Angiofibroma of the mandible: Rare sight for juvenile tumor.

Angiofibroma also called juvenile nasopharyngeal angiofibroma are tumors of adolescence and the commonest site is the nasopharynx. Extra nasopharyngeal sites include upper respiratory and digestive tracts, oral cavity, tonsils, larynx, trachea, and esophagus. Intraosseous angiofibroma is the rarest of a rare entity.

Ameloblastic fibroma: A case report.

Ameloblastic fibroma is a rare mixed odontogenic benign tumor that can occur in either mandible or maxilla but mostly it is found in posterior region of mandible. It can present either peripherally or centrally with a majority of the cases predominantly occurring in first two decades of life and mostly affects male patients. It is characterized by epithelial islands and cords submerged in ectomesenchyme that bear resemblance to the dental papilla and enamel organ but without actual hard tissue formation. Ameloblastic fibroma is a rare odontogenic tumor consisting of neoplastic epithelial and mesenchymal tissues. Recent reports have suggested that this lesion has the potential for high recurrence (18%) and greater chances of recurrent Ameloblastic fibroma transforming into Ameloblastic fibrosarcoma (45%). A 34-year-old male patient presented with pain and swelling in right mandibular posterior region. Intraorally expansion of buccal cortical plate with tenderness over swelling was present. Extraoral examination revealed facial asymmetry on right side. In view of imaging and clinical findings, provisional diagnosis of Odontogenic Keratocyst or Recurrent Ameloblastoma was considered. After obtaining informed consent and general systemic evaluation, the lesion was enucleated under general anesthesia and biopsied which confirmed the diagnosis of Ameloblastic fibroma. Ameloblastic fibroma is a mixed odontogenic tumor composed of odontogenic ectomesenchyme resembling dental papilla with epithelial strands and nests similar to the dental lamina and enamel organ, but with no dental hard tissue formation. Odontogenic tumors, Ameloblasts, Ameloblastoma, Jaw neoplasm.

SAR Probing of KX2-391 Provided Analogues With Juxtaposed Activity Profile Against Major Oncogenic Kinases.

Tirbanibulin (KX2-391, KX-01), a dual non-ATP (substrate site) Src kinase and tubulin-polymerization inhibitor, demonstrated a universal anti-cancer activity for variety of cancer types. The notion that KX2-391 is a highly selective Src kinase inhibitor have been challenged by recent reports on the activities of this drug against FLT3-ITD mutations in some leukemic cell lines. Therefore, we hypothesized that analogues of KX2-391 may inhibit oncogenic kinases other than Src. A set of 4-aroylaminophenyl-N-benzylacetamides were synthesized and found to be more active against leukemia cell lines compared to solid tumor cell lines. N-(4-(2-(benzylamino)-2-oxoethyl)phenyl)-4-chlorobenzamide (4e) exhibited activities at IC50 0.96 µM, 1.62 µM, 1.90 µM and 4.23 µM against NB4, HL60, MV4-11 and K562 leukemia cell lines, respectively. We found that underlying mechanisms of 4e did not include tubulin polymerization or Src inhibition. Such results interestingly suggested that scaffold-hopping of KX2-391 may change the two main underlying cytotoxic mechanisms (Src and tubulin). Kinase profiling using two methods revealed that 4e significantly reduces the activities of some other potent oncogenic kinases like the MAPK member ERK1/2 (>99%) and it also greatly upregulates the pro-apoptotic c-Jun kinase (84%). This research also underscores the importance of thorough investigation of total kinase activities as part of the structure-activity relationship studies.

Insights on Cancer Cell Inhibition, Subcellular Activities, and Kinase Profile of Phenylacetamides Pending 1H-Imidazol-5-One Variants.

