Comparison of pharmacological thrombolysis with mechanical thrombectomy in thrombosed arteriovenous fistulas and grafts: a systemic review and meta-analysis.

AIM: To compare the effectiveness and safety of pharmacological thrombolysis and mechanical thrombectomy. MATERIAL AND METHODS: This review was conducted in accordance with the PRISMA guidelines. Pooled proportions and subgroup analysis were calculated for primary and secondary patency rates, technical success, clinical success, major and minor complications rates. RESULTS: This systematic review identified a total of 6,492 studies of which 17 studies were included for analysis. A total of 1,089 patients comprising 451 (41.4 %) and 638 (58.6 %) patients who underwent thrombolysis and mechanical thrombectomy procedures, respectively, were analysed. No significant differences were observed between thrombolysis and mechanical thrombectomy procedures in terms of technical success, clinical success, major and minor complications rates, primary and secondary patency rates; however, subgroup analysis of overall arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) demonstrated a significantly higher rate of major complications within the AVF group (p=0.0248). CONCLUSION: The present meta-analysis suggests that pharmacological thrombolysis and mechanical thrombectomy procedures are similarly effective and safe; however, AVFs are subject to higher major complications compared to AVGs.

Precision medicine in united airways disease: A "treatable traits" approach.

United airways disease (UAD) is the concept that the upper and lower airways, which are anatomically and immunologically related, form a single organ. According to this concept, upper and lower airway diseases are frequently comorbid because they reflect manifestations of a single underlying disease at different sites of the respiratory tract. Allergic asthma-allergic rhinitis is the archetypal UAD, but emerging data indicate that UAD is a heterogeneous condition and consists of multiple phenotypes (observable clinical characteristics) and endotypes (pathobiologic mechanisms). The UAD paradigm also extends to myriad sinonasal diseases (eg, chronic rhinosinusitis with or without nasal polyps) and lower airway diseases (eg, bronchiectasis, chronic obstructive pulmonary disease). Here, we review currently known phenoendotypes of UAD and propose a "treatable traits" approach for the classification and management of UAD, wherein pathophysiological mechanisms and factors contributing to disease are identified and targeted for treatment. Treatable traits in UAD can be analyzed according to a framework comprising airway inflammation (eosinophilic, neutrophilic), impaired airway mucosal defense (impaired mucociliary clearance, antibody deficiency), and exogenous cofactors (allergic sensitizers, tobacco smoke, microbes). Appreciation of treatable traits is necessary in advancing the effort to deliver precise treatments and achieve better outcomes in patients with UAD.

Comorbid "treatable traits" in difficult asthma: Current evidence and clinical evaluation.

The care of patients with difficult-to-control asthma ("difficult asthma") is challenging and costly. Despite high-intensity asthma treatment, these patients experience poor asthma control and face the greatest risk of asthma morbidity and mortality. Poor asthma control is often driven by severe asthma biology, which has appropriately been the focus of intense research and phenotype-driven therapies. However, it is increasingly apparent that extra-pulmonary comorbidities also contribute substantially to poor asthma control and a heightened disease burden. These comorbidities have been proposed as "treatable traits" in chronic airways disease, adding impetus to their evaluation and management in difficult asthma. In this review, eight major asthma-related comorbidities are discussed: rhinitis, chronic rhinosinusitis, gastroesophageal reflux, obstructive sleep apnoea, vocal cord dysfunction, obesity, dysfunctional breathing and anxiety/depression. We describe the prevalence, impact and treatment effects of these comorbidities in the difficult asthma population, emphasizing gaps in the current literature. We examine the associations between individual comorbidities and highlight the potential for comorbidity clusters to exert combined effects on asthma outcomes. We conclude by outlining a pragmatic clinical approach to assess comorbidities in difficult asthma.

Comparison of the sensitivity and specificity of p16/Ki-67 dual staining and HPV DNA testing of abnormal cervical cytology in the detection of histology proven cervical intraepithelial neoplasia grade 2 and above (CIN 2+).

