Novel experimental therapies for intestinal ischaemia and reperfusion injury

Intestinal ischaemia and reperfusion (I/R) contributes to the pathogenesis of numerous clinical conditions in all age groups. Many of these diseases, including neonatal necrotizing enterocolitis (NEC), result in significant morbidity and mortality through multiple organ dysfunction, and available treatment is currently limited to supporting vital functions. My aims were: to investigate novel therapeutic strategies such as moderate hypothermia and peroxynitrite decomposition catalyst FeTMPyP [5,10,15,20- tetrakis(N-methyl-4'-pyridyl)porphyrinato iron (III)] in experimental models of adult and infant intestinal I/R; and to characterise the inflammatory process in human NEC, evaluating its relationship with clinical outcome. In an adult rat model, total-body moderate hypothermia applied throughout ischaemia and reperfusion counteracts oxidative stress in both the intestine and distant organs. This suggests that hypothermia could be beneficial as a preventative measure when intestinal ischaemia can be foreseen. However, in clinical practice therapy can usually be commenced only after ischaemia has occurred. In two sets of experiments, I showed that rescue hypothermia applied after mesenteric ischaemia improves outcome in both adult and neonatal rats, and this benefit is maintained after rewarming. Hypothermic protection could result from prevention of multiple organ dysfunction through several different pathways, including modulation of hepatic phosphoenergetics, pulmonary inflammatory infiltrate, cardiac energy metabolism, and systemic oxidative stress. Administration of peroxynitrite decomposition catalyst FeTMPyP as a rescue therapy at reperfusion also exerts a protective effect in neonatal rats, possibly via inhibition of adhesion molecule expression, leukocyte recruitment, and lipid peroxidation in the intestine, leading to prevention of systemic oxidative stress. In a study conducted on human specimens from neonates with NEC, tissue injury seems to be mediated via increased expression of endothelial adhesion molecules ICAM-1 and P-Selectin, leading to macrophage and neutrophil infiltration. Endothelial E-Selectin is expressed exclusively in NEC patients, and appears to be a marker of rapidly evolving disease and distant organ failure

Morphology of the tropopause layer and lower stratosphere above a tropical cyclone : a case study on cyclone Davina (1999)

During the APE-THESEO mission in the Indian Ocean the Myasishchev Design Bureau stratospheric research aircraft M55 Geophysica performed a flight over and within the inner core region of tropical cyclone Davina. Measurements of total water, water vapour, temperature, aerosol backscattering, ozone and tracers were made and are discussed here in comparison with the averages of those quantities acquired during the campaign time frame. Temperature anomalies in the tropical tropopause layer (TTL), warmer than average in the lower part and colder than average in the upper TTL were observed. Ozone was strongly reduced compared to its average value, and thick cirrus decks were present up to the cold point, sometimes topped by a layer of very dry air. Evidence for meridional transport of trace gases in the stratosphere above the cyclone was observed and perturbed water distribution in the TTL was documented. The paper discuss possible processes of dehydration induced by the cirrus forming above the cyclone, and change in the chemical tracer and water distribution in the lower stratosphere 400–430 K due to meridional transport from the mid-latitudes and link with Davina. Moreover it compares the data prior and after the cyclone passage to discuss its actual impact on the atmospheric chemistry and thermodynamics

A cross-national investigation of cardiovascular survival in homozygous familial hypercholesterolemia: The Sino-Roman Study

Background: Homozygous familial hypercholesterolemia (hoFH) is a rare inherited disorder characterized by extreme elevation of low-density lipoprotein (LDL) cholesterol, accelerated coronary artery disease, and premature death. Aggressive LDL-lowering therapies are important for survival, but these are not available worldwide. Objective: The aim of the study was to compare and contrast cardiovascular outcomes and mortality of hoFH patients in 2 countries with disparate use of lipoprotein apheresis (LA) and modern therapies for lowering LDL cholesterol. Methods: A retrospective study was undertaken comparing cardiovascular disease (CVD)-free survival and mortality in 44 hoFH patients who were treated with statins but not LA, from a center in Beijing, China, and 18 hoFH patients who were treated with LA and novel therapies from an early age, from a center in Rome, Italy. Results: CVD-free survival and survival were significantly reduced in Chinese patients compared with the Italian patients after 30 years of follow-up (log-rank P <.01). In a pooled analysis, cardiovascular survival was significantly increased with earlier age at treatment, longer duration of treatment, and lower on-treatment LDL cholesterol concentrations (P <.05). In addition, the probability of a CVD event and death were increased in patients that carried a null mutation in the LDLR or had elevated lipoprotein(a). Conclusions: We show that coronary artery disease outcomes in patients with hoFH can be significantly improved with earlier and potent LDL cholesterol lowering with pharmacotherapies and LA. This has major implications for countries, such as China, where the models of care for hoFH remains underdeveloped