Structural changes of small-molecule drugs may bring interesting biological properties, especially in the field of kinase inhibitors. We sought to study tirbanibulin, a first-in-class dual Src kinase (non-ATP competitive)/tubulin inhibitor because there was not enough reporting about its structure-activity relationships (SARs). In particular, the present research is based on the replacement of the outer ring of the biphenyl system of 2-[(1,1'-biphenyl)-4-yl]-N-benzylacetamide, the identified pharmacophore of KX chemotype, with a heterocyclic ring. The newly synthesized compounds showed a range of activities in cell-based anticancer assays, agreeing with a clear SAR profile. The most potent compound, (Z)-N-benzyl-4-[4-(4-methoxybenzylidene)-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl]phenylacetamide (KIM-161), demonstrated cytotoxic IC50 values at 294 and 362 nM against HCT116 colon cancer and HL60 leukemia cell lines, respectively. Profiling of this compound (aqueous solubility, liver microsomal stability, cytochrome P450 inhibition, reactivity with reduced glutathione, and plasma protein binding) confirmed its adequate drug-like properties. Mechanistic studies revealed that this compound does not depend on tubulin or Src kinase inhibition as a factor in forcing HL60 to exit its cell cycle and undergo apoptosis. Instead, KIM-161 downregulated several other kinases such as members of BRK, FLT, and JAK families. It also strongly suppresses signals of ERK1/2, GSK-3α/ß, HSP27, and STAT2, while it downregulated AMPKα1 phosphorylation within the HL60 cells. Collectively, these results suggest that phenylacetamide-1H-imidazol-5-one (KIM-161) could be a promising lead compound for further clinical anticancer drug development.

LC-MS/MS-based metabolic profiling of Escherichia coli under heterologous gene expression stress.

Escherichia coli is frequently exploited for genetic manipulations and heterologous gene expression studies. We have evaluated the metabolic profile of E. coli strain BL21 (DE3) RIL CodonPlus after genetic modifications and subjecting to the production of recombinant protein. Three genetically variable E. coli cell types were studied, normal cells (susceptible to antibiotics) cultured in simple LB medium, cells harboring ampicillin-resistant plasmid pET21a (+), grown under antibiotic stress, and cells having recombinant plasmid pET21a (+) ligated with bacterial lactate dehydrogenase gene grown under ampicillin and standard isopropyl thiogalactoside (IPTG)-induced gene expression conditions. A total of 592 metabolites were identified through liquid chromatography-mass spectrometry/mass spectrometry analysis, feature and peak detection using XCMS and CAMERA followed by precursor identification by METLIN-based procedures. Overall, 107 metabolites were found differentially regulated among genetically modified cells. Quantitative analysis has shown a significant modulation in DHNA-CoA, p-aminobenzoic acid, and citrulline levels, indicating an alteration in vitamin K, folic acid biosynthesis, and urea cycle of E. coli cells during heterologous gene expression. Modulations in energy metabolites including NADH, AMP, ADP, ATP, carbohydrate, terpenoids, fatty acid metabolites, diadenosine tetraphosphate (Ap4A), and l-carnitine advocate major metabolic rearrangements. Our study provides a broader insight into the metabolic adaptations of bacterial cells during gene manipulation experiments that can be prolonged to improve the yield of heterologous gene products and concomitant production of valuable biomolecules.

Nummularic acid, a triterpenoid, from the medicinal plant Fraxinus xanthoxyloides, induces energy crisis to suppress growth of prostate cancer cells.

We recently identified and characterized nummularic acid (NA) as a major chemical constituent of Fraxinus xanthoxyloides, a medicinal plant used for over hundred years in traditional medicine. In this study, we describe its potential anti-cancer activity using prostate cancer (PCa) cells as a model. We found that NA treatment (5-60 µM) significantly reduced the proliferation and colony formation capabilities of PCa DU145 and C4-2 cells in a time and dose dependent manner, reduced the migratory and invasive properties and increased apoptotic cell population. Mechanistically, we found that NA treatment to PCa cells resulted in a sustained activation of adenosine monophosphate-activated protein kinase (AMPK). NA simultaneously increased acetyl CoA carboxylase phosphorylation and decreased pS6 phosphorylation, the two major substrates of AMPK. Further, NA treatment significantly elevated the cellular ADP/ATP ratio and altered glycolytic rate. We further observed a reversible decrease in oxygen consumption rate in NA treated cells when compared to the control. Finally, we performed global untargeted metabolomics which showed that NA treatment alters PCa cell metabolism at multiple sites including glycolysis, tricarboxylic acid, and glutamine metabolism which supported our observation of a possible AMPK activation. In summary, we report NA as a novel small molecule activator of AMPK that alters cellular metabolism to induce energy crisis and ultimately cancer cell death. Because of its unique mechanism NA could be potentially applicable against other cancer types.

