Application of a comprehensive subtelomere array in clinical diagnosis of mental retardation

In 2-8% of patients with mental retardation, small copy number changes in the subtelomeric region are thought to be the underlying cause. As detection of these genomic rearrangements is labour intensive using FISH, we constructed and validated a high-density BAC/PAC array covering the first 5 Mb of all subtelomeric regions and applied it in our routine screening of patients with idiopathic mental retardation for submicroscopic telomeric rearrangements. The present study shows the efficiency of this comprehensive subtelomere array in detecting terminal deletions and duplications but also small interstitial subtelomeric rearrangements, starting from small amounts of DNA. With our array, the size of the affected segments, at least those smaller than 5 Mb, can be determined simultaneously in the same experiment. In the first 100 patient samples analysed in our diagnostic practice by the use of this comprehensive telomere array, we found three patients with deletions in 3p, 10q and 15q, respectively, four patients with duplications in 9p, 12p, 21q and Xp, respectively, and one patient with a del 6q/dup 16q. The patients with del 3p and 10q and dup 12p had interstitial rearrangements that would have been missed with techniques using one probe per subtelomeric region chosen close to the telomere.     

Effect of GSH and niacin combination on protein oxidation, ER stress, glycation and aggregation in HLE cells under high glucose condition

AIM: To evaluate the effects of reduced glutathione (GSH) and niacin combination on protein oxidative stress, endoplasmic reticulum (ER) stress, glycation, and aggregation of the αβ crystalline in human lens epithelial (HLE) cells treated with high glucose levels. METHODS: HLE cells were cultured and exposed to 25 mmol/L glucose to promote high glucose conditions. Groups of cells were co-treated with three different combinations of dosages: 10 μmol/L GSH+25 μmol/L niacin (P1), 30 μmol/L GSH+25 μmol/L niacin (P2), and 100 μmol/L GSH+25 μmol/L niacin (P3). After 72h incubation, protein carbonyl content (PCC) and glucose reactive protein (GRP78) content were assessed using ELISA examinations. After two-week incubation, advanced glycation end products (AGEs) were also assessed and the expression of αβ crystalline was measured using Western blot examination. RESULTS: PCC and GRP78 levels in the co-treated groups were not significantly reduced compared to control (P>0.05). In contrast, there was a significant decrease of the AGEs levels in all groups co-treated with GSH and niacin when compared with the control group (P<0.05). In addition, the αβ crystalline expression increased after high dose glucose administration, but decreased in all groups co-treated with GSH and combinations of GSH and niacin. CONCLUSION: Combinations of GSH and niacin inhibit the aggregation of proteins and prevent glycation in hyperglycemic HLE cells. This study shows that this combination may play an active role in preventing diabetic cataract mainly from the AGEs pathway.     

Iron oxide nanoparticles supported on biogenic silica derived from bamboo leaf ash for rhodamine B photodegradation

This research demonstrates the use of biogenic silica derived from bamboo leaf ash as a support for iron oxide nanoparticles. The preparation includes silica extraction from bamboo leaf ash and iron oxide nanoparticle impregnation into the silica gel under hydrothermal conditions, which is followed by calcination at 400 °C for 2 h. The physicochemical characterization includes X-ray diffraction analysis, gas sorption analysis, scanning electron microscopic analysis and transmission electron microscopic analysis. The light absorption capability and the band gap energy of the materials were determined by diffuse-reflectance UV–visible spectrophotometry. The materials obtained by varying the Fe content to 5 and 10% wt. were evaluated in rhodamine B photocatalytic degradation and photooxidation systems. It was found that the materials have a combined hematite and magnetite nanostructure, with the ratio of 9:10, and the particle sizes range from 10 to 40 nm. With a band gap energy of 2.27 eV, the prepared materials produce the successive photocatalytic degradation of rhodamine B. It was clarified that the formation of composite enhances stability and reusability of photocatalyst as shown by the stable initial rate at wide pH range and reuse for 5 cycles. Degradation mechanism is enhanced by the addition of H₂O₂ as an oxidant, and the investigation of the effect of scavengers shows that the degradation rate not only depends on radical formation but also on other species related to the formation of oxidizing agent.     

Systemic bevacizumab to facilitate anticoagulation in antiphospholipid syndrome and bleeding gastrointestinal angiodysplasia

Journal of Thrombosis and Thrombolysis - Bleeding gastrointestinal angiodysplasia may occur in patients with vasculitis and can be challenging to treat. We describe the novel use of bevacizumab...     

Systemic bevacizumab as salvage therapy for persistent severe bleeding and anemia in heyde syndrome following aortic valve replacement

Journal of Thrombosis and Thrombolysis - Heyde syndrome is characterized by the co-occurrence of aortic stenosis and bleeding gastrointestinal angiodysplasias, often with acquired von Willebrand...     

A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumor s and hematologic malignancies

Chemotherapy-induced thrombocytopenia (CIT) frequently complicates cancer treatment causing chemotherapy treatment delays, dose reductions, and discontinuation. There is no US Food and Drug Administration (FDA)-approved agent available to manage CIT. This study retrospectively evaluated patients with CIT treated on institutional romiplostim treatment pathways at four US centers. The primary outcome was achievement of a romiplostim response (median on-romiplostim platelet count ≥75x10⁹/L and ≥30x10⁹/L above baseline). Secondary outcomes included time to platelet count ≥100x10⁹/L and rates of the following: platelet count <100×10⁹/L, platelet count <75x10⁹/L, platelet count <50x10⁹/L, thrombocytosis, chemotherapy dose reduction/treatment delay, platelet transfusion, bleeding, and thromboembolism. Multivariable regression was used to identify predictors of romiplostim non-response and compare weekly dosing with intracycle/intermittent dosing. A total of 173 patients (153 solid tumor, 20 lymphoma or myeloma) were treated, with 170 (98%) receiving a median of four (range: 1-36) additional chemotherapy cycles on romiplostim. Romiplostim was effective in solid tumor patients: 71% of patients achieved a romiplostim response, 79% avoided chemotherapy dose reductions/treatment delays, and 89% avoided platelet transfusions. Median per-patient platelet count on romiplostim was significantly higher than baseline (116x10⁹/L vs. 60x10⁹/L; P<0.001). Bone marrow (BM) tumor invasion, prior pelvic irradiation, and prior temozolomide exposure predicted romiplostim non-response. Bleeding rates were lower than historical CIT cohorts and thrombosis rates were not elevated. Weekly dosing was superior to intracycle dosing with higher response rates and less chemotherapy dose reductions/treatment delays/bleeding; intracycle dosing had an incidence rate ratio (IRR) for dose reduction/treatment delay of 3.00 (95%CI: 1.30-6.91; P=0.010) and an IRR for bleeding of 4.84 (95%CI: 1.18-19.89, P=0.029) compared with weekly dosing. Blunted response (10% response rate) was seen in non-myeloid hematologic malignancy patients with BM involvement. In conclusion, romiplostim was safe and effective for CIT in most solid tumor patients.     

The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

Individuals harboring the loss-of-function (LOF) proprotein convertase subtilisin/kexin type 9 Gln152His variation (PCSK9^Q152H) have low circulating low-density lipoprotein cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of proPCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes, where it would be expected to contribute to ER storage disease (ERSD), a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9^Q152H variation. We report that PCSK9^Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9^Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress-response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than inducing them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress–driven conditions of the liver. In summary, we have uncovered a cochaperone function for PCSK9^Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.