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Evidence suggests that patients with obstructive sleep apnea (OSA) are at increased risk of suffering from periodontitis, a chronic inflammatory disease of the tooth-supporting tissues associated with a dysbiotic oral microbiota. This systematic review aims to explore the current literature about the composition of the oral microbiota in patients with OSA compared to those without OSA.Medline, Embase, and Cochrane Library were searched in May 2022 to identify original articles investigating the oral microbiota composition and/or oral microbiome (any microbiological technique) of patients with OSA (adults or children) vs. controls. Case report, reviews, and animal studies were excluded.Of over 279 articles initially identified, 8 were selected, of which 3 dealt with pediatric patients. Overall, 344 patients with OSA and 131 controls were included. Five studies used salivary samples, 2 oral mucosal swabs, and 1 subgingival plaque sample. With different methods to characterize oral microbiota, 6/8 studies observed significant differences between patients with OSA patients and controls in the composition and relative abundance of several bacteria species/genera linked to periodontitis.Within the limitations of the available literature, the present systematic review indicates that OSA and related conditions (e.g., mouth breathing) are associated with different oral microbiota compositions, which may underlie the association between OSA and periodontitis.

In the recent years, robotic technology has been drastically improved and the last generation of robotic platforms is hardly comparable with the earlier ones. The present study aims to investigate the short-term outcomes of minor hepatectomies performed with da Vinci Xi surgical system vs. Si surgical systems.Consecutive patients operated on between 2013 and 2020 in two referral centers were selected if underwent elective robotic minor hepatectomy (3 consecutive segments) for primarily resectable benign or malignant lesions. Operative, postoperative, and cost outcomes were compared between the two groups by univariate and multivariate analyses.Eighty-nine patients were selected (64 in the Si system vs. 25 in the Xi system group). Wedge resection was the most commonly performed procedure (49.4%). The Si system group showed a significantly greater total incisional length (+8.99 mm; p0.0001) related to the use of a higher number of robotic/laparoscopic ports. Pedicle clamping was more frequent in patients operated on by the Xi system (80% vs. 21.9%; p0.0001) but without group differences in ischemia duration when clamping. A significantly shorter time to flatus (-0.75 days; p=0.015) was observed for patients operated on by the Xi system, whereas no group differences were found for operative time, conversion rate, estimated blood loss, postoperative complications, mortality, use of analgesics, and costs.The da Vinci Xi system represents a technological advancement with a potential clinical relevance, although further studies are needed to clearly detect the clinical impact of the use of this robotic platform in liver surgery.

Background: Anastomotic leakage (AL) is one of the dreaded complications following surgery in the digestive tract. Near-infrared fluorescence (NIRF) imaging is a means to intraoperatively visualize anastomotic perfusion, facilitating fluorescence image-guided surgery (FIGS) with the purpose to reduce the incidence of AL. The aim of this study was to analyze the current practices and results of NIRF imaging of the anastomosis in digestive tract surgery through the EURO-FIGS registry. Methods: Analysis of data prospectively collected by the registry members provided patient and procedural data along with the ICG dose, timing, and consequences of NIRF imaging. Among the included upper-GI, colorectal, and bariatric surgeries, subgroup analysis was performed to identify risk factors associated with complications. Results: A total of 1240 patients were included in the study. The included patients, 74.8% of whom were operated on for cancer, originated from 8 European countries and 30 hospitals. A total of 54 surgeons performed the procedures. In 83.8% of cases, a pre-anastomotic ICG dose was administered, and in 60.1% of cases, a post-anastomotic ICG dose was administered. A significant difference (p < 0.001) was found in the ICG dose given in the four pathology groups registered (range: 0.013–0.89mg/kg) and a significant (p < 0.001) negative correlation was found between the ICG dose and BMI. In 27.3% of the procedures, the choice of the anastomotic level was guided by means of NIRF imaging which means that in these cases NIRF imaging changed the level of anastomosis which was first decided based on visual findings in conventional white light imaging. In 98.7% of the procedures, the use of ICG partly or strongly provided a sense of confidence about the anastomosis. A total of 133 complications occurred, without any statistical significance in the incidence of complications in the anastomoses, whether they were ICG-guided or not. Conclusion: The EURO-FIGS registry provides an insight into the current clinical practice across Europe with respect to NIRF imaging of anastomotic perfusion during digestive tract surgery.