Drugs - Do we need them? Applications of non-pharmaceutical therapy in anterior eye disease: A review.

Natural products have been in use long before the introduction of modern drug therapies and are still used in various communities worldwide for the treatment of anterior eye disease. The aim of this review is to look at the current non-pharmaceutical modalities that have been tried and assess the body of existing evidence behind them. This includes alternative medicine, existing non-pharmaceutical therapy and more recent low and high tech solutions. A detailed search of all available databases including MEDLINE, Pubmed and Google was made to look for English-language studies for complementary and alternative treatment modalities (CAM), natural therapies and new modalities for anterior eye disease such as blepharitis, dry eye and microbial keratitis. We have included a broad discussion ranging from traditional treatments like honey and aloe vera which have been used for centuries, to the more recent technological advances like Intense Pulsed Light (IPL), LipiFlow and photoactivated chromophore for corneal cross linking in infectious keratitis (PACK-CXL). Alternative management strategies may have a role in anterior eye diseases and have a potential in changing the way we currently approach them. Some of the available CAM could play a role if incorporated in to current management practices of not only chronic diseases like blepharitis and dry eye, but also acute conditions with significant morbidity like microbial keratitis. Further large-scale randomized control trials stratified by disease severity are required to improve our understanding and to evaluate the use of non-pharmaceutical therapy against current practice.

Sex-Specific Differences in an ApoE(-/-):Ins2(+/Akita) Mouse Model of Accelerated Atherosclerosis.

Diabetic patients have a twofold to fourfold increased risk of cardiovascular disease. Despite a vast amount of research, the underlying mechanisms that predispose individuals with diabetes to the development of cardiovascular disease are unclear. To further our understanding of how diabetes promotes atherosclerosis, we have established, characterized, and manipulated a new model of hyperglycemia-induced atherosclerosis: the apolipoprotein E-deficient (ApoE(-/-)):Ins2(+/Akita) mouse. All mice were fed a standard chow diet. Male ApoE(-/-):Ins2(+/Akita) mice developed chronic hyperglycemia, which significantly accelerated atherosclerosis. Female ApoE(-/-):Ins2(+/Akita) mice presented hyperglycemia that normalized by 15 weeks of age. Despite the transient hyperglycemia, advanced atherosclerosis was observed at 15 weeks of age compared with ApoE(-/-) females. To better understand these differences, subsets of mice were castrated or ovariectomized at 5 weeks of age. Castrated ApoE(-/-):Ins2(+/Akita) mice showed a reduction in blood glucose levels that correlated with the amelioration of atherosclerosis. Interestingly, castrated normoglycemic ApoE(-/-) mice developed larger atherosclerotic lesions than sham-operated on controls. Ovariectomized ApoE(-/-):Ins2(+/Akita) mice presented chronic hyperglycemia, and atherosclerosis appeared to be advanced. We have characterized the distinctive sex-specific phenotypes exhibited by the ApoE(-/-):Ins2(+/Akita) mouse model and present evidence for the action of sex hormones on pancreatic ß-cell function and the vasculature that affect the regulation of blood glucose levels and the development of atherosclerosis. This model will provide a test bed to further delineate these effects.

The use of toric intraocular lens to correct astigmatism at the time of cataract surgery.