INTRODUCTION: Human papillomavirus (HPV) testing is used as a means of triaging cervico-vaginal smears with low grade squamous abnormalities or as part of co-testing with cytology. While HPV testing has a high sensitivity, it has a low specificity in detecting cervical intraepithelial neoplasia grade 2 and above (CIN 2+) leading to unnecessary colposcopy referrals. We investigate the accuracy of the p16/Ki-67 dual immunocytochemical stain in determining the presence of CIN 2+ lesions on histology and its potential as a superior biomarker for triage. METHODS: Liquid based cervico-vaginal cytology specimens with squamous abnormalities and corresponding histology from 97 women with subsequent colposcopy and biopsy were included. The specimens were then subjected to the dual stain and Roche Cobas 4800 multiplex real time PCR HPV DNA testing. The sensitivity and specificity of the dual stain and HPV testing were calculated using CIN 2+ on histology as a reference standard. RESULTS: The sensitivity and specificity of the dual stain in detecting histology proven CIN 2+ was 93.7% and 76.5% while HPV testing was 85.7% and 14.7% respectively. Of the 44 women with ASCUS or LSIL on cytology, the dual stain also reduced the number of unnecessary colposcopy referrals from 27 to 7 when used as a triage marker compared to HPV testing. CONCLUSION: p16/Ki-67 dual stain was more sensitive and specific than HPV testing in determining the presence of CIN 2+ on histology. It could triage low grade cervico-vaginal specimens more effectively and potentially help women avoid unnecessary colposcopies. Future studies are needed to further evaluate its role in cervical cancer screening programmes.

Profile of difficult to treat asthma patients referred for systematic assessment.

AIM: We determined the proportion of asthma patients under specialist care who remain difficult-to-treat and might benefit from systematic assessment. We additionally report the characteristics and indications for referral in 90 patients who received systematic assessment for difficult asthma. METHODS: We conducted a three-month prospective audit of our hospital's general asthma clinic. We then analyzed consecutive patients over 18 months referred on for systematic assessment of difficult asthma. RESULTS: Over 3 months, 22/166 patients (13.3%) in the general asthma clinic were considered likely to benefit from systematic assessment of difficult asthma. These patients had higher inhaled steroid requirements (890 ± 604 mg), lower lung function (FEV1: 65 ± 18%), and more often received GINA step 5 treatment (22.7%). However, 7/22 (32%) of suitable patients were not referred for assessment, mainly due to patient factors. Over 18 months, 90 patients received systematic assessment for difficult asthma, on account of poor symptom control (62%), frequent exacerbations (44%), poor lung function (42%), patient factors (29%), and diagnostic uncertainty (26%). There was a high disease burden with a mean (±SD) asthma control test score and asthma quality of life questionnaire score of 14 ± 5 and 4.26 ± 1.45 respectively. 80% fulfilled criteria for severe asthma. The majority were either atopic (66.7%) or eosinophilic (54.4%); only 15.6% were neither. Patients had a median of three extra-pulmonary comorbidities, of which most were previously unrecognised. CONCLUSION: One-in-eight asthma patients already under specialist care were suitable for systematic assessment of difficult asthma, but a third of these were not referred due to patient factors. Diagnostic uncertainty and patient factors were important indications for systematic assessment. Most patients who underwent systematic assessment exhibited severe asthma phenotypes potentially responsive to targeted treatment, but also had multiple comorbidities. Our results highlight the importance of management strategies to address patient factors, severe asthma biology, and concurrent contributory conditions.

Elevated total serum immunoglobulin E (>1000 IU/mL): implications?

Atopic eczema, allergic broncho-pulmonary aspergillosis, helminthic infections and rare primary immunodeficiencies are known to elevate total serum immunoglobulin E (IgE) above 1000 IU/mL. However, of 352 patients with IgE >1000 IU/mL seen in our hospital over a 5-year period, less than 50% had these conditions. Markedly elevated IgE levels in the rest of the patients were associated with asthma, allergic rhinitis and food allergy, instances where the test is of limited diagnostic utility.