Optical coherence tomography of retinal and choroidal layers in patients with familial hypercholesterolaemia treated with lipoprotein apheresis

PURPOSE: Detect and quantify morpho-functional alterations of the retina and choroid in patients affected by familial hypercholesterolemia (FH) treated with lipoprotein apheresis (LA) using optic coherence tomography (OCT) and optic coherence tomography-angriography (OCTA). DESIGN: Observational study. SUBJECTS: To be diagnosed: A group of 20 patients (40 eyes) being clinically and genetically diagnosed as FH and under treatment (FH-Group)", for at least 2 years, was compared to a control group of 20 healthy subjects (40 eyes), with a normal lipid profile and no ocular disease (CT-Group). METHODS: Participants were studied with the slit lamp, binocular indirect fundoscopy, OCT and OCTA. MAIN OUTCOME MEASURES: Best corrected visual acuity (BVCA), spherical equivalent (SE), intraocular pressure (IOP), central macular thickness (CMT), choroidal thickness (CHT), retinal nerve fiber layer in four quadrants (RNFL (Superior = Sup; Inferior = Inf; Nasal = Nas Temporal = Temp), and the mean value across the four quadrants (RNFL G), foveal avascular zone (FAZ) and vascular density (VD). RESULTS: FH subjects had smaller RNFL superiorly (108 ± 19,38 μm OD/111 ± 16,56 μm OS FH-Group vs 127 ± 7,42 μm OD/129 ± 14,64 μm OS CT-Group; P < 0,001 for both OD and OS) and inferiorly (108 ± 23,58 μm OD/115 ± 17,33 μm OS FH-Group vs 128 ± 18,15 μm OD/133 ± 17,38 μm OS CT-Group; P = 0,002 OD; P = 0,001 OS). G RNFL was consequently smaller (93 ± 12,94 μm OD/94 ± 10,49 μm OS FH-Group vs 101 ± 9,01 μm OD/101 ± 10,20 μm OS CT-Group; P = 0,03 OD; P = 0,02 OS). FH subjects had a larger FAZ (0,31 ± 0,08 mm2 OD/0,33 ± 0,10 mm2 in OS FH-Group vs 0,21 ± 0,05 mm2 OD/0,21 ± 0,07 mm2 OS CT-Group; P < 0,001 OD; P = 0,002 OS). CONCLUSIONS: Early signs of retinal vessel damage in FH patients can be detected and quantified with OCT and OCTA

Ozone, aerosols and polar stratospheric clouds measurements during the EASOE Campaign

Preliminary results are presented of observations obtained during the EASOE campaign, with an airborne backscatter lidar and a ground-based DIAL ozone lidar system. Although the main signature observed on the lidar signals was due to the Pinatubo cloud which erupted in June 1991, distinct PSC events were detected on several occasions by the airborne lidar often in relation with orographic wave activity over the norvegian mountains. The ozone profiles obtained in Sodankyla with the ground based lidar are locally perturbed by the presence of the volcanic cloud. After a first correction of the aerosols effect, they present however a reasonably good agreement with the ozone sondes profiles performed on the same site

Ultrathin Tropical Tropopause Clouds (UTTCs) : I. Cloud morphology and occurrence

Subvisible cirrus clouds (SVCs) may contribute to dehydration close to the tropical tropopause. The higher and colder SVCs and the larger their ice crystals, the more likely they represent the last efficient point of contact of the gas phase with the ice phase and, hence, the last dehydrating step, before the air enters the stratosphere. The first simultaneous in situ and remote sensing measurements of SVCs were taken during the APE-THESEO campaign in the western Indian ocean in February/March 1999. The observed clouds, termed Ultrathin Tropical Tropopause Clouds (UTTCs), belong to the geometrically and optically thinnest large-scale clouds in the Earth´s atmosphere. Individual UTTCs may exist for many hours as an only 200--300 m thick cloud layer just a few hundred meters below the tropical cold point tropopause, covering up to 105 km2. With temperatures as low as 181 K these clouds are prime representatives for defining the water mixing ratio of air entering the lower stratosphere

