). CONCLUSIONS: CAD/CAM-fabricated anterior feldspathic ceramic crowns bonded to one-piece zirconia implants provide sufficient resistance to intraoral forces.

Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2.

BACKGROUND: Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown. METHODS: We took advantage of Acvrl1+/- mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1+/- mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans. RESULTS: Acvrl1+/- retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial "tip cells" at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1+/- mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1+/- embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1+/- (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1+/- embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1+/- endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1+/- mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1+/- tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies. CONCLUSIONS: Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.

Influence of cement type and ceramic primer on retention of polymer-infiltrated ceramic crowns to a one-piece zirconia implant.

STATEMENT OF PROBLEM: The best procedure for cementing a restoration to zirconia implants has not yet been established. PURPOSE: The purpose of this in vitro study was to measure the retention of polymer-infiltrated ceramic crowns to zirconia 1-piece implants using a wide range of cements. The effect of ceramic primer treatment on the retention force was also recorded. The retention results were correlated with the shear bond strength of the cement to zirconia and the indirect tensile strength of the cements to better understand the retention mechanism. MATERIAL AND METHODS: The retention test was performed using 100 polymer-infiltrated ceramic crowns (Vita Enamic) and zirconia implants (ceramic.implant CI) The crowns were cemented with either interim cement (Harvard Implant semipermanent, Temp Bond), glass-ionomer cement (Ketac Cem), self-adhesive cement (Perma Cem 2.0, RelyX Unicem Automix 2, Panavia SA), or adhesive cement (Multilink Implant, Multilink Automix, Vita Adiva F-Cem, RelyX Ultimate, Panavia F 2.0, Panavia V5 or Panavia 21) (n=5). Additionally ceramic primer was applied on the intaglio crown surface and implant abutment before cementation for all adhesive cements (Multilink Implant, Multilink Automix: Monobond plus; RelyX Ultimate Scotchbond Universal; Vita Adiva F-Cem: Vita Adiva Zr-Prime; Panavia F2.0, Panavia V5: Clearfil Ceramic Primer) and 1 self-adhesive cement containing 10-methacryloyloxydecyl dihydrogen phosphate (MDP) (Panavia SA: Clearfil Ceramic Primer). Crown debond fracture patterns were recorded. Shear bond strength was determined for the respective cement groups to polished zirconia (n=6). The diametral tensile strength of the cements was measured (n=10). Statistical analysis was performed using 1-way or 2-way analysis of variance followed by the Fisher LSD test (α=.05) within each test parameter. RESULTS: Adhesive and self-adhesive resin cements had shear bond strength values of 0.0 to 5.3 MPa and revealed similar retention forces. Cements containing MDP demonstrated shear bond strength values above 5.3 MPa and displayed increased retention. The highest retention values were recorded for Panavia F 2.0 (318 ±28 N) and Panavia 21 (605 ±82 N). All other adhesive and self-adhesive resin cements attained retention values between 222 ±16 N (Multilink Automix) and 270 ±26 N (Panavia SA), which were significantly higher (P<.05) than glass-ionomer (Ketac Cem: 196 ±34 N) or interim cement (Harvard Implant semipermanent: 43 ±6 N, Temp Bond: 127 ±13 N). Application of manufacturer-specific ceramic primer increased crown retention significantly only for Panavia SA. CONCLUSIONS: Products containing MDP provided a high chemical bond to zirconia. Self-adhesive and adhesive resin cements with low chemical bonding capabilities to zirconia provided retention force values within a small range (220 to 290 N).

Correlations between fracture load of zirconia implant supported single crowns and mechanical properties of restorative material and cement.

Zirconia implants that were restored with veneered zirconia displayed severe chipping rates of the restorations in clinical studies. Purpose of this study was to evaluate the fracture load of different zirconia implant supported monolithic crown materials (zirconia, alumina, lithium disilicate, feldspar ceramic and polymer-infiltrated ceramic) cemented with various cements (Harvard LuteCem SE, Harvard Implant Semi-permanent, Multilink Automix, VITA Adiva F-Cem). Flexural strength and fracture toughness of crown materials and compressive strength of the cements were measured. Fracture load values of crowns fabricated from lithium disilicate, feldspar ceramic and polymer-infiltrated ceramic were increased when cement with high compressive strength was used. Fracture loads for zirconia and alumina crowns were not influenced by the cement. Flexural strength and fracture toughness of the ceramics correlated linearly with the respective fracture load when using adhesive cement with high compressive strength. To achieve sufficient fracture load values, cementation with adhesive cement is essential for feldspar and polymer-infiltrated ceramic.

A New Wnt1-CRE TomatoRosa Embryonic Stem Cell Line: A Tool for Studying Neural Crest Cell Integration Capacity.

Neural crest (NC) cells are a migratory, multipotent population giving rise to numerous lineages in the embryo. Their plasticity renders attractive their use in tissue engineering-based therapies, but further knowledge on their in vivo behavior is required before clinical transfer may be envisioned. We here describe the isolation and characterization of a new mouse embryonic stem (ES) line derived from Wnt1-CRE-R26 RosaTomatoTdv blastocyst and show that it displays the characteristics of typical ES cells. Further, these cells can be efficiently directed toward an NC stem cell-like phenotype as attested by concomitant expression of NC marker genes and Tomato fluorescence. As native NC progenitors, they are capable of differentiating toward typical derivative phenotypes and interacting with embryonic tissues to participate in the formation of neo-structures. Their specific fluorescence allows purification and tracking in vivo. This cellular tool should facilitate a better understanding of the mechanisms driving NC fate specification and help identify the key interactions developed within a tissue after in vivo implantation. Altogether, this novel model may provide important knowledge to optimize NC stem cell graft conditions, which are required for efficient tissue repair.

