Evaluating the druggability of TrmD, a potential antibacterial target, through design and microbiological profiling of a series of potent TrmD inhibitors.

The post-transcriptional modifier tRNA-(NG37) methyltransferase (TrmD) has been proposed to be essential for growth in many Gram-negative and Gram-positive pathogens, however previously reported inhibitors show only weak antibacterial activity. In this work, optimisation of fragment hits resulted in compounds with low nanomolar TrmD inhibition incorporating features designed to enhance bacterial permeability and covering a range of physicochemical space. The resulting lack of significant antibacterial activity suggests that whilst TrmD is highly ligandable, its essentiality and druggability are called into question.

SMA-BmobaSNO: an intelligent photoresponsive nitric oxide releasing polymer for drug nanoencapsulation and targeted delivery.

Nitric oxide (NO) is an important biological signalling molecule that acts to vasodilate blood vessels and change the permeability of the blood vessel wall. Due to these cardiovascular actions, co-administering NO with a therapeutic could enhance drug uptake. However current NO donors are not suitable for targeted drug delivery as they systemically release NO.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC of 0.5 μg mL against , favourable pharmacokinetic properties, selectivity human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.

The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.

Generating the curvature perturbation at the end of inflation in string theory.

In brane inflationary scenarios, the cosmological perturbations are supposed to originate from the vacuum fluctuations of the inflaton field corresponding to the position of the brane. We show that a significant, and possibly dominant, contribution to the curvature perturbation is generated at the end of inflation through the vacuum fluctuations of fields, other than the inflaton, which are light during the inflationary trajectory and become heavy at the brane-antibrane annihilation. These fields appear generically in string compactifications where the background geometry has exact or approximate isometries and parametrize the internal angular directions of the brane.

Inflationary prediction for primordial non-gaussianity.

We extend the deltaN formalism so that it gives all of the stochastic properties of the primordial curvature perturbation zeta if the initial field perturbations are Gaussian. The calculation requires only the knowledge of some family of unperturbed universes. A formula is given for the normalization f(NL) of the bispectrum of zeta, which is the main signal of non-Gaussianity.

Tension-free vaginal tape: 162 cases in a district general hospital.

From March 1999 to July 2002 a prospective study was carried out of 162 consecutive cases of urodynamically confirmed stress and mixed incontinence who underwent the tension-free vaginal tape (TVT) procedure. Patients were followed up at 6 weeks and 6 months and with a quality of life questionnaire at 1 year. The intraoperative complication rate was 7.

The infusion trial of micturition.

Objective: To compare three methods for a trial of micturition (TOM) (the midnight removal of the catheter, dawn removal, and a new infusion method) in a randomized prospective study.

Patients And Methods: A total of 118 consecutive patients who had undergone transurethral resection of the prostate (TURP) or bladder neck incision (BNI) underwent TOM by one of the three methods. In the infusion method, the bladder was filled at a fast-drip rate via the catheter from a bag of normal saline connected by an intravenous supply set.

Does ethamsylate reduce haemorrhage in transurethral prostatectomy?

A double-blind, randomised trial of 44 consecutive patients undergoing transurethral prostatectomy demonstrated that ethamsylate (Dicynene) did not reduce blood loss during either the operative or the post- operative periods.