Systematic stratospheric observations on the Antarctic continent at Dumont d'Urville

Results of different routine measurements performed in Dumont d'Urville (66 deg S, 140 deg E) since 1988 are presented. They include the seasonal variation of total ozone and NO2 as measured by a SAOZ UV-Visible spectrometer, Polar Stratospheric Cloud observations by a backscatter lidar and more recently, vertical ozone profiles by ECC sondes and ozone and aerosols stratospheric profiles by a DIAL lidar. The particular results of 1991 in relation with the volcanic events of Mount Pinatubo and Mount Hudson, and the position of the polar vortex over Dumont d'Urville are discussed

Assessment of the effects of different sample perfusion procedures on phase-contrast tomographic images of mouse spinal cord

Synchrotron X-ray Phase Contrast micro-Tomography (SXrPC\u3bcT) is a powerful tool in the investigation of biological tissues, including the central nervous system (CNS), and it allows to simultaneously detect the vascular and neuronal network avoiding contrast agents or destructive sample preparations. However, specific sample preparation procedures aimed to optimize the achievable contrast- and signal-to-noise ratio (CNR and SNR, respectively) are required. Here we report and discuss the effects of perfusion with two different fixative agents (ethanol and paraformaldehyde) and with a widely used contrast medium (MICROFIL\uae) on mouse spinal cord. As a main result, we found that ethanol enhances contrast at the grey/white matter interface and increases the contrast in correspondence of vascular features and fibres, thus providing an adequate spatial resolution to visualise the vascular network at the microscale. On the other hand, ethanol is known to induce tissue dehydration, likely reducing cell dimensions below the spatial resolution limit imposed by the experimental technique. Nonetheless, neurons remain well visible using either perfused paraformaldehyde or MICROFIL\uae compound, as these latter media do not affect tissues with dehydration effects. Paraformaldehyde appears as the best compromise: it is not a contrast agent, like MICROFIL\uae, but it is less invasive than ethanol and permits to visualise well both cells and blood vessels. However, a quantitative estimation of the relative grey matter volume of each sample has led us to conclude that no significant alterations in the grey matter extension compared to the white matter occur as a consequence of the perfusion procedures tested in this study

Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia

Background: Mutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). Objective: The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Methods: Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Results: Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39–114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10–165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Conclusion: Clinically meaningful LDL-C–lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH

Evolocumab and lipoprotein apheresis combination therapy may have synergic effects to reduce low-density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemia: A case report

A 49 years old woman (weight 68 kg, BMI 27.3 kg/m2 ) with heterozygous familial hypercholesterolemia (HeFH) and multiple statin intolerance with muscle aches and creatine kinase elevation, presented at the Outpatient Lipid Clinic of Verona University Hospital in May 2015. Hypercholesterolemia was firstly diagnosed during adolescence, followed in adulthood by a diagnosis of Cogan's syndrome, a rheumatologic disorder characterized by corneal and inner ear inflammation. No xanthomas, corneal arcus, or vascular bruits were detectable at physical examination. Screening for macrovascular complications did not reveal relevant damages. Ongoing medical therapy included salicylic acid, methylprednisolone, methotrexate, and protonic-pump inhibitor. In the absence of specific lipid-lowering therapy, plasma lipid levels at first visit were: total-cholesterol\u2009=\u2009522 mg/dL, LDL-cholesterol\u2009=\u2009434 mg/dL, HDL-cholesterol\u2009=\u200984 mg/dL, triglycerides\u2009=\u2009120 mg/dL, Lp(a)\u2009=\u200913 mg/dL. On December 2015, evolocumab 140 mg sc every 2 weeks was initiated. After a 24-week treatment, the LDL-cholesterol levels decreased by an average of 21.2% to 342\u2009\ub1\u200922 mg/dL (mean\u2009\ub1\u2009SD). On May 2016, LDL-apheresis (H.E.L.P.system) was started as add-on therapy. Compared to the average levels obtained during the evolocumab monotherapy period, the LDL-cholesterol was reduced by 49.4%, thus reaching an inter-apheresis level (mean\u2009\ub1\u2009SD) of 173\u2009\ub1\u200937 mg/dL. This report suggests that a combination therapy with evolocumab and lipoprotein-apheresis may have synergic effects on circulating lipid levels. Its relevance as a highly effective treatment option for hyperlipidemia in HeFH patients warrants further investigation in larger datasets