BACKGROUND: To evaluate the visual and refractive outcomes of cataract surgery with toric intraocular lens (IOL) implantation at a teaching hospital of the United Kingdom. DESIGN: Prospective interventional case series. MATERIALS AND METHODS: This study compared the outcome of 3 groups of patients: Group 1 included 25 eyes with cataract and more than 2.5 diopters (D) of corneal astigmatism receiving a toric monofocal IOL; Group 2 had 18 patients with cataract and more than 2.5 D of astigmatism but receiving a non-toric monofocal IOL; while Group 3 had 25 patients with cataract and less than 1.5 D of astigmatism and receiving a non-toric monofocal IOL. Data collected included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction and corneal keratometry. Postoperative examinations were scheduled at 1 and 6 weeks. RESULTS: Postoperatively the mean UDVA was LogMAR 0.27 ± 0.20 (equivalent snellen acuity of 20/37) in Group 1, 0.54 ± 0.22 (20/69) in Group 2 and 0.16 ± 0.20 (20/29) in Group 3. The mean CDVA was LogMAR 0.08 ± 0.13 (20/24) in Group 1, 0.23 ± 0.16 (20/34) in Group 2 and 0.04 ± 0.13 in Group 3 (20/22). The mean preoperative keratometric cylinder was 3.78 ± 1.0 D in Group 1, 3.41 ± 1.47 D in Group 2 and 0.97 ± 0.43D in Group 3; the mean postoperative subjective cylinder was 1.2 ± 0.68 D in Group 1, 3.23 ± 1.41 D in Group 2 and 0.95 ± 0.58 D in Group 3. The difference was statistically significant for the postoperative refractive cylinder values when comparing Group 1 to Group 2 (P = <0.0001) but the difference was insignificant between Group 1 and Group 3 (P = 0.23). CONCLUSION: Toric IOL implantation is an effective option to manage corneal astigmatism at the time of cataract surgery and to optimise visual outcomes for astigmatic patients when comparing to outcomes for their non-astigmatic counterparts.

Glycogen synthase kinase 3α deficiency attenuates atherosclerosis and hepatic steatosis in high fat diet-fed low density lipoprotein receptor-deficient mice.

Studies have implicated signaling through glycogen synthase kinase (GSK) 3α/ß in the activation of pro-atherogenic pathways and the accelerated development of atherosclerosis. By using a mouse model, we examined the role of GSK3α in the development and progression of accelerated atherosclerosis. We crossed Gsk3a/GSK3α-knockout mice with low-density lipoprotein receptor (Ldlr) knockout mice. Five-week-old Ldlr(-/-);Gsk3a(+/+), Ldlr(-/-);Gsk3a(+/-), and Ldlr(-/-);Gsk3a(-/-) mice were fed a chow diet or a high-fat diet for 10 weeks and then sacrificed. GSK3α deficiency had no detectible effect on any measured parameters in chow-fed mice. High-fat-diet fed Ldlr(-/-) mice that were deficient for GSK3α had significantly less hepatic lipid accumulation and smaller atherosclerotic lesions (60% smaller in Ldlr(-/-);Gsk3a(+/-) mice, 80% smaller in Ldlr(-/-);Gsk3a(-/-) mice; P < 0.05), compared with Ldlr(-/-);Gsk3a(+/+) controls. GSK3α deficiency was associated with a significant increase in plasma IL-10 concentration and IL-10 expression in isolated macrophages. A twofold to threefold enhancement in endoplasmic reticulum stress-induced IL-10 expression was observed in Thp-1-derived macrophages that were pretreated with the GSK3α/ß inhibitor CT99021. Together, these results suggest that GSK3α plays a pro-atherogenic role, possibly by mediating the effects of endoplasmic reticulum stress in the activation of pro-atherogenic pathways.

Postprandial lipemia induces pancreatic α cell dysfunction characteristic of type 2 diabetes: studies in healthy subjects, mouse pancreatic islets, and cultured pancreatic α cells.

BACKGROUND: Type 2 diabetes is associated with pancreatic α cell dysfunction, characterized by elevated fasting plasma glucagon concentrations and inadequate postprandial glucose- and insulin-induced suppression of glucagon secretion. The cause and the underlying mechanisms of α cell dysfunction are unknown. OBJECTIVE: Because Western dietary habits cause postprandial lipemia for a major part of a day and, moreover, increase the risk of developing type 2 diabetes, we tested the hypothesis that postprandial lipemia with its characteristic elevation of triglyceride-rich lipoproteins (TGRLs) might cause pancreatic α cell dysfunction. DESIGN: In a crossover study with 7 healthy volunteers, 2 experiments using 2 fat-enriched meals were performed on each volunteer; meal 1 was designed to increase plasma concentrations of both TGRLs and nonesterified fatty acids and meal 2 to increase TGRLs only. Intravenous glucose boli were injected at 0800 after an overnight fast and postprandially at 1300, 3 h after ingestion of a fat-enriched meal. Glucagon concentrations were measured throughout the days of the experiments. In addition to the study in humans, in vitro experiments were performed with mouse pancreatic islets and cultured pancreatic alpha TC 1 clone 9 (αTC1c9) cells, which were incubated with highly purified TGRLs. RESULTS: In humans, postprandial lipemia increased plasma glucagon concentrations and led to an inadequate glucose- and insulin-induced suppression of glucagon. There was no difference between the 2 meal types. In mouse pancreatic islets and cultured pancreatic αTC1c9 cells, purified postprandial TGRLs induced abnormalities in glucagon kinetics comparable with those observed in humans. The TGRL-induced α cell dysfunction was due to reduced γ-aminobutyric acid A receptor activation in pancreatic α cells. CONCLUSION: We concluded that postprandial lipemia induces pancreatic α cell dysfunction characteristic of type 2 diabetes and, therefore, propose that pancreatic α cell dysfunction could be viewed, at least partly, as a postprandial phenomenon.

