Therapeutic Periocular Vaccination with a Subunit Vaccine Induces Higher Levels of Herpes Simplex Virus-Specific Tear Secretory Immunoglobulin A Than Systemic Vaccination and Provides Protection against Recurrent Spontaneous Ocular Shedding of Virus in Latently Infected Rabbits

AbstractRabbits latently infected with herpes simplex virus type 1 (HSV-1) were vaccinated either periocularly or systemically with a subunit vaccine (gB2 + gD2) plus adjuvant or adjuvant alone. Tear films were collected daily to measure recurrent infectious HSV-1 shedding. After systemic vaccination, the latently infected rabbits were not protected against recurrent ocular viral shedding (HSV-1-positive tear film cultures/total cultures) compared with either the systemic or periocular adjuvant controls (systemic vaccination = 49 of 972, 5.0%; systemic control = 46 of 972, 4.7%; periocular control = 43 of 930, 4.6%;P> 0.8). In contrast, latently infected rabbits vaccinated periocularly with the same vaccine had significantly reduced recurrent shedding (20 of 1026, 2.0%) compared with controls (P< 0.001) or systemic vaccination (P= 0.0002). Thus, recurrent HSV-1 shedding was significantly reduced by therapeutic local periocular subunit vaccination but not by therapeutic systemic subunit vaccination. Neutralizing antibody titers in the serum of systemically and ocularly vaccinated rabbits was similar. In contrast, HSV-specific tear secretory immunoglobulin A was significantly higher in the ocularly vaccinated group (P< 0.01). These results strongly suggest that in the rabbit, and presumably in humans, the local ocular (mucosal) immune response is much more important than the systemic immune response for therapeutic protection against recurrent ocular HSV-1. Thus development of a therapeutic vaccine against recurrent ocular HSV-1 should be directed at enhancing the local ocular (mucosal) immune response

Anti-proliferative effects of compounds derived from glucopyranuronamide

Chemotherapy is a major cancer treatment option. The synthesis of new compounds with better anti-proliferative properties and higher specificity is a current challenge in drug discovery today. Our goal with this work was to develop compounds derived from D-glucuronic acid and to evaluate their anti-proliferative properties. We have synthetized a library of hydroxyamide derivatives of D-glucuronic acid using amines and aminoalcohols. The synthesis of these compounds were based on the work of El-Nezhawy's group, who have designed some novel D-glucuronic acid acetylated and deacetylated derivatives, which showed interesting results with breast cancer cell lines. Anti-proliferative activity of the newly synthesized compounds was examined against human breast adenocarcinoma (MCF-7) and human colon carcinoma (MDST8) cell lines. Cell growth and viability was analysed by the Cell Counting Kit-8 method. The chemotherapeutic agent 5-fluoroacil was used as a positive control, allowing one to estimate the maximal anti-proliferative action expected in both carcinoma cell lines. All the compounds were studied in the 10-9-10-5M range. The compound N-(ethanol)-α/β D-glucopyranuronamide presented the best anti-proliferative potential with an IC50 (concentration of the compound causing 50% decrease in net cell growth) of 1.4x10-7M in MCF-7 cells. The 1-pheny-l-2-hydroxy-ethane-2-yl and the 1-propanol derivatives evoked weak anti-proliferative effects in MCF-7, with slight growth inhibition of 37% and 35%, respectively, for the highest concentration used (10-5M). On the contrary, the MDST-8 cell growth was not affected by these compounds. On the contrary, the 1-hydroxy-2-isopropyl-ethane-2-yl and 3-phenyl-1-hydroxy-propane-2-yl derivatives, exhibited weak anti-proliferative effects (22% and 40%, respectively) at 10-5M, in the MDST8 cell line, without affecting MCF-7 cell growth. None of the compounds exihibited toxic effects, at least up to 72h exposure, in the concentration range studied. These results show that the ethyl substituent was the most effective N-substituent for glucopyranuronamide for anti-proliferative actions in MCF-7 cell line, whilst in the case of the MDST8 cells, 3-phenyl-1-hydroxy-propane-2-yl was the most effective N-substituent. Moreover, all the glucopyranonamide compounds studied presented selective anti-proliferative effects for the different carcinoma cell lines used

Avaliação e Caraterização da Ação Inibitória de Iminociclitóis na Atividade α-Glucosidase de Enterócitos de Mamífero

A diabetes, em particular a diabetes mellitus tipo 2, constitui um distúrbio metabólico que se carateriza por glicemias aumentadas resultantes de diminuição da libertação e/ou ação da insulina. Os inibidores das α-glucosidases surgem como agentes de elevado interesse terapêutico uma vez que podem contribuir para a diminuição da absorção intestinal de glicose e, consequentemente, para um desagravamento da hiperglicemia. Alguns compostos da família iminociclitol são inibidores das α- glucosidases [1] e têm vindo a ser sintetizados diversos compostos novos que podem ser promissores e cuja ação sobre a atividade α-glucosidase de mamífero ainda não foi estudada. Neste trabalho procurou-se estudar a ação de alguns novos compostos da família iminociclitol (figura 1) na atividade α-glucosidase de enterócitos de mamífero, tendo-se também avaliado o grau de toxidade. O efeito dos pares dos enantiómeros foi também estudado