Effectiveness of a positive psychology intervention combined with cognitive behavioral therapy in university students / Eficacia de una intervención en psicología positiva combinada con terapia cognitivo conductual en estudiantes universitarios

The aim of this study was to design and implement a positive intervention combined with cognitive-behavioral therapy to enhance subjective and psychological well-being and other positive functioning constructs in a convenience sample. Participants analysed were 48 university students (mean age 22.25), 25 assigned nonrandomized to intervention condition and 23 to no-treatment waiting-list control condition. All participants were assessed pre- and post-intervention to test the treatment program effectiveness. Repeated-measures ANCOVAs, controlling baseline differences between the two groups, indicated that the intervention group reported greater social support after the intervention period than the waiting-list control group. Within-group differences were found for happiness, selfacceptance, positive relations with others, optimism, and self-esteem in the intervention group; these differences did not appear in the waiting-list control group. These findings suggest the limited capacity of this intervention program for improving well-being through positive activities combined with cognitive-behavioral therapy. Future research should analyse what kind of activities could be more effective in promoting well-being depending on the characteristics of participants

El objetivo de este estudio fue diseñar e implementar una intervención positiva combinada con técnicas de terapia cognitivo-conductual para mejorar el bienestar subjetivo y psicológico, así como otras variables de funcionamiento positivo en una muestra de conveniencia. Los participantes analizados fueron 48 estudiantes universitarios (media 22.25 años). Se llevó a cabo una asignación no aleatorizada de los participantes a la condición de intervención (n = 25) y a la condición de control en lista de espera sin tratamiento (n = 23). Todos los participantes fueron evaluados antes y después de la intervención para probar la efectividad del programa de tratamiento. Los ANCOVAs de medidas repetidas, controlando las diferencias de la línea base entre los dos grupos, indicaron que el grupo de intervención mostraba mayor apoyo social después del período de intervención que en el grupo control en lista de espera. Se encontraron diferencias intragrupo en felicidad, auto-aceptación, relaciones positivas con los otros, optimismo y autoestima para el grupo de intervención, mientras que estas diferencias no aparecían en el grupo de control en lista de espera. Estos hallazgos sugieren la capacidad limitada de este programa de intervención para mejorar el bienestar a través de actividades positivas combinado con terapia cognitivo-conductual. Las investigaciones futuras deberían analizar qué tipo de actividades podrían ser más eficaces en la promoción del bienestar en función de las características de los participantes

Morbilliform eruption related to eltrombopag: emerging data on the cutaneous toxicity of thrombopoietin receptor agonists.

Eltrombopag is a thrombopoietin mimetic used for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia, hepatitis C patients undergoing antiviral therapy, and thrombocytopenia secondary to aplastic anemia that is refractory to immunosuppressive therapy. We report a case of a 25-year-old man with a history of aplastic anemia who presented with fever and a monomorphic papular rash. Subsequent labs, biopsy, and clinical course favored drug-induced cutaneous toxicity, with eltrombopag as the likely culprit. Eltrombopag is generally well-tolerated; however, clinicians should be aware of the possibility of dose-independent drug-induced cutaneous toxicity with this medication. This report reviews the mechanism and use of eltrombopag along with a summary of associated adverse cutaneous reactions.

Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations.

OBJECTIVE: To determine the role of Gja5 that encodes for the gap junction protein connexin40 in the generation of arteriovenous malformations in the hereditary hemorrhagic telangiectasia type 2 (HHT2) mouse model. APPROACH AND RESULTS: We identified GJA5 as a target gene of the bone morphogenetic protein-9/activin receptor-like kinase 1 signaling pathway in human aortic endothelial cells and importantly found that connexin40 levels were particularly low in a small group of patients with HHT2. We next took advantage of the Acvrl1(+/-) mutant mice that develop lesions similar to those in patients with HHT2 and generated Acvrl1(+/-); Gja5(EGFP/+) mice. Gja5 haploinsufficiency led to vasodilation of the arteries and rarefaction of the capillary bed in Acvrl1(+/-) mice. At the molecular level, we found that reduced Gja5 in Acvrl1(+/-) mice stimulated the production of reactive oxygen species, an important mediator of vessel remodeling. To normalize the altered hemodynamic forces in Acvrl1(+/-); Gja5(EGFP/+) mice, capillaries formed transient arteriovenous shunts that could develop into large malformations when exposed to environmental insults. CONCLUSIONS: We identified GJA5 as a potential modifier gene for HHT2. Our findings demonstrate that Acvrl1 haploinsufficiency combined with the effects of modifier genes that regulate vessel caliber is responsible for the heterogeneity and severity of the disease. The mouse models of HHT have led to the proposal that 3 events-heterozygosity, loss of heterozygosity, and angiogenic stimulation-are necessary for arteriovenous malformation formation. Here, we present a novel 3-step model in which pathological vessel caliber and consequent altered blood flow are necessary events for arteriovenous malformation development.

Widespread calciphylaxis and normal renal function: no improvement with sodium thiosulfate.

Although calciphylaxis generally occurs in patients with chronic renal failure, we present a patient with widespread calciphylaxis in the setting of normal renal function following renal transplant. IV and IL sodium thiosulfate injections were not beneficial in our patient.