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Biosynthesis of glycosylphosphatidylinositol (GPI) is required for anchoring proteins to the plasma membrane, and is essential for the integrity of the fungal cell wall. Here, we use a reporter gene-based screen in Saccharomyces cerevisiae for the discovery of antifungal inhibitors of GPI-anchoring of proteins, and identify the oligocyclopropyl-containing natural product jawsamycin (FR-900848) as a potent hit. The compound targets the catalytic subunit Spt14 (also referred to as Gpi3) of the fungal UDP-glycosyltransferase, the first step in GPI biosynthesis, with good selectivity over the human functional homolog PIG-A. Jawsamycin displays antifungal activity in vitro against several pathogenic fungi including Mucorales, and in vivo in a mouse model of invasive pulmonary mucormycosis due to Rhyzopus delemar infection. Our results provide a starting point for the development of Spt14 inhibitors for treatment of invasive fungal infections. Biosynthesis of glycosylphosphatidylinositol (GPI) is essential for the integrity of the fungal cell wall. Here, the authors show that the natural product jawsamycin inhibits GPI biosynthesis by targeting a subunit of the fungal UDP-glycosyltransferase, and displays pronounced activity against pathogenic fungi of the order Mucorales.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

We present a technique of direct optical entry through Palmer's point (3 cm below the left costal margin in the mid-clavicular line) as an alternative laparoscopic entry method for those gynaecological patients at risk of periumbilical adhesions. This method has been used in 15 patients and allowed the adhesions to be cleared where necessary. We feel that this technique can provide a safe approach to the abdominal cavity and should be considered as another method alongside closed and open umbilical techniques in the laparoscopic gynaecologist's repertoire.

AbstractObjectivesTo evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain.DesignThe PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial.Setting34 UK hospitals.Participants405 women of reproductive age undergoing conservative surgery for endometriosis.InterventionsParticipants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill.Main outcome measuresThe primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment).Results405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference −0.8, 95% confidence interval −5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00).ConclusionsPostoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some.Trial registrationISRCTN registry ISRCTN97865475.

The decision to freeze or replace embryos (and risk worsening ovarian hyperstimulation syndrome if a pregnancy occurs) around this time is difficult as the success rates after replacement of frozen embryos tend to be poorer. 4 Unfortunately, recent legislation changes in Italy have removed this option for safety 5 and would drastically alter Tommy's management if she were treated today.

Argyrins, produced by myxobacteria and actinomycetes, are cyclic octapeptides with antibacterial and antitumor activity. Here, we identify elongation factor G (EF-G) as the cellular target of argyrin B in bacteria, via resistant mutant selection and whole genome sequencing, biophysical binding studies and crystallography. Argyrin B binds a novel allosteric pocket in EF-G, distinct from the known EF-G inhibitor antibiotic fusidic acid, revealing a new mode of protein synthesis inhibition. In eukaryotic cells, argyrin B was found to target mitochondrial elongation factor G1 (EF-G1), the closest homologue of bacterial EF-G. By blocking mitochondrial translation, argyrin B depletes electron transport components and inhibits the growth of yeast and tumor cells. Further supporting direct inhibition of EF-G1, expression of an argyrin B-binding deficient EF-G1 L693Q variant partially rescued argyrin B-sensitivity in tumor cells. In summary, we show that argyrin B is an antibacterial and cytotoxic agent that inhibits the evolutionarily conserved target EF-G, blocking protein synthesis in bacteria and mitochondrial translation in yeast and mammalian cells.

FR171456 is a natural product with cholesterol-lowering properties in animal models, but its molecular target is unknown, which hinders further drug development. Here we show that FR171456 specifically targets the sterol-4-alpha-carboxylate-3-dehydrogenase (S accharomyces cerevisiae —Erg26p, Homo sapiens —NSDHL (NAD(P) dependent steroid dehydrogenase-like)), an essential enzyme in the ergosterol/cholesterol biosynthesis pathway. FR171456 significantly alters the levels of cholesterol pathway intermediates in human and yeast cells. Genome-wide yeast haploinsufficiency profiling experiments highlight the erg26/ERG26 strain, and multiple mutations in ERG26 confer resistance to FR171456 in growth and enzyme assays. Some of these ERG26 mutations likely alter Erg26 binding to FR171456, based on a model of Erg26. Finally, we show that FR171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. The discovery of the target and binding site of FR171456 within the target will aid further development of this compound. FR171456 is a bioactive chemical produced by some microorganisms. Here, the authors identify the enzyme NSDHL of the sterol synthesis pathway as the molecular target of FR171456, rendering it the first compound to specifically target this class of enzyme in yeast and mammalian cells.

Obesity is having an increasingly significant impact on health care services across the developed world. Although initially laparoscopic surgery was thought to be contraindicated in cases of obesity, surgeons, including gynaecologists, are now routinely performing laparoscopic surgery on obese patients. Limited research has been conducted into the effect of obesity on outcomes of major laparoscopic pelvic surgery. Some authors report worsening outcomes in obese women having laparoscopic hysterectomies; others suggest that complication rates do not increase, but operating times are longer. Here, we report our experience from 250 total laparoscopic hysterectomies performed for benign, malignant and pre-malignant conditions, and we compare outcomes among normal, overweight, obese and morbidly obese patients. We used a composite score index calculated on the basis of operating and theatre times, estimated blood loss, length of stay and number and severity of complications for our comparisons. Our conclusions suggest that meticulous, consistent surgical technique may produce similar outcomes in normal and obese patients having total laparoscopic hysterectomy, with longer operating/theatre times noted only at BMI levels >40.

Pregnancy in a uterine rudimentary horn carries a high risk of uterine rupture with severe and potentially lethal intra-abdominal haemorrhage. There is now growing evidence that this condition can be safely managed by minimally invasive surgery. We report a case of an unruptured 11-week rudimentary horn pregnancy that was diagnosed and treated laparoscopically. We have performed a literature review using PubMed, Embase and Cochrane Database of Systematic Reviews to identify relevant cases and draw conclusions with regards to their management. We have collated 20 published cases of rudimentary horn pregnancies that were managed by laparoscopy. The surgical technique appears consistent among these cases with few variations. In advanced gestations, feticide may need to be performed. Morcellation has been shown to be possible without compromising patient safety from trophoblast spill. The possibility of uncommon presentations such as duplicated or absent ureter should be taken into account. Extracorporeal Roeder knot can be used safely to secure unusually dilated vascular pedicles. Overall, laparoscopy appears to be as safe as and potentially superior to laparotomy for the management of rudimentary horn pregnancies.