Endurance interval training in obese mice reduces muscle inflammation and macrophage content independently of weight loss.

Obesity is associated with chronic low-grade inflammation that involves infiltration of macrophages into metabolic organs such as skeletal muscle. Exercise enhances skeletal muscle insulin sensitivity independently of weight loss; but its role in regulating muscle inflammation is not fully understood. We hypothesized that exercise training would inhibit skeletal muscle inflammation and alter macrophage infiltration into muscle independently of weight loss. Wild type C57BL/6 male mice were fed a chow diet or a high-fat diet (HFD, 45% calories fat) for 6 weeks. Then, mice maintained on the HFD either remained sedentary (HFD Sed) or exercised (HFD Ex) on a treadmill for another 6 weeks. The exercise training protocol involved conducting intervals of 2 min in duration followed by 2 min of rest for 60 min thrice weekly. Chow-fed control mice remained sedentary for the entire 12 weeks. Muscle cytokine and macrophage gene expression analysis were conducted using qRT-PCR, and muscle macrophage content was also measured using immunohistochemistry. Muscle cytokine protein content was quantified using a cytokine array. The HFD increased adiposity and weight gain compared to chow-fed controls. HFD Sed and HFD Ex mice had similar body mass as well as total and visceral adiposity. However, despite similar adiposity, exercise reduced inflammation and muscle macrophage infiltration. We conclude that Endurance exercise training modulates the immune-metabolic crosstalk in obesity independently of weight loss, and may have potential benefits in reducing obesity-related muscle inflammation.

Mean bone mineral density and frequency of occurrence of osteopenia and osteoporosis in patients on hemodialysis: a single-center study.

Chronic renal disease changes both quality and quantity of bone through multi-factorial influences on bone metabolism, leading to osteopenia, osteoporosis and increased risk of fracture. The objectives of our present cross-sectional study were to determine the mean bone mineral density (BMD) and frequency of occurrence of osteoporosis and osteopenia in Saudi patients on hemodialysis (HD) for longer than 1 year. Forty-two male and 78 female patients with age between 20 and 50 years were enrolled in this study. The BMD of the lumbar vertebral spine (LV) and the neck of femur (FN) were measured in all patients. Data were analyzed using SPSS version 17.0 software and the level of significance was considered as P <0.05. The mean BMD in the LV (L2-L4) was 1.155 ± 0.026 g/cm 2 in male and 1.050 ± 0.025 g/cm 2 in female patients (P = 0.016). The mean BMD in the FN was 1.010 ± 0.023 g/cm 2 in male and 0.784 ± 0.020 g/cm 2 in female patients (P = 0.00). Based on the World Health Organization criteria, 73.8% of the male and 44.9% of the female patients in our study had normal BMD (P = 0.002); 16.7% male and 28.2% female patients had osteopenia (P = 0.14), while 9.5% male and 26.9% female patients had osteoporosis (P = 0.01). This study showed a marked decrease in mean BMD in the cortical bone (FN) compared with trabecular bone (LV) (P = 0.00) as well as in female patients on HD compared with male patients (P = 0.016 for LV and P = 0.00 for FN).

Improved accessibility of emergency obstetrics and newborn care (EmONC) services for maternal and newborn health: a community based project.