Novel hydroxyamides and amides containing D-glucopyranose or D-fructose units: biological assays in MCF-7 and MDST8 cell lines

A novel library of 15 compounds, hydroxyamides and amides containing a β-d-glucopyranose (d-Gluc) or a β-d-fructose (d-Fruc) units was designed and synthesized for antiproliferative assays in breast (MCF-7) and colon (MDST8) cancer cell lines. Twelve of them were hydroxyamides and were successfully synthesized from β-d-glucuronic acid (d-GluA). Six of these hydroxyamides which were acetylated hydroxy-β-d-glucopyranuronamide 2a–2f (1st Family) and the other six were their respective isomers, that is, hydroxy-β-d-fructuronamide 3a–3f (2nd Family), obtained by acid–base catalyzed isomerization. These compounds have the general structure, d-Glucsingle bondCdouble bond; length as m-dashONHsingle bondCHRsingle bond(CH2)nsingle bondOH and d-Frucsingle bondCdouble bond; length as m-dashONHsingle bondCHRsingle bond(CH2)nsingle bondOH, where R = an aromatic, alkyl or a hydrogen substituent, with n = 0 or 1. Eight of these contained a chiral aminoalcohol group. Three compounds were amides containing a d-glucopyranose unit (3rd Family). SAR studies were conducted with these compounds. Antiproliferative studies showed that compound 4a, the bromo-amide containing the β-d-glucopyranose ring, potently inhibits the proliferation of the MDST8 cells. Five compounds (2e, 2f, 3d, 3e, and 3f) were shown to potently selectively inhibit the proliferation of the MCF-7 cells. Compound 4b was the only one showing inhibition in both cell lines. In general, the more active compounds were the amides and hydroxyamides containing the β-d-fructose moiety, and containing an alkyl group or hydrogen. Half-inhibitory concentrations (IC50) of between 0.01 and 10 μM, were observed

BVRIJHK photometry and proper motion analysis of NGC 6253 and the surrounding field

Context. We present a photometric and astrometric catalog of 187963 stars located in the field around the old super-metal-rich Galactic open cluster NGC 6253. The total field-of-view covered by the catalog is 34' x 33'. In this field, we provide CCD BVRI photometry. For a smaller region close to the cluster's center, we also provide near-infrared JHK photometry. Aims. We analyze the properties of NGC 6253 by using our new photometric data and astrometric membership. Methods. In June 2004, we targeted the cluster during a 10 day multi-site campaign, which involved the MPG/ESO 2.2m telescope with its wide-field imager and the Anglo-Australian 3.9m telescope, equipped with the IRIS2 near-infrared imager. Archival CCD images of NGC 6253 were used to derive relative proper motions and to calculate the cluster membership probabilities. Results. We have refined the cluster's fundamental parameters, deriving (V_0-M_v)=11.15, E(B - V)=0.15, E(V - I)=0.25, E(V - J)=0.50, and E(V - H)=0.55. The color excess ratios obtained using both the optical and near infrared colors indicate a normal reddening law in the direction of NGC 6253. The age of NGC 6253 at 3.5 Gyr, determined from our best-fitting isochrone appears to be slightly older than the previous estimates. Finally, we estimated the binary fraction among the cluster members to be \sim20%-30% and identified 11 blue straggler candidates.Comment: 16 pages, 13 figures, 11 tables. Accepted for publication in A&A. Catalog avaiable via CD

Decadal-scale hotspot methane ebullition within lakes following abrupt permafrost thaw

Thermokarst lakes accelerate deep permafrost thaw and the mobilization of previously frozen soil organic carbon. This leads to microbial decomposition and large releases of carbon dioxide (CO2) and methane (CH4) that enhance climate warming. However, the time scale of permafrost-carbon emissions following thaw is not well known but is important for understanding how abrupt permafrost thaw impacts climate feedback. We combined field measurements and radiocarbon dating of CH4 ebullition with (a) an assessment of lake area changes delineated from high-resolution (1–2.5 m) optical imagery and (b) geophysical measurements of thaw bulbs (taliks) to determine the spatiotemporal dynamics of hotspot-seep CH4 ebullition in interior Alaska thermokarst lakes. Hotspot seeps are characterized as point-sources of high ebullition that release 14C-depleted CH4 from deep (up to tens of meters) within lake thaw bulbs year-round. Thermokarst lakes, initiated by a variety of factors, doubled in number and increased 37.5% in area from 1949 to 2009 as climate warmed. Approximately 80% of contemporary CH4 hotspot seeps were associated with this recent thermokarst activity, occurring where 60 years of abrupt thaw took place as a result of new and expanded lake areas. Hotspot occurrence diminished with distance from thermokarst lake margins. We attribute older 14C ages of CH4 released from hotspot seeps in older, expanding thermokarst lakes (14CCH4 20 079 ± 1227 years BP, mean ± standard error (s.e.m.) years) to deeper taliks (thaw bulbs) compared to younger 14CCH4 in new lakes (14CCH4 8526 ± 741 years BP) with shallower taliks. We find that smaller, non-hotspot ebullition seeps have younger 14C ages (expanding lakes 7473 ± 1762 years; new lakes 4742 ± 803 years) and that their emissions span a larger historic range. These observations provide a first-order constraint on the magnitude and decadal-scale duration of CH4-hotspot seep emissions following formation of thermokarst lakes as climate warms

