Efficacy, safety and tolerability of GSK3858279, an anti-CCL17 monoclonal antibody and analgesic, in healthy volunteers and patients with knee osteoarthritis pain: a phase I, randomised, double-blind, placebo-controlled, proof-of-mechanism and proof-of-concept study.

Objectives: The objective of this study was to evaluate efficacy, safety and tolerability of the first-in-class, anti-CCL17 monoclonal antibody, GSK3858279, in treating knee osteoarthritis (OA) pain.

Methods: This was a phase I, randomised, placebo-controlled, two-part, proof-of-mechanism and proof-of-concept study. In part A, healthy participants were randomised 3:1 to receive GSK3858279 as either single intravenous (0.

De Garengeot hernias. Over a century of experience. A systematic review of the literature and presentation of two cases.

De Garengeot hernia is a rare femoral hernia that contains the vermiform appendix. It has always been a subject of interest, mainly because of its uncommon entity, but also because of the diagnostic challenge it presents and the lack of consensus in its surgical management. It mainly presents as an emergency, with strangulation of the femoral hernia and acute inflammation of the appendix.

Transforming Growth Factor Beta Gene Signatures are Spatially Enriched in Keloid Tissue Biopsies and Ex vivo-Cultured Keloid Fibroblasts.

The keloid lesion is recognised as a spatially heterogeneous mass both in cellular and acellular composition and biological activity. Here, we have utilised a bioinformatic approach to determine whether this spatial heterogeneity is also evident at the molecular level and to identify key upstream regulators of signalling pathways enriched in the lesion in a spatially-restricted manner. Differentially expressed genes (20% change, p < 0.

Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors.

Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic profile in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described.

p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression.

p38alpha MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFalpha and IL-1beta at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38alpha/beta inhibitors using crystal structures of our inhibitors bound to p38alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.

Biphenyl amide p38 kinase inhibitors 3: Improvement of cellular and in vivo activity.

The biphenyl amides (BPAs) are a novel series of p38alpha MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode.

Forgotten vaginal pessary eroding into rectum.

Vaginal pessaries still have a role in the management of uterine prolapse, particularly in elderly patients. However, they are known to cause serious complications if proper care is not taken. We present a case of a rectovaginal fistula, developing secondary to a forgotten vaginal pessary.

Copper toxicity affects proliferation and viability of human hepatoma cells (HepG2 line).

In Wilson's disease and Indian childhood cirrhosis (ICC) copper accumulates in the liver resulting in poor hepatocyte regeneration and fibrosis. An inhibition of hepatocyte proliferation and an increase in cell death could account for these outcomes. To establish how the toxicity of this metal ion impacts upon the proliferation and viability of the HepG2 cells they were cultured in 4-32 microM copper(II) sulphate (CuSO4)).

Traumatic pseudocyst of the spleen.

Four patients with pseudocyst of the spleen gave histories of abdominal trauma. In one patient the pseudocyst had ruptured, necessitating emergency splenectomy 34 years after the original injury. In a second patient the pseudocyst was discovered incidentally, and was managed by spleen-preserving excision; and the third and fourth presented with abdominal pain and had splenectomy and spleen-preserving surgery, respectively.

An animal model for copper-associated cirrhosis in infancy.

In Indian childhood cirrhosis (ICC) and related disorders of infancy, hepatic copper overload is associated with cirrhosis. Since copper administration alone has not been shown to induce cirrhosis in animals, synergy between copper and a second hepatotoxin has been suggested. This study investigates the ability of long-term exposure to copper and a pyrrolizidine alkaloid, retrorsine, to produce a model of copper-associated cirrhosis in rats.

Abdominal tuberculosis.

Throughout the world tuberculosis is associated with poverty, deprivation, and human immunodeficiency virus infection. Abdominal tuberculosis is usually of insidious onset with diverse symptoms and signs. A few present with acute complications of perforation, obstruction, or bleeding.

Retrorsine in breast milk influences copper handling in suckling rat pups.

Aims: To explore the hypothesis that a second xenobiotic agent is required with excess copper to produce Indian Childhood Cirrhosis, this study investigated the effect of the pyrrolizidine alkaloid retrorsine fed to the mother during the suckling period upon the serial changes in neonatal copper status.

Methods: Female Wistar rats with new-born litters were fed either a control or a retrorsine (50 mg/kg) diet. At 0, 4, 8, 11, 15, 18 and 21 days, pups from each litter were weighed, sacrificed and their livers removed for copper, DNA and metallothionein analysis.

Alpha 1A-adrenoceptor subtype mediates contraction of the rat urethra.

1. The alpha 1-adrenoceptor-mediated responses of the rat urethra to phenylephrine have been examined in vitro. Phenylephrine caused concentration-dependent contractions of the isolated urethra which were antagonized by WB4101 (3-30 nM) and prazosin (10-100 nM) but not idazoxan (1.

The distribution of atherosclerosis in the lower limbs.

Sixty-seven consecutive aortograms in non-diabetic patients were studied to establish the distribution of atherosclerosis in the arteries of 134 lower limbs. Prolonged filming and multiple exposures of the feet showed ankle vessels in 131 of the limbs (98%) and a pedal arch or collaterals in 126 (93%). In 51% of the limbs at least one of the calf arteries was occluded and only 24% had two patent arteries at ankle level.

Duodenal ulcer hemorrhage in the puerperium.

Hemorrhage from a peptic ulcer during pregnancy is a rare complication that occurs most frequently near term or in the puerperium. A case of massive hematemesis from a duodenal ulcer on the third puerperal day is described. Emergency surgery with vagotomy and pyloroplasty was performed.

A modified technique of pre-operative aortography to demonstrate the complete arterial tree of the lower limb.

One hundred consecutive aortograms were studied to establish the efficacy of conventional arteriography in demonstrating distal vessels and the pedal arch. The standard technique was modified by using a long injection time, a large volume of contrast material (iopamidol 370), prolonged filming and multiple exposures of the feet. On the basis of these examinations each limb was classified as having aorto-iliac disease (18 limbs), superficial femoral disease (103 limbs), combined segment disease (28 limbs) or generalised disease (51 limbs).

Abdominal tuberculosis.

Over a four-year period, 28 patients with abdominal tuberculosis were seen, of whom 24 were immigrants and 22 under 45 years. Emergency surgery was carried out in 10 patients; another 14 had elective laparotomy. The diagnosis was suspected pre-operatively in 75 per cent of those having elective surgery and 10 per cent of those having emergency laparotomy.

Endoscopic balloon dilatation of colonic anastomotic strictures.

Nine postoperative colonic and rectal strictures were treated using dilatation balloons passed over a guide-wire introduced endoscopically. Six strictures resolved after a single dilatation. The method is simple, safe, effective and avoids further surgery.