A customizable 3D printed device for enzymatic removal of drugs in water

The infiltration of drugs into water is a key global issue, with pharmaceuticals being detected in all nearly aqueous systems at often alarming concentrations. Pharmaceutical contamination of environmental water supplies has been shown to negatively impact ecological equilibrium and pose a risk to human health. In this study, we design and develop a novel system for the removal of drugs from water, termed as Printzyme. The device, fabricated with stereolithography (SLA) 3D printing, immobilises laccase sourced from Trametes Versicolor within a poly(ethylene glycol) diacrylate hydrogel. We show that SLA printing is a sustainable method for enzyme entrapment under mild conditions, and measure the stability of the system when exposed to extremes of pH and temperature in comparison to free laccase. When tested for its drug removal capacity, the 3D printed device substantially degraded two dissolved drugs on the European water pollution watch list. When configured in the shape of a torus, the device effectively removed 95% of diclofenac and ethinylestradiol from aqueous solution within 24 and 2 h, respectively, more efficiently than free enzyme. Being customizable and reusable, these 3D printed devices could help to efficiently tackle the world's water pollution crisis, in a flexible, easily scalable, and cost-efficient manner

Ileocolonic-Targeted JAK Inhibitor: A Safer and More Effective Treatment for Inflammatory Bowel Disease

Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and filgotinib (Jyseleca), have been approved for treatment of ulcerative colitis with several other JAK inhibitors in late-stage clinical trials for inflammatory bowel disease (IBD). Despite their impressive efficacy, the risk of adverse effects accompanying the use of JAK inhibitors has brought the entire class under scrutiny, leading to them receiving an FDA black box warning. In this study we investigated whether ileocolonic-targeted delivery of a pan-JAK inhibitor, tofacitinib, can lead to increased tissue exposure and reduced systemic exposure compared to untargeted formulations. The stability of tofacitinib in the presence of rat colonic microbiota was first confirmed. Next, in vivo computed tomography imaging was performed in rats to determine the transit time and disintegration site of ileocolonic-targeted capsules compared to gastric release capsules. Pharmacokinetic studies demonstrated that systemic drug exposure was significantly decreased, and colonic tissue exposure increased at 10 mg/kg tofacitinib dosed in ileocolonic-targeted capsules compared to gastric release capsules and an oral solution. Finally, in a rat model of LPS-induced colonic inflammation, targeted tofacitinib capsules significantly reduced concentrations of proinflammatory interleukin 6 in colonic tissue compared to a vehicle-treated control (p = 0.0408), unlike gastric release tofacitinib capsules and orally administered dexamethasone. Overall, these results support further development of ileocolonic-targeted tofacitinib, and potentially other specific JAK inhibitors in pre-clinical and clinical development, for the treatment of IBD

A Novel, “Double-Clamp” Binding Mode for Human Heme Oxygenase-1 Inhibition

The development of heme oxygenase (HO) inhibitors is critical in dissecting and understanding the HO system and for potential therapeutic applications. We have established a program to design and optimize HO inhibitors using structure-activity relationships in conjunction with X-ray crystallographic analyses. One of our previous complex crystal structures revealed a putative secondary hydrophobic binding pocket which could be exploited for a new design strategy by introducing a functional group that would fit into this potential site. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have synthesized and characterized 1-(1H-imidazol-1-yl)-4,4-diphenyl-2-butanone (QC-308). Using a carbon monoxide (CO) formation assay on rat spleen microsomes, the compound was found to be ∼15 times more potent (IC50 = 0.27±0.07 µM) than its monophenyl analogue, which is already a potent compound in its own right (QC-65; IC50 = 4.0±1.8 µM). The crystal structure of hHO-1 with QC-308 revealed that the second phenyl group in the western region of the compound is indeed accommodated by a definitive secondary proximal hydrophobic pocket. Thus, the two phenyl moieties are each stabilized by distinct hydrophobic pockets. This “double-clamp” binding offers additional inhibitor stabilization and provides a new route for improvement of human heme oxygenase inhibitors

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Posterosuperior rotator cuff repair by an independent double-row technique. Technical note and radiological and clinical results

The present study reports an original independent double-row technique for arthroscopic posterosuperior rotator cuff repair. Clinical and ultrasound results were assessed at 6-month follow-up in a single-center series of 78 patients with a mean age of 57years. Constant score improved from 55 to 73 (P<0.05). Seven patients (9%) had re-tear: 6 tendon avulsions from the bone and 1 tear at the myotendinous junction. This repair technique provided a high rate of tendon healing on the bone, with a lower rate of complications than with traditional double-row repair techniques

The pathogenicity of Clostridium difficile

AbstractIt is now well established that the major virulence factors of C. difficile are the two toxins A and B. However, the organism possesses an array of other putative virulence factors that may be important for localisation within the colon, and in evasion of the immune system. It has been observed that certain types of C. difficile are more commonly found causing disease than others, and this seems to be independent of toxin production. Is this simply a reflection of their abundance in the hospital environment, or is it due to their virulence determinants? This review covers our current knowledge of the modes of action of toxins A and B at the cellular and molecular level. Many unanswered questions are posed that require answers before we can fully understand the pathogenic mechanisms of the organism and be in a position to manage better the spectrum of diseases it causes

Energy transfer in polyatomic molecules: I. Catalysis of energy transfer with isotopic molecules

info:eu-repo/semantics/publishe