Purpose In colorectal cancer (CRC), lymphovascular invasion (LVI) is a predictor of poor outcome and its analysis is nowadays recommended. Literature is still extremely heterogeneous, and we hypothesize that, within such a group of patients, there are any further predictors of survival. Methods A total of 2652 patients with I–III-stage CRC undergoing resection between 2002 and 2018 were included in a retrospective analysis of demographic, clinical, and histology with the aim of defining the impact of LVI on overall survival (OS) and its relationship with other prognostic factors. Results Overall, 5-year-OS was 62.6% (77-month-median survival). LVI was found in 558 (21%) specimens and resulted associated with 44.9%-5-year-OS (44 months) vs. 64.1% (104 months) of LVI cases. At multivariate analysis, LVI (p = 0.009), T3–4 (p p p p p p p p p Within the LVI + patients, T3–4 (p = 0.009) and N ≠ 0 (p p = 0.020), whereas it did not impact the prognosis of patients with T1–2 tumors (p = 0.393). Three groups (T1–2anyN, T3–4N0, T3–4 N ≠ 0), with distinct outcome (approximately 70%-, 52%-, and 35%-5-year-OS, respectively), were identified. Conclusions LVI is associated with more aggressive/more advanced CRC and is confirmed as predictor of poor outcome. By using T- and N-stage, a simple algorithm may easily allow re-assessing the expected survival of patients with LVI + tumors.

Gastrointestinal (GI) cancers often require a multidisciplinary approach involving surgeons, endoscopists, oncologists, and interventional radiologists to diagnose and treat primitive cancers, metastases, and related complications. In this context, interventional radiology (IR) represents a useful minimally-invasive tool allowing to reach lesions that are not easily approachable with other techniques. In the last years, through the development of new devices, IR has become increasingly relevant in the context of a more comprehensive management of the oncologic patient. Arterial embolization, ablative techniques, and gene therapy represent useful and innovative IR tools in GI cancer treatment. Moreover, IR can be useful for the management of GI cancer-related complications, such as bleeding, abscesses, GI obstructions, and neurological pain. The aim of this study is to show the principal IR techniques for the diagnosis and treatment of GI cancers and related complications, as well as to describe the future perspectives of IR in this oncologic field.

International audience; Background: Short and long-term outcomes after repeat anti-reflux surgery (RARS) are still debated and generally not considered as satisfying as after primary anti-reflux surgery (PARS). The aim of this study was to evaluate functional outcomes after RARS and risk factors associated to intra-operative and post-operative complications.Methods: This is a multicenter retrospective survey from four European laparoscopic centers. Patients who underwent elective RARS from January 2005 to October 2017 for dysphagia or for persistent reflux disease refractory to medical treatment were analyzed. Data on demographic characteristics, including type and timing of previous operations as well as intra-operative details (surgical technique, type of RARS, conversion to open surgery, prosthetic material placement) were collected. Patients who underwent operations in the emergency setting, interventions mixed with bariatric procedures and PARS performed in other surgical departments were not included in this study. Primary endpoint of this study was to evaluate risk factors associated with intraoperative and postoperative complications. Secondary endpoint was to evaluate clinical outcomes and to identify any possible correlation with clinical and surgical parameters.Results: Among 1662 patients who underwent PARS, failure occurred in 174 (10.5%) patients. Repeat surgery was performed in 117 (7%) patients, after a mean time of 80 months (range 4-315). RARS was carried out laparoscopically in 88% of cases. Prosthetic mesh to reinforce hiatoplasty was used in 22.2% of patients. Intra-operative upper gastro-intestinal tract's injuries occurred in 6 (5.1%) patients. Perioperative mortality was nil and 13 (11.1%) patients experienced postoperative complications. Mean length of hospital stay was 9.6 ± 6.4 days. Based on a multivariable analysis, age >70 years (OR 1.074, C.I.95% 1.018-1.133, p = 0.008) and body mass index (BMI) < 23 (OR 0.172, C.I.95% 0.052-0.568, p = 0.004) were independently associated to postoperative complications. After a mean follow-up time of 36 months (range 6-107), 24 (20.5%) patients presented recurrent symptoms. Based on a multivariable analysis, early onset of dysphagia (OR 3.539, C.I.95% 1.254-9.990, p = 0.017), open approach (OR 4.505, C.I.95% 1.314-15.442, p = 0.016) and the use of prosthetic material (OR 2.790, C.I.95% 0.930-8.776, p = 0.047) were significantly associated to good clinical outcomes.Conclusions: Repeat anti-reflux surgery is a safe and feasible procedure in high-volume centers, with acceptable perioperative outcomes. Long-term results are favorable with a success rate of almost 80%. Advanced age (>70 years) and low BMI (