Prevalence and Outcomes of Percutaneous Coronary Interventions for Ostial Chronic Total Occlusions: Insights From a Multicenter Chronic Total Occlusion Registry

Ostial chronic total occlusions (CTOs) can be challenging to recanalize.We sought to examine the prevalence, angiographic presentation, and procedural outcomes of ostial (side-branch ostial and aorto-ostial) CTOs among 1000 CTO percutaneous coronary interventions (PCIs) performed in 971 patients between 2015 and 2017 at 14 centres in the US, Europe, and Russia.Ostial CTOs represented 16.9% of all CTO PCIs: 9.6% were aorto-ostial, and 7.3% were side-branch ostial occlusions. Compared with nonostial CTOs, ostial CTOs were longer (44 ± 33 vs 29 ± 19 mm, P < 0.001) and more likely to have proximal-cap ambiguity (55% vs 33%, P < 0.001), moderate/severe calcification (67% vs 45%, P < 0.001), a diffusely diseased distal vessel (41% vs 26%, P < 0.001), interventional collaterals (64% vs 53%, P = 0.012), and previous coronary artery bypass graft surgery (CABG) (51% vs 27%, P < 0.001). The retrograde approach was used more often in ostial CTOs (54% vs 29%, P < 0.001) and was more often the final successful crossing strategy (30% vs 18%, P = 0.003). Technical (81% vs 84%, P = 0.280), and procedural (77% vs 83%, P = 0.112) success rates and the incidence of in-hospital major complication were similar (4.8% vs 2.2%, P = 0.108), yet in-hospital mortality (3.0% vs 0.5%, P = 0.010) and stroke (1.2% vs 0.0%, P = 0.030) were higher in the ostial CTO PCI group. In multivariable analysis, ostial CTO location was not independently associated with higher risk for in-hospital major complications (adjusted odds ratio 1.27, 95% confidence intervals 0.37 to 4.51, P = 0.694).Ostial CTOs can be recanalized with similar rates of success as nonostial CTOs but are more complex, more likely to require retrograde crossing and may be associated with numerically higher risk for major in-hospital complications

A randomised controlled trial of a physical activity and nutrition program targeting middle-aged adults at risk of metabolic syndrome in a disadvantaged rural community

Background: Approximately 70% of Australian adults aged over 50 are overweight or obese, with the prevalence significantly higher in regional/remote areas compared to cities. This study aims to determine if a low-cost, accessible lifestyle program targeting insufficiently active adults aged 50-69 y can be successfully implemented in a rural location, and whether its implementation will contribute to the reduction/prevention of metabolic syndrome, or other risk factors for type 2 diabetes, and cardiovascular disease.Methods/Design: This 6-month randomised controlled trial will consist of a nutrition, physical activity, and healthy weight intervention for 50–69 year-olds from a disadvantaged rural community. Five hundred participants with central obesity and at risk of metabolic syndrome will be recruited from Albany and surrounding areas in Western Australia (within a 50 kilometre radius of the town). They will be randomly assigned to either the intervention (n = 250) or wait-listed control group (n = 250). The theoretical concepts in the study utilise the Self-Determination Theory, complemented by Motivational Interviewing. The intervention will include a custom-designed booklet and interactive website that provides information, and encourages physical activity and nutrition goal setting, and healthy weight management. The booklet and website will be supplemented by an exercise chart, calendar, newsletters, resistance bands, accelerometers, and phone and email contact from program staff. Data will be collected at baseline and post-intervention.Discussion: This study aims to contribute to the prevention of metabolic syndrome and inter- related chronic illnesses: type 2 diabetes mellitus, cardiovascular disease, and some cancers; which are associated with overweight/obesity, physical inactivity, and poor diet. This large rural community-based trial will provide guidelines for recruitment, program development, implementation, and evaluation, and has the potential to translate findings into practice by expanding the program to other regional areas in Australia. Trial registration: Australian and New Zealand Clinical Trials Registry [ACTRN12614000512628, registration date 14th May 2014]