Do we need transbronchial lung biopsy if we have bronchoalveolar lavage Xpert® MTB/RIF?

BACKGROUND: Studies evaluating the role of transbronchial lung biopsy (TBLB) in diagnosing pulmonary tuberculosis (PTB) date back decades and have shaped current practice. However, with the recent advent of bronchoalveolar lavage (BAL) Xpert® MTB/RIF, it is time to re-evaluate the role of TBLB. OBJECTIVE: To assess the impact of BAL and TBLB with the addition of BAL Xpert on diagnostic PTB yields and time to treatment initiation in sputum-scarce or acid-fast bacilli (AFB) smear-negative PTB patients. METHODS: We retrospectively reviewed all sputum-scarce or AFB smear-negative patients who underwent both BAL and TBLB for suspected PTB between March 2011 and October 2013. Xpert was performed on all BAL specimens. RESULTS: Of 158 patients included in our analysis, 44 were culture-proven PTB. Ninety-four per cent of the patients had AFB smear-negative BAL samples. The sensitivity and specificity of Xpert in AFB smear-negative BAL samples were respectively 60% and 98%. The addition of BAL Xpert expedited the institution of PTB treatment while having diagnostic yields comparable to those of conventional BAL with TBLB. CONCLUSIONS: The use of BAL Xpert may obviate the need for TBLB in increasing the diagnostic yield of PTB in sputum-scarce or AFB smear-negative patients.

Strong and superplastic nanoglass.

The strength-ductility tradeoff has been a common long-standing dilemma in materials science. For example, superplasticity with a tradeoff in strength has been reported for Cu50Zr50 nanoglass (NG) with grain sizes below 5 nm. Here we report an improvement in strength without sacrificing superplasticity in Cu50Zr50 NG by using a bimodal grain size distribution. Our results reveal that large grains impart high strength, which is in striking contrast to the physical origin of the improvement in strength reported in the traditional nanostructured metals/alloys. Furthermore, the mechanical properties of NG with a bimodal nanostructure depend critically upon the fraction of large grains. By increasing the fraction of the large grains, a transition from superplastic flow to failure by shear banding is clearly observed. We expect that these results will be useful in the development of a novel strong and superplastic NG.

Comparing the effects of meal replacements with an isocaloric reduced-fat diet on nutrient intake and lower urinary tract symptoms in obese men.

BACKGROUND: Lower urinary tract symptoms (LUTS) in men are associated with obesity, particularly central obesity as measured by waist circumference (WC), and may improve with weight loss. We aimed to compare effects of a meal-replacement based diet with isocaloric reduced-fat plan on LUTS and nutrient intake in obese Asian men. METHODS: Obese Asian [mean (range) body mass index of 32.9 (30.5-42.3) kg m(-2) ] men [mean (range) age 40.2 (30-61) years] were randomised to a reduced-fat (< 30% of energy) diet [conventional reduced-fat diet (CD) group; n = 23] or meal-replacement-based plan [meal replacement (MR) group; n = 23], to reduce daily intake by 2000 kJ for 12 weeks. RESULTS: CD and MR groups had statistically significant and similar reductions in weight (-2.6 ± 1.9 kg versus -4.2 ± 3.8 kg), overall LUTS severity measured with International Prostate Symptom Scale (IPSS) scores (-1.71 ± 1.93 points versus -2.42 ± 2.12 points) and insulin resistance [homeostasis model assessment (HOMA) calculated from plasma glucose and insulin]. The MR group had significantly greater decreases in WC (-4.8 ± 3.3 cm versus -2.5 ± 2.3 cm), fat mass (-2.47 ± 3.63 kg versus -1.59 ± 2.32 kg), fat intake, plasma C-reactive protein, and in storage LUTS score (-1.59 ± 1.33 points versus -1.00 ± 0.87 points), which was associated with a decreased fat intake (r = 0.48, P = 0.03). A decrease in overall IPSS score was associated with reductions in weight, WC and HOMA. CONCLUSIONS: Weight loss as a result of CD or MR had similar efficacy in relieving LUTS. MR produced greater reductions in fat intake, adiposity and storage LUTS.