Iatrogenic colonoscopy perforation (ICP) is a severe complication that can occur during both diagnostic and therapeutic procedures. Although 45–60% of ICPs are diagnosed by the endoscopist while performing the colonoscopy, many ICPs are not immediately recognized but are instead suspected on the basis of clinical signs and symptoms that occur after the endoscopic procedure. There are three main therapeutic options for ICPs: endoscopic repair, conservative therapy, and surgery. The therapeutic approach must vary based on the setting of the diagnosis (intra- or post-colonoscopy), the type of ICP, the characteristics and general status of the patient, the operator’s level of experience, and surgical device availability. Although ICPs have been the focus of numerous publications, no guidelines have been created to standardize the management of ICPs. The aim of this article is to present the World Society of Emergency Surgery (WSES) guidelines for the management of ICP, which are intended to be used as a tool to promote global standards of care in case of ICP. These guidelines are not meant to substitute providers’ clinical judgment for individual patients, and they may need to be modified based on the medical team’s level of experience and the availability of local resources.

// Nicola de’Angelis 1 , Frederic Pigneur 2 , Aleix Martinez-Perez 3 , Giulio Cesare Vitali 4 , Filippo Landi 5 , Teresa Torres-Sanchez 3 , Victor Rodrigues 5 , Riccardo Memeo 1 , Giorgio Bianchi 1 , Francesco Brunetti 1 , Eloy Espin 5 , Frederic Ris 4 and Alain Luciani 2 , on behalf of the EuMaRCS Study Group 1 Unit of Digestive, Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, AP-HP, University of Paris Est, UPEC, Creteil, France 2 Department of Radiology, Henri Mondor Hospital, AP-HP, University of Paris Est, UPEC, Creteil, France 3 Unit of Colorectal Surgery, Department of General and Digestive Surgery, Hospital Universitario Doctor Peset, Valencia, Spain 4 Service of Abdominal Surgery, Geneva University Hospitals and Medical School, Geneva, Switzerland 5 Unit of Colorectal Surgery, Department of General and Digestive Surgery, Hospital Universitario Vall d’Hebron, Barcelona, Spain Correspondence to: Nicola de’Angelis, email: nic.deangelis@yahoo.it Keywords: rectal cancer; laparoscopic surgery; total mesorectal excision; magnetic resonance imaging; pelvimetry Received: March 24, 2018 Accepted: April 28, 2018 Published: May 18, 2018 ABSTRACT Background: Locally advanced rectal cancer (LARC) requires a multimodal therapy tailored to the patient and tumor characteristics. Pretreatment magnetic resonance imaging (MRI) is necessary to stage the primary tumor, while restaging MRI, which is not systematically performed, may be of interest to identify poor responders to neoadjuvant chemoradiation therapy (NCRT), and redefine therapeutic approach. The EuMaRCS study group aimed to investigate the role and accuracy of pretreatment (including pelvimetry) and restaging MRIs in predicting surgical difficulties and surgical outcomes in LARC therapy. Methods: Patients with mid or low LARC who were administered NCRT, who underwent laparoscopic total mesorectal excision, and for whom pretreatment and restaging MRIs were available, were included. Results: MRIs of 170 patients (median age: 61 years) were reanalyzed by the same radiologist. Pelvimetry differed significantly between males and females, but no gender difference was noted in the clinical and tumor characteristics. Tumor volume and tumor height assessed on the restaging MRI were associated, respectively, with operative time and estimated blood loss. Conversion was predicted by tumor volume, interischial distance and pubic tubercle height. The quality of the surgical resection was found to be a predictor of overall and disease-free survival. The sensitivity and specificity of tumor regression grade 1 to identify a pathologic complete response were 76.9% and 89.3%, respectively. Conclusions: In LARC management, pelvimetry and restaging MRI may be useful to predict surgical difficulties and surgical outcomes. However, the main independent predictor of patient survival appears to be the achievement of a successful surgical resection.