BACKGROUND: Every year an estimated three million neonates die globally and two hundred thousand of these deaths occur in Pakistan. Majority of these neonates die in rural areas of underdeveloped countries from preventable causes (infections, complications related to low birth weight and prematurity). Similarly about three hundred thousand mother died in 2010 and Pakistan is among ten countries where sixty percent burden of these deaths is concentrated. Maternal and neonatal mortality remain to be unacceptably high in Pakistan especially in rural areas where more than half of births occur. METHOD/DESIGN: This community based cluster randomized controlled trial will evaluate the impact of an Emergency Obstetric and Newborn Care (EmONC) package in the intervention arm compared to standard of care in control arm. Perinatal and neonatal mortality are primary outcome measure for this trial. The trial will be implemented in 20 clusters (Union councils) of District Rahimyar Khan, Pakistan. The EmONC package consists of provision of maternal and neonatal health pack (clean delivery kit, emollient, chlorhexidine) for safe motherhood and newborn wellbeing and training of community level and facility based health care providers with emphasis on referral of complicated cases to nearest public health facilities and community mobilization. DISCUSSION: Even though there is substantial evidence in support of effectiveness of various health interventions for improving maternal, neonatal and child health. Reduction in perinatal and neonatal mortality remains a big challenge in resource constrained and diverse countries like Pakistan and achieving MDG 4 and 5 appears to be a distant reality. A comprehensive package of community based low cost interventions along the continuum of care tailored according to the socio cultural environment coupled with existing health force capacity building may result in improving the maternal and neonatal outcomes. The findings of this proposed community based trial will provide sufficient evidence on feasibility, acceptability and effectiveness to the policy makers for replicating and scaling up the interventions within the health system.

The role of capsule endoscopy in small bowel pathology: a review of 122 cases.

AIM: Small bowel capsule endoscopy (CE) has been introduced in New Zealand (NZ) in all of the tertiary and some secondary centres over the last few years. We describe our experience with CE from a single centre in NZ. METHODS: In this 2-year, retrospective, study of 122 consecutive patients, data was collected on multiple variables from the patient clinical, laboratory, and radiology records. Pillcam of Given Imaging Diagnostic System (Given Imaging Ltd, Yogneam, Israel) was used to image the small bowel. Descriptive statistics were used to analyse the data. RESULTS: Good preparation was noted in 69% of the cases. The most common indication for referral was obscure GI bleeding (70%). The overall diagnostic yield for relevant findings was 52%, with angioectasia as the most common specific finding (37%). The diagnostic yield in those with overt bleeds improved with inpatient status (74%). Incomplete examinations were noted in 12% and were significantly more common in the male gender. Preliminary imaging (barium, CT/MR) was noted to have a lower diagnostic yield. Enteroscopies were considered in 25% of the patients post CE procedure. CONCLUSION: Apart from a lower diagnostic yield in patients with overt bleeds, our data is consistent with that reported in literature and support the role of CE as the minimally invasive gold standard investigation for small bowel imaging.

Doctors and the nurse endoscopist issue in New Zealand.

AIM: Training and recruitment of Nurse Endoscopists (NEs) is currently actively debated in medical circles. The aim of this survey was to obtain the views of doctors regarding the role of NEs in New Zealand (NZ). METHODS: A web-based, self-administered questionnaire was sent to 84 endoscopists currently working in 25 public hospitals across all the 20 District Health Boards. The survey period was July 2011. Data was analysed using descriptive statistics. RESULTS: The response rate was 47.5%. Fifty percent of the respondents worked in tertiary hospitals. Only 30% had a positive attitude towards the introduction of NEs in NZ. The majority (62%) believed that doctors would deliver better quality of endoscopy services than NEs. Only 37% thought that the introduction of NEs will reduce the cost of services. Forty-one percent thought it was inappropriate for the NEs to be enrolled in the Bowel Cancer Screening Programme and only 6 doctors (18%) thought that NEs should be allowed to perform therapeutic endoscopic procedures. CONCLUSION: Only a minority of doctors had a positive attitude towards the role of NEs. The majority considered doctors to deliver 'higher' quality of service and only a minority thought that the introduction of NEs will lower the cost of services.

Endoplasmic reticulum stress and glycogen synthase kinase-3ß activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis.

