Arginase 1 (A1) is the enzyme that hydrolyzes the amino acid, L-arginine, to ornithine and urea. We have previously shown that A1 deletion worsens retinal ischemic injury, suggesting a protective role of A1. In this translational study, we aimed to study the utility of systemic pegylated A1 (PEG-A1, recombinant human arginase linked to polyethylene glycol) treatment in mouse models of acute retinal and brain injury. Cohorts of WT mice were subjected to retinal ischemia-reperfusion (IR) injury, traumatic optic neuropathy (TON) or brain cerebral ischemia via middle cerebral artery occlusion (MCAO) and treated with intraperitoneal injections of PEG-A1 or vehicle (PEG only). Drug penetration into retina and brain tissues was measured by western blotting and immunolabeling for PEG. Neuroprotection was measured in a blinded fashion by quantitation of NeuN (neuronal marker) immunolabeling of retina flat-mounts and brain infarct area using triphenyl tetrazolium chloride (TTC) staining. Furthermore, ex vivo retina explants and in vitro retina neuron cultures were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (R) and treated with PEG-A1. PEG-A1 given systemically did not cross the intact blood-retina/brain barriers in sham controls but reached the retina and brain after injury. PEG-A1 provided neuroprotection after retinal IR injury, TON and cerebral ischemia. PEG-A1 treatment was also neuroprotective in retina explants subjected to OGD/R but did not improve survival in retinal neuronal cultures exposed to OGD/R. In summary, systemic PEG-A1 administration is neuroprotective and provides an excellent route to deliver the drug to the retina and the brain after acute injury.

IF: 1.965

BACKGROUND: The aim of this study was to compare the efficacy of antagonist rescue protocol (replacing GnRH agonist with GnRH antagonist and reducing the dose of gonadotropins) combined with cabergoline versus cabergoline alone in the prevention of ovarian hyperstimulation syndrome (OHSS) in patients pretreated with GnRH agonist long protocol who were at high risk for OHSS.

METHODS: Two hundred and thirty six patients were randomized in a 1:1 ratio to the cabergoline group or the antagonist rescue combined with cabergoline group. Both groups received oral cabergoline (0.5 mg/day) for eight days beginning on the day of HCG administration. In the antagonist rescue combined with cabergoline group, when the leading follicle reached 16 mm, GnRH agonist (triptorelin) was replaced with GnRH antagonist (cetrorelix acetate) and the dose of HP-uFSH was reduced to 75 IU/day. HCG (5,000 IU/I.M) was administered when the serum estradiol level dropped below 3500 pg/ml. The study was open label and the outcome assessors (laboratory staff and the doctor who performed oocyte retrieval) were blind to treatment allocation.

RESULTS: The incidence of moderate/severe OHSS was significantly lower in the antagonist rescue combined with cabergoline group [5.08 % Vs 13.56 %, P value =0.025, OR = 0.342, 95 % CI, 0.129-0.906]. Four cycles were cancelled in the cabergoline group. There were no significant differences between the groups with respect to the number of retrieved oocytes, metaphase II oocytes, high quality embryos and fertilization rate. Moreover, the implantation and pregnancy rates were comparable between both groups.

CONCLUSION: GnRH antagonist rescue protocol combined with cabergoline is more effective than cabergoline alone in the prevention of OHSS.

TRIAL REGISTRATION: Clinical trial.gov ( NCT02461875 ).

The lack of effective therapies to limit neurovascular injury in ischemic retinopathy is a major clinical problem. This study aimed to examine the role of ureohydrolase enzyme, arginase 1 (A1), in retinal ischemia-reperfusion (IR) injury. A1 competes with nitric oxide synthase (NOS) for their common substrate L-arginine. A1-mediated L-arginine depletion reduces nitric oxide (NO) formation by NOS leading to vascular dysfunction when endothelial NOS is involved but prevents inflammatory injury when inducible NOS is involved. Studies were performed using wild-type (WT) mice, global A1 knockout (KO), endothelial-specific A1 KO, and myeloid-specific A1 KO mice subjected to retinal IR injury. Global as well as myeloid-specific A1 KO mice showed worsened IR-induced neuronal loss and retinal thinning. Deletion of A1 in endothelial cells had no effect, while treatment with PEGylated (PEG) A1 improved neuronal survival in WT mice. In addition, A1 KO mice showed worsened vascular injury manifested by increased acellular capillaries. Western blotting analysis of retinal tissue showed increased inflammatory and necroptotic markers with A1 deletion. In vitro experiments showed that macrophages lacking A1 exhibit increased inflammatory response upon LPS stimulation. PEG-A1 treatment dampened this inflammatory response and decreased the LPS-induced metabolic reprogramming. Moreover, intravitreal injection of A1 KO macrophages or systemic macrophage depletion with clodronate liposomes increased neuronal loss after IR injury. These results demonstrate that A1 reduces IR injury-induced retinal neurovascular degeneration via dampening macrophage inflammatory responses. Increasing A1 offers a novel strategy for limiting neurovascular injury and promoting macrophage-mediated repair.