INTRODUCTION In the last decades, the use of minimally invasive surgery has dramatically increased for the treatment of rectal cancer. However, no clear evidence exists on the role of laparoscopy for locally advanced rectal cancer, especially for cT4 tumors, after neoadjuvant therapy. EVIDENCE ACQUISITION A literature search was performed on Embase, Medline, and Cochrane databases to identify relevant studies published up to November 2017 analyzing the outcomes of laparoscopic surgery for locally advanced rectal cancer. EVIDENCE SYNTHESIS Systematic reviews and meta-analyses showed that laparoscopic proctectomy is associated with faster recovery compared to open approach while oncologic and survival outcomes are equivalent. However, concerns still exist on the quality of laparoscopic mesorectal excision. In the majority of the available studies, cT4 tumors were not included, but based on few retrospective series in tertiary referral centers laparoscopic rectal resection of T4 rectal cancer appeared to be safe and feasible, with faster recovery and adequate oncologic outcomes. Robotics and transanal approaches are promising minimally invasive alternatives. CONCLUSIONS Locally advanced rectal cancers require multidisciplinary management including neoadjuvant chemo-radiotherapy and surgery. Preoperative re-staging may be useful to plan the best surgical procedure. Minimally invasive surgery, especially laparoscopy, can provide adequate outcomes in selected patients with locally advanced rectal cancer with the advantage of faster recovery compared to open surgery. However, the overall evidence is poor, and further studies are needed to elucidate the role of minimally invasive surgery for cT4 rectal cancer.

Background: More evidence is needed to assess the pros and cons of maintaining age-limit policies in heart transplantation (HT). Methods: We analyzed clinical data from a heart failure management unit to investigate the impact of age on prognosis of two distinct cohorts: (i) 309 patients (median age, 57 yr; 62% male) with severe chronic heart failure (CHF) consecutively screened for HT; (ii) 336 HT recipients (median age 56 yr, 82% male). Results: In CHF patients (screened for HT), prognosis was conditioned by the underlying severity of cardiac disease (i.e., New York Heart Association class III–IV, decreasing blood pressure, presence of atrial fibrillation and severe mitral regurgitation), whereas increasing age showed no sign of predicting all-cause or cardiovascular mortality (both p ≥ 0.4). In HT recipients, age did not retain significance at multivariate analysis as an independent predictor (p ≥ 0.14 for both all-cause and cardiovascular death), whereas ischemic etiology of pre-existing CHF did (p ≤ 0.02). Conclusions: Age did not appear to be a primary determinant of all-cause or cardiovascular mortality among potential HT candidates or eventual recipients (ischemic etiology of CHF turned out to be the major determinant of post-transplant outcome). These results support the concept that HT may be considered a treatment option in patients with more advanced age strata, particularly when affected by non-ischemic cardiomyopathy.

The use of grain-size distribution of muds for the reconstruction of past deep ocean currents is becoming established and applied in the palaeoceanographic community. The methods are also applicable to shallow marine and tidal flat muds with similar inferences concerning the energy of wave and current sorting being drawn. Fine sediment grain-size distributions can be obtained using a variety of instruments based on fundamentally different theoretical principles. These machines may give varying, sometimes misleading, results giving divergent interpretations of flow speed history. The new evidence presented here, combined with earlier work, suggests that of the three most commonly used analytical methods for fine silts with clays, settling velocity (Sedigraph) should be the method and instrument of choice, with electrical resistance pulse counters (e.g. Coulter Counter) as a suitable alternative. The data also show that laser particle sizers should be avoided for palaeocurrent reconstructions because the measured size of platey minerals can be dominated by their large projected area. This causes them to be recorded as the same size as larger equant grains although they have much smaller settling velocity and were deposited in aggregates. This produces results with a weaker relationship to the dynamics of deposition. The central problem is thus that some coarse clay/fine silt is recorded as medium to coarse silt, the key size in the ‘sortable silt’ mean size method of inferring changes in flow speed. For coarse silts (e.g. loess) the laser gives more satisfactory results.