OBJECTIVE: The goal of this study was to examine the role of endoplasmic reticulum (ER) stress signaling and the contribution of glycogen synthase kinase (GSK)-3ß activation in hyperglycemic, hyperhomocysteinemic, and high-fat-fed apolipoprotein E-deficient (apoE(-/-)) mouse models of accelerated atherosclerosis. METHODS AND RESULTS: Female apoE(-/-) mice received multiple low-dose injections of streptozotocin (40 µg/kg) to induce hyperglycemia, methionine-supplemented drinking water (0.5% wt/vol) to induce hyperhomocysteinemia, or a high-fat (21% milk fat+0.2% cholesterol) diet to induce relative dyslipidemia. A subset of mice from each group was supplemented with sodium valproate (625 mg/kg), a compound with GSK3 inhibitory activity. At 15 and 24 weeks of age, markers of ER stress, lipid accumulation, GSK3ß phosphorylation, and GSK3ß activity were analyzed in liver and aorta. Atherosclerotic lesions were examined and quantified. Hyperglycemia, hyperhomocysteinemia, and high-fat diet significantly enhanced GSK3ß activity and also increased hepatic steatosis and atherosclerotic lesion volume compared with controls. Valproate supplementation blocked GSK3ß activation and attenuated the development of atherosclerosis and the accumulation of hepatic lipids in each of the models examined. The mechanism by which GSK3ß activity is regulated in these models likely involves alterations in phosphorylation at serine 9 and tyrosine 216. CONCLUSIONS: These findings support the existence of a common mechanism of accelerated atherosclerosis involving ER stress signaling through activation of GSK3ß. Furthermore, our results suggest that atherosclerosis can be attenuated by modulating GSK3ß phosphorylation.

Sutureless large incision cataract extraction: Indications and results from two teaching hospital eye departments in the United Kingdom.

OBJECTIVE: To highlight the role of Sutureless Large Incision Cataract Extraction (SLICE) in the United Kingdom for the treatment of cataracts at high risk for intra- or postoperative complications. SETTING: Two University Hospitals in the United Kingdom MATERIALS AND METHODS: Retrospective case note review of planned SLICE performed over a 12-month period. RESULTS: SLICE was performed on 11 eyes of 11 patients (mean age, 79 years) having preoperative vision of hand motions (10 eyes) with very dense or mobile cataracts and high risk for phacoemulsification. Mean follow up was 12 weeks, with no operative or postoperative complications. Nine patients (without ocular or systemic comorbidity) achieved best corrected vision of 0.3 LogMAR (20/40) or better. CONCLUSIONS: SLICE is safe and effective for dense or mobile cataracts and can play a role in patients where conventional phacoemulsification carries higher risks of complications.

Synergistic effects of conjugating cell penetrating peptides and thiomers on non-viral transfection efficiency.

Nanoparticles generated by complex coacervation of plasmid DNA (pDNA) and modified chitosans namely chitosan-thioglycolic acid (TGA) conjugate and chitosan-HIV-1 Tat peptide conjugate were evaluated as gene delivery systems. In order to optimize transfection efficiency, chitosan-HIV-1 Tat peptide conjugate was combined with chitosan-TGA before its complexation with pDNA. Particle size and zeta potential measurements were performed to characterize the generated nanoparticles. The nanoparticles transfection efficiencies were assessed by exploitation of the green fluorescent protein (GFP) reporter gene. HEK293 cells were incubated for 24 h with the nanoparticles and the GFP positive cells were observed by fluorescence microscopy. The nanoparticles in the size range of 200-300 nm could transfect HEK293 cells as a model cell line with different transfection efficiencies. Unlike chitosan-TGA, chitosan-HIV-1 Tat peptide led to increased zeta potential of nanoparticles as compared to unmodified chitosan. The transfection efficiency of the nanoparticles generated by combination of chitosan-HIV-1 Tat peptide with chitosan-TGA was comparatively higher than that of the nanoparticles generated by either chitosan-TGA or the combination of chitosan-HIV-1 Tat peptide with unmodified chitosan. After 72 h of incubation, the combination of chitosan-HIV-1 Tat peptide with chitosan-TGA was found to be 7.12- and 67.37 times more efficient than unmodified chitosan and pDNA alone, respectively and showed a synergistic effect in transfection of pDNA into the cells. Moreover, none of the nanoparticles showed any severe cytotoxicity. Accordingly, this strategy might result in a potent carrier for gene delivery.