Comparing the effects of meal replacements with reduced-fat diet on weight, sexual and endothelial function, testosterone and quality of life in obese Asian men.

Sexual dysfunction is more prevalent in obese than in normal-weight men. Meal replacements (MRs) are useful weight-loss strategies. We randomized obese (body mass index 27.5 kg m(-2), waist circumference (WC) 90 cm) Asian men (mean age 40.5 years, range 30-61) to a conventional reduced-fat diet (CD) (n=24) or MR-based plan (n=24) to reduce daily intake by 400 kcal for 12 weeks. There were significantly greater reductions in weight (4.2 ± 0.8 kg), WC (4.6 ± 0.7 cm), calorie and fat intake in the MR group, compared with the CD group (2.5 ± 0.4 kg, 2.6 ± 0.5 cm). Erectile function (International Index of Erectile Function 5-item score) improved comparably in the MR (3.4 ± 0.7 points) and CD (2.5 ± 0.5 points) groups, as did the Sexual Desire Inventory score (5.5 ± 2.3 vs 7.7 ± 2.1 points), quality of life (36-item Short Form survey score), plasma testosterone and endothelial function (Reactive Hyperemia Index). Subjects were switched to or continued CD for another 28 weeks. Weight, WC and erectile function were maintained at 40 weeks. MR induces greater reductions in weight and abdominal obesity than conventional diet, and comparable improvements in sexual and endothelial function, testosterone and quality of life.

Glycogen synthase kinase-3ß inhibition improved survivability of mice infected with Burkholderia pseudomallei.

The disease melioidosis, caused by the soil bacteria Burkholderia pseudomallei, often manifests as acute septicemia with high fatality. Glycogen synthase kinase-3ß (GSK3ß) plays a key role during the inflammatory response induced by bacteria. We used a murine model of acute melioidosis to investigate the effects of LiCl, a GSK3 inhibitor on experimental animal survivability as well as TNF-α, IL-1ß, IFN-γ, IL-10 and IL-1Ra cytokine levels in blood, lung, liver and spleen of B. pseudomallei-infected mice. Our results showed that administration of 100 µg/g LiCl improved survivability of mice infected with 5 X LD50 of B. pseudomallei. Bacterial counts in spleen, liver and lungs of infected mice administered with LiCl were lower than non-treated controls. Our data also revealed that GSK3ß is phosphorylated in the spleen, liver and lung of animals infected with B. pseudomallei. However in infected animals administered with LiCl, higher levels of pGSK3 were detected in the organs. Levels of proinflammatory cytokines (TNF-α, IL-1ß and IFN-γ) and anti-inflammatory cytokines (IL-10 and IL-1Ra) in sera and organs tested were elevated significantly following B. pseudomallei infection. With GSK3ß inhibition, pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1ß) were significantly decreased in all the samples tested whilst the levels of anti-inflammatory cytokines, IL-10 (spleen and lung) and IL-1Ra (spleen, liver and sera) were further elevated. This study represents the first report implicating GSK3ß in the modulation of cytokine production during B. pseudomallei infection thus reiterating the important role of GSK3ß in the inflammatory response caused by bacterial pathogens.

Larvicidal activity of some secondary lichen metabolites against the mosquito Culiseta longiareolata Macquart (Diptera: Culicidae).

The larvicidal activity of some lichen metabolites, (+)-usnic acid, atranorin, 3-hydroxyphysodic acid and gyrophoric acid, against the second and third instar larvae of the mosquito Culiseta longiareolata were studied. All metabolites caused high larvicidal activities. When metabolites were compared on the basis of their LC(50) values, the order of increasing toxicity was as follows: gyrophoric acid (0.41 ppm) > (+)-usnic acid (0.48 ppm) > atranorin (0.52 ppm) > 3-hydroxyphysodic acid (0.97 ppm). However, when LC(90) values were compared, the order of toxicity was (+)-usnic acid (1.54 ppm) > gyrophoric acid (1.93 ppm) > 3-hydroxyphysodic acid (4.33 ppm) > atranorin (5.63 ppm). In conclusion, our results found that lichen secondary metabolites may have a promising role as potential larvicides.