Acrylonitrile is a very high volume industrial chemical used primarily in the manufacture of plastics and rubber, which displays a pronounced acute toxicity and may be carcinogenic. The damage to the hematopoietic function by acrylonitrile may result from interference with cytokine production and cytokine receptor binding. Our present data show that acrylonitrile modulates the expression of some genes implicated in cell differentiation, cell-cycle progression, and clonogenic potential of human cord blood cells. A macroarray hybridization analysis showed that expression of the CXCR4, MCP-1, and MRP8 genes was modified by acrylonitrile exposure. Moreover, the acrylonitrile cell target seems to be the myeloid compartment, as assessed by a CFU-GM assay. In particular, the downregulation of CXCR4, MCP1, and MRP8 can be responsible for the observed reduction of cell proliferation and clonogenic capability of CFU-GM precursors. A Western blot assay showed an acrylonitrile-dependent induction of Bax, while Bcl-2 expression changed only after 48 h of chemical exposure. Bax was overexpressed in respect to Bcl-2, and this fact can be responsible for the induction in cell death after 24 h of treatment. C-fos and c-jun were also downregulated after 24 h and 6 h of treatment, respectively. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:204–212, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20090

Styrene is one of the most important monomers produced worldwide, and it finds major use in the production of polystyrene, acrylonitrile-butadiene-styrene resins and unsaturated polystyrene resins. Epidemiological studies on styrene showed that the malignancies observed most frequently in humans after exposure are related to the lymphatic and haemopoietic system. IARC classified styrene a possible carcinogenic to humans (Group 2B). In this study, we evaluated the effect of styrene on gene expression profiles of human cord blood cells, as well as its activity on the apoptosis and bcl-2 related protein expression. Data demonstrated that, after 24 and 48 h of exposure, styrene (800 microM) induced an increase in the necrosis of mononuclear cord blood cells, whereas it did not cause any increase in the apoptotic process. Western blot analysis revealed a modified expression of Bax, BCl-2, c-Jun, c-Fos and Raf-1 proteins in the human cord blood cells after direct exposure to styrene, whereas p53 expression did not change. Furthermore, Macroarray analysis showed that styrene changed cord blood gene expression, inducing up-regulation of monocyte chemotactic protein 1 (MCP-1), and down-regulation of CC chemokine receptor type 1 (CCR-1) and SLP-76 tyrosine-phosphoprotein.

The stability of the Earth's climate is strongly linked to the steadiness of the atmospheric and oceanic transport of heat from low to high latitudes. High resolution Holocene sedimentary records from the subpolar North Atlantic demonstrate a persistent link between centennial to millennial scale fluctuations in the flow speed of Iceland-Scotland Overflow Water inferred from granulometric proxy data and both the surface North Atlantic Current component of the meridional overturning circulation (MOC) and published Fennoscandian atmospheric temperature variability. However, these data also highlight the difficulties associated with the interpretation of geochemical and sedimentological deep water circulation proxies as they do not provide a wholly consistent picture. The similarity between surface and deep ocean δ13C records suggests a preformed component in the deep ocean δ13C signal. On the other hand, the sedimentological results display a strong linkage to changing conditions in the overlying surface ocean waters, suggesting this proxy better reflects the activity of the MOC at least during the Holocene of this region. The most widespread oceanic perturbation coincides with an interval of possibly global climatic deterioration around 2700 years ago. These results firmly establish deep water production in the Nordic Seas as a key component in the assortment of variables affecting climate during the Holocene.