The aim of this randomised controlled trial was to compare efficacy and safety of two doses of low molecular weight heparin (enoxaparin) in pregnant women with a history of recurrent abortion secondary to antiphospholipid syndrome. A total of 60 women with a minimum of three consecutive abortions before 10 weeks' gestation and positive lupus anticoagulant and/or anticardiolipin antibodies on at least two occasions at least 12 weeks apart were randomised into two groups based on computer generated randomisation list concealed in opaque envelopes. Pregnant women were treated with enoxaparin 40 mg plus low dose aspirin (LDA) (n = 30) or enoxaparin 20 mg plus LDA (n = 30). The live birth rate was 76.67% in enoxaparin 40 mg group and 70% in enoxaparin 20 mg group (p value = 0.559). There were no significant differences between both groups with respect to neonatal outcome, obstetric and maternal complications during pregnancy or puerperium. No cases of severe bleeding, thrombocytopenia or spontaneous fractures were reported in both groups.

A 65-year-old Egyptian lady suffering from non-alcoholic liver cirrhosis was referred to our unit for evaluation of a massive pericardial effusion. Few weeks before presentation, she suffered from progressive abdominal distention and dyspnoea. She denied fever, rigors or other cardiorespiratory symptoms. Examination revealed shrunken liver, spleenomegaly and ascites. Chest was clear to auscultation and heart sounds were distant. Chest radiograph showed cardiomegaly and clear lung fields. Abdominal ultrasound confirmed the results of abdominal examination. Transthoracic echocardiogram (TTE) revealed a massive pericardial effusion (PEF) and rheumatic mitral stenosis. Chest tomography showed PEF and clear lung fields. One litre of exudate was removed via TTE-guided needle pericardiocentesis. A pericardio-peritoneal shunt was suspected, which was confirmed via a radioisotopic study. This case is among very few cases that reported PEF in a cirrhotic ascetic patient secondary to a radio-isotopically confirmed pericardio-peritoneal shunt in the literature.

OBJECTIVE: To compare the effectiveness of misoprostol with uterine straightening by bladder distension in minimising the pain experienced by postmenopausal patients during diagnostic office hysteroscopy.

STUDY DESIGN: Seventy-six postmenopausal patients were randomly allocated in a 1:1 ratio to the misoprostol group or to the bladder distension group. Patients in the misoprostol group were instructed to insert two misoprostol tablets (400μg) in the vagina 12h before office hysteroscopy. Patients in the bladder distension group were instructed to drink one litre of water and to avoid urination during a period of 2h before office hysteroscopy. The severity of pain experienced by the patients during and at 30min after the procedure was measured using a 100-mm visual analogue scale (VAS). The ease of passing the hysteroscope through the cervical canal was assessed by the hysteroscopists using a 100-mm VAS.

RESULTS: The passage of the hysteroscope through the cervical canal was easier in the misoprostol group [60.37±15.78 vs. 50.05±19.88, p=0.015]. The mean VAS pain score during the procedure was significantly lower in the misoprostol group [39.47±13.96 vs. 50.18±15.44, p=0.002]. The mean VAS pain score 30min post-procedure was comparable between both groups [11.82±3.71 vs. 12.61±4.06, p=0.379].

CONCLUSION: Vaginal misoprostol is more effective than uterine straightening by bladder distension in relieving the pain experienced by postmenopausal patients during office hysteroscopy.

TRIAL REGISTRATION: Clinicaltrials.gov [NCT02328495]. https://clinicaltrials.gov/ct2/show/NCT02328495.

OBJECTIVE: To compare the efficacy and cost-effectiveness of extended high dose letrozole regimen/HPuFSH-gonadotropin releasing hormone antagonist (GnRHant) protocol with short low dose letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.

METHODS: In this randomized controlled trial, 136 women who responded poorly to GnRH agonist long protocol in their first IVF cycle were randomized into two equal groups using computer generated list and were treated in the second IVF cycle by either extended letrozole regimen (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) combined with HPuFSH-GnRHant protocol or short letrozole regimen (2.5 mg/day from cycle day 3-7) combined with HPuFSH-GnRHant protocol.

RESULTS: There were no significant differences between both groups with regard to number of oocytes retrieved and clinical pregnancy rate (5.39 ± 2.08 vs. 5.20 ± 1.88 and 22.06% vs. 16.18%, respectively).The total gonadotropins dose and medications cost per cycle were significantly lower in extended letrozole group (44.87 ± 9.16 vs. 59.97 ± 14.91 ampoules and 616.52 ± 94.97 vs. 746.84 ± 149.21 US Dollars ($), respectively).The cost-effectiveness ratio was 2794 $ in extended letrozole group and 4616 $ in short letrozole group.

CONCLUSION: Extended letrozole regimen/HPuFSH-GnRHant protocol was more cost-effective than short letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.