Glycogen synthase kinase-3β inhibition improved survivability of mice infected with Burkholderia pseudomallei

The disease melioidosis, caused by the soil bacteria Burkholderia pseudomallei, often manifests as acute septicemia with high fatality. Glycogen synthase kinase-3β (GSK3β) plays a key role during the inflammatory response induced by bacteria. We used a murine model of acute melioidosis to investigate the effects of LiCl, a GSK3 inhibitor on experimental animal survivability as well as TNF-α, IL-1β, IFN-γ, IL-10 and IL-1Ra cytokine levels in blood, lung, liver and spleen of B. pseudomallei-infected mice. Our results showed that administration of 100 μg/g LiCl improved survivability of mice infected with 5 X LD50 of B. pseudomallei. Bacterial counts in spleen, liver and lungs of infected mice administered with LiCl were lower than non-treated controls. Our data also revealed that GSK3β is phosphorylated in the spleen, liver and lung of animals infected with B. pseudomallei. However in infected animals administered with LiCl, higher levels of pGSK3 were detected in the organs. Levels of proinflammatory cytokines (TNF-α, IL-1β and IFN-γ) and anti-inflammatory cytokines (IL-10 and IL-1Ra) in sera and organs tested were elevated significantly following B. pseudomallei infection. With GSK3β inhibition, pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β) were significantly decreased in all the samples tested whilst the levels of anti-inflammatory cytokines, IL-10 (spleen and lung) and IL-1Ra (spleen, liver and sera) were further elevated. This study represents the first report implicating GSK3β in the modulation of cytokine production during B. pseudomallei infection thus reiterating the important role of GSK3β in the inflammatory response caused by bacterial pathogens.

Di(n-butyl) phthalate induces vimentin filaments disruption in rat sertoli cells: a possible relation with spermatogenic cell apoptosis.

Phthalate esters have been extensively used as a plasticizer of synthetic polymers. Previous studies have revealed that some phthalate esters including di(n-butyl) phthalate (DBP) induce spermatogenic cell apoptosis, although its mechanism is not yet clear. The present study describes that disruption of Sertoli cell vimentin filaments by DBP administration may relate to spermatogenic cell apoptosis. The present histopathological study revealed that a single oral administration of 500 mg/kg DBP caused progressive detachment and displacement of spermatogenic cells away from the seminiferous epithelium and sloughing of them into the lumen. Degenerative spermatogenic cells characterized by chromatin condensation were frequently observed in DBP-treated rats. Ultrastructurally, the degenerative spermatogenic cells were separated from their neighbours, and a collapse of Sertoli cell vimentin filaments was recognized in DBP-treated rats. Sertoli cell cultures showed the increased number and size of vacuoles in their cytoplasm. In agreement with the in vivo experiment, vimentin filaments clearly showed a gradual collapse in DBP-exposed Sertoli cells in vitro. These in vivo and in vitro experiments indicate that DBP-induced collapse of Sertoli cell vimentin filaments may lead to detachment of spermatogenic cells, and then detached cells may undergo apoptosis because of loss of the support and nurture provided by Sertoli cells.

Glass transition temperature influence on crosslinked and entangled polymer interfaces.

The influence of glass transition temperature (Tg) on crosslinked and entangled polymer interfaces was investigated using coarse grained molecular dynamics (MD). A crosslinked polymer interface and an entangled polymer interface were built and the Tg for each system were obtained by confining a thin film between two rigid walls. The physical properties of each system above and under Tg were compared. The mechanical properties were also explored by pulling the interfaces apart at different temperature. The results are qualitatively agreed with experimental observations. Furthermore, the present results show that, when under tensile loading at temperature higher than Tg, the entangled interface exhibits strain softening while the crosslinked thin film is still able to show strain hardening. The different performances may due to that, at high temperature, the high mobility of monomers tend to unravel the entangled chain in linear polymer system while in crosslinked system, monomers with high mobility tend to arrest the void and decrease the void propagation.