The karite (Vitellaria paradoxa Gaertner) is an economically important African tree with significant but little studied variation across its broad distribution range. Differences in economically important fat characteristics were determined for 42 karite populations in 11 countries. The results showed very high variability in all measured parameters both within and between populations. Kernel fat content range is generally 20–50%. Fatty acid composition is dominated by stearic (25–50%) and oleic (37–62%) acids. The variable relative proportions of these two fatty acids produces major differences in karite butter consistency across the species distribution range. The principal triglycerides are stearic-oleic-stearic (13–46%) and stearic-oleic-oleic (16–31%). Ugandan karite fat is liquid and requires fractionation to obtain a butter. West African karite butter is more variable, with soft and hard consistencies produced within the same local populations. The hardest butters are produced on the Mossi Plateau in Burkina Faso and northern Ghana. The implications of distinctive population characteristics as germplasm resources for the chocolate and cosmetic industries are discussed.

The olive fruit is essentially constituted by the epicarp, or skin, mesocarp, or pulp, and the endocarp, or stone, and the latter includes the seed. Table olives (also called eating olives) are prepared from healthy, specifically cultivated, olive varieties picked at the right maturation stage and whose quality, after appropriate processing, corresponds to that of an edible well preserved product. The most important industrial preparations of table olives are the Spanish (or Sevillian) for green olives, the Californian for oxidised black olives, and the Greek for naturally black olives. In the Spanish and Californian procedures, olives are treated with a diluted aqueous NaOH solution, that brings about several changes in the susceptible classes of compounds in the fruit. Note, however, that the composition of the triglycerides remain unaffected by these procedures. After the treatment the olives are rinsed to remove the alkali, and the fruit is then left to ferment in brine for several months. The production of naturally black olives in brine, according to the Greek traditional method, is a simple, natural process which does not use chemicals. The main phenols in the olive are oleuropein, hydroxytyrosol (β(3-4-dihydroxyphenyl)ethanol), tyrosol (β(4-hydroxyphenyl) ethanol) and verbascoside; the major polycyclic triterpenes are the oleanolic and maslinic acids. The NaOH treatment hydrolysed oleuropein into β(3-4-dihydroxyphenyl) ethanol, oleoside 11-methylester and oleoside. These last glucosides and the oleuropein itself, in acidic medium, yielded glucose and a number of compounds called, collectively, oleuropein aglycones. During the fermentation process phenols diffuse from the pulp into the brine. Also, even during the alkaline treatment, there is the rapid diffusion of the pentacyclic oleanolic and maslinic acids salts into the brine.

In this study, the effect of naphthalene on the induction of apoptosis and gene expression profiles in cord blood cells has been evaluated, as well as its activity on the BCL-2 related protein expression. After 6, 24, and 48 h of exposure to naphthalene (500 μM), a decrease in cell death was observed: the cells became more resistant to the toxicant and capable of surviving after the treatment. A Western blot analysis revealed an overexpression of BCL-2, c-JUN, c-FOS, and RAF-1 proteins, which are involved in the antiapoptotic response and in the regulation of cell growth, differentiation, and development. Furthermore, macroarray analysis showed that naphthalene modified cord blood gene expression, inducing IL-8 precursor and T-cell transcription factor and decreasing the level of RNA-binding protein FUS/TLS. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:286–294, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10091

This research work was conducted to establish whether monovarietal olive oils could be differentiated by their basic classes of compounds, ie (a) fatty acids, (b) fatty alcohols, (c) polycyclic triterpenes and (d) squalene. The ratio values of biosynthetically correlated acids were also examined. The mentioned classes of compounds, formed in distinct biosynthetic compartments of the olive fruit, should represent characteristic compositional data of an olive cultivar. The widely cultivated Italian olive cultivars studied were Frantoio, Bosana, Dritta and Leccino. Principal component analysis (PCA) was applied to the analytical data to reveal the compounds (variables) with the highest weights (loadings), with the aim of using them in subsequent computations. These variables were tetracosanol, hexacosanol Δ5-avenasterol, cycloartenol, 24-methylencycloartenol, oleic, linoleic, linolenic, stearic and palmitoleic acids and the ratios palmitic/stearic, palmitic/palmitoleic and linoleic/linolenic. Linear discriminant analysis (LDA), carried out on a training set of 57 oils (13 Dritta, 25 Leccino, 12 Frantoio and seven Bosana) produced a 96% correct group classification. The prediction LDA model created with the training set was validated with a test set of 19 oil samples (six Dritta, seven Leccino, four Frantoio and two Bosana), permitting accurate classification of all the ‘unknown’ olive oils. Copyright © 2003 Society of Chemical Industry

Radiolytically generated phenoxyl radicals derived from the structurally similar phenols cresol, tyrosine, tyramine and tyrosol were reacted with O2˙− [k = (1–4.5) × 109 dm3 mol−1 s−1, by pulse radiolysis] and the consumption of the phenol determined. Although the reduction potentials of these phenoxyl radicals are very close, ranging between +0.64 and +0.68 V, the yields of phenol consumption vary considerably [between 8% (tyrosol) and 90% (tyrosine)]. This indicates that electron transfer with restitution of the phenol does not necessarily occur to a major extent, although this reaction is thermodynamically favoured (reduction potential of O2˙−, −0.33 V). The reactivity of phenoxyl radicals from phenols that are structurally different from the above has also been studied. In the case of the reaction of O2˙− with 2,4,6-trimethylphenoxyl, hydroperoxides are formed which revert to the phenol by eliminating dioxygen (perhaps in the singlet state) in a slow reaction on a time-scale of many minutes. The rate of this reaction increases with increasing pH and increasing temperature. From these data it is calculated that the hydroperoxides from 2,4,6-trimethylphenol have a pKa of 11.3 and that the reaction requires an activation energy of 105 kJ mol−1 (frequency factor, 3.5 × 1014 s−1). In competition with the elimination of dioxygen, depending on the presence of suitable substituents, such hydroperoxides can undergo other reactions. In the case of tyrosine, there is a cyclization reaction followed by the elimination of hydrogen peroxide. Phenoxyl radicals that carry hydrogen in the ortho or para-position (e.g. such as those derived from 4-methylphenol, 2,6-dimethylphenol or 2-methoxy-4-methylphenol) give rise to hydroperoxides which can eliminate water to produce the corresponding quinones. These subsequently suffer stepwise reduction by O2˙− to the corresponding catechols or hydroquinones.

A series of asymmetric 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates characterized by the presence of a 3,3-diphenyl-propylamino moiety in one of the ester groups were synthesized. They exhibited remarkable antihypertensive activity in spontaneously hypertensive rats as well as affinity for the 1,4-dihydropyridines binding site labelled by 3 H -nitrendipine in the calcium channel. Introduction of this bulky and lipophilic amine confers to the whole series an elevated level of antihypertensive activity and a long duration of action, a structure-dependent modulation of the activity being found only in the subset characterized by the presence of a branched propylene bridge between the ester and the amino groups. The presence of the amino group is essential for oral activity. Out of this series, compound 9u (Rec 15/2375-lercanidipine) was selected for clinical development and obtained marketing authorization as an antihypertensive in several countries.

Copyright (c) 1997 Elsevier Science B.V. All rights reserved. There is strong evidence that consumption of olive oil, especially extra virgin olive oil, reduces the risk of circulatory system diseases. Such oil is generally more expensive than other edible oils, Italian - and in particular Tuscan - oils being particularly favoured by connoisseurs, and commanding an even higher price. There is therefore a great temptation to adulterate olive oil with a cheaper oil, or falsify its origin or grade. An easy and reliable method to identify different types of olive oil is required. Our work has focused on discriminating extra virgin olive oils by their region and variety. We have applied Principal Components Analysis (PCA), Principal Components Regression (PCR) and Partial Least Squares (PLS) to discriminate olive oils on the basis of their 13 C NMR spectra. Variable Selection was used in order to reduce the number of variables in the data. Two main methods of variable selection have been used; these are the Fisher Ratio, and the ratio of Inner Variance to Outer Variance or Characteristicity [W. Eshuis, P.G. Kistemaker and H.L.C. Meuzelaar, in C.E.R. Jones and C.A. Cramers (Eds.), Analytical Pyrolysis, Elsevier, Amsterdam, 1977, pp. 151-156.]. Both these methods proved successful in improving the PCA clustering, and the prediction results of PCR and PLS, although the optimal number of variables varied between datasets. PCR2 and PLS2 models, in which a single model is used to predict each variety or each region simultaneously, achieved a successful prediction rate of some 70%. However, multiple PLS1 models routinely achieved successful predictions of over 90% and in many cases 100% of the data in test sets. Indeed the variety of all but 1 of 66 samples was correctly predicted. It is clear that multiple, specialised models perform much better than global ones, and that the inclusion of certain variables can be highly detrimental to the multivariate calibration process.