Multiscale modeling of polymers-bridging the molecular continuum divide.

A method to reduce the degrees freedom in molecular mechanics simulation is presented. Although the approach is formulated for amorphous materials, it is equally applicable to crystalline materials. The method is selectively applied to regions where molecular displacements are expected to be small while simultaneously using classical molecular mechanics for regions undergoing large deformation. Its accuracy and computational efficiency are demonstrated through the simulation of a polymer-like substrate indented by a rigid indentor. The region directly below the indentor is modelled by classical molecular mechanics while the region further away has the degrees of freedom reduced by about 50 times.

Significance of water molecules in the inhibition of cylin-dependent kinase 2 and 5 complexes.

Interest in CDK2 and CDK5 has stemmed mainly from their association with cancer and neuronal migration or differentiation related diseases and the need to design selective inhibitors for these kinases. In the present paper, eight Molecular Dynamics (MD) simulations are carried out to examine the importance of structure and dynamics of water in the active site of both CDK2 and CDK5 complexes with roscovitine and indirubin analogues. Together with previous results, the current work shows a highly conserved water-involved hydrogen bonding (HB) network in both CDK2- and CDK5-indirubin combinations to complete information from the X-ray crystallography. The simulations suggest the importance of such a network for combining the inhibitor to the host protein as well as the significance of using an activated CDK as a template when designing new inhibitors. Different binding patterns of roscovitine in CDK2 and CDK5 are detected during the simulations because of the different binding conformations of the group on the C2 side chain, which might offer a clue toward finding highly selective inhibitors with regards to CDK2 and CDK5.

The activation and inhibition of cyclin-dependent kinase-5 by phosphorylation.

Despite the very similar 3-dimensional structures as reflected by the more than 60% identity in amino acid sequences, CDK2 and CDK5 have very different functions and characteristics. Phosphorylation on a conserved Thr14 can inhibit activities of both the kinases, but phosphorylating another conserved Tyr15, however, can lead to totally opposite inhibition and stimulation consequences in CDK2 and CDK5. Our molecular dynamics (MD) simulations suggest a similar inhibition mechanism of phosphorylation on the Thr14 as in the CDK2 system. In both the systems, the kinase activities are inhibited by the phosphorylation because it causes ATP phosphate moiety misalignment and changes in the Mg2+ ion coordination sphere, which have been proven to be critical for the phosphate group of the ATP transferring to the hydroxyl group on the serine in the substrate peptide. The calculations indicate that ATP adopts a more favorable conformation and location in the phosphorylated Tyr15 complex to facilitate the interactions with the substrate and the Mg2+ is wrapped more strongly by the phosphate group than in the unphosphorylated system, which might be favored by the transfer reaction.

Phagocytosis plays an important role in clearing dead cells caused by mono(2-ethylhexyl) phthalate administration.

The role of phagocytosis in eliminating apoptotic spermatogenic cells caused by mono(2-ethylhexyl) phthalate (MEHP) was studied. Twenty-one-day-old C57Bl/6N male mice were given a single dose of 800 mg/kg MEHP in corn oil by oral gavage and sacrificed at 1, 3, 5, 7 and 9 days after initial exposure. At the same time, the role of phagocytosis in MEHP related apoptosis was examined using microinjection of annexin V into the seminiferous tubules of living mice. Results showed that mice treated with MEHP had a lower rate of testis weight gain (lower regression line) and a significant TUNEL-positive spermatogenic cell number compared to control. However, this incident was reversible, and the number of TUNEL-positive cells returned to normal after 9 days. Mice microinjected with annexin V and later treated with MEHP showed a large amount of TUNEL-positive cells compared to mice treated with MEHP only. This clearly proves that phagocytosis plays an efficient and highly important role in eliminating dead cells in the injured testis of mice treated with MEHP.