In this work free phenolics and phenolic glucosides present in the water content (vegetation water, VW) of olive fruits of the three Italian cultivars (cvs.) Cipressino, Dritta, and Leccino were identified by 1H NMR. The phenolic metabolite content of the three cultivars was studied at three fruit growth stages. The major phenolic compounds, common to all three cultivars, were 4-hydroxyphenylethanol (tyrosol) (1), 4-hydroxyphenylethanol glucoside (2), and oleuropein (3). Considerable differences in the content of compounds (1−3) were found to occur in the fruits during growth and maturation of the drupe. Glucoside (4), a major component of the low molecular weight solutes of Dritta and Leccino cvs., was not detected in Cipressino fruits. The quinol glucoside (4) was thought to derive from oxidation of the glucoside of 4-hydroxyphenylethanol (2). Hydrolysis of (4) followed by cyclization yielded the bicyclic compound halleridone (5). Keywords: Olea europaea; Oleaceae; 1H NMR; free and conjugated phenolics;...

e22056 Background: Cell-free tumor DNA (cftDNA) is released into the circulation and its recovery from plasma is a non-invasive alternative to tumor biopsy for applications related to molecular profiling. A potential use in therapeutic interventions is the periodic monitoring of cftDNA for the identification of molecular changes associated with resistance to target-specific treatments or when the mutational status in tumor tissue is not available. Methods: Samples (6 ml) of peripheral blood were drawn from patients with colorectal (CRC, n= 19) and thyroid (n= 1) cancers and melanoma (n= 8). CRC tumors were KRAS wild-type (n= 3) or carried the BRAF V600E (n= 6), KRAS G12D (n= 9) and G12V (n= 4) mutations. All melanomas and the thyroid cancer carried the BRAF V600E mutation. DNA was extracted from plasma with QIAamp Circulating Nucleic Acid Kit to recover DNA fragments of ≤1000 bp. PCR amplification was carried out with a QX100 ddPCR System (Bio-Rad) on 20 μL-samples containing cftDNA and TaqMan probes for BRAF V600E (1799T>A), KRAS G12D (35G>A) and G12V (35G>T) labeled with FAM/VIC. Samples were then loaded into a droplet reader, which discriminates the difference in fluorescence amplitudes on the basis of target gene amplification. Results: The concordance between mutations in tumors (T) and plasma (P) for BRAF V600E was: melanomas 8 T vs. 6 P; thyroid cancer 1 T vs. 0 P; CRC 6 T vs 3 P. Concerning KRAS in CRC the results were: G12D 9 T vs. 7 P, G12V 4 T vs. 0 P. Overall, the percentage of concordant samples were: V600E 60%, G12D 77,8%, G12V 0%. Interestingly, in 2 patients with wild-type KRAS tumor, the G12D and G12V mutations were found in plasma. Conclusions: ddPCR is a third-generation PCR technique for highly sensitive detection of DNA fragments. Detection of mutations in cftDNA by advanced technological platforms has important applications in the monitoring of patients for the occurrence of secondary mutations, amplifications and expansion of cell clones that render their tumors resistant to target-specific anticancer agents, unraveling the resistant phenotype before the clinical progression of the disease. Acknowledgments: this study was funded in part by MIUR/PRIN 2011-2012 (Rome, Italy).

Analysis of the NMR shifts of unsaturated carbon in monounsaturated linear long-chain esters, alcohols and acids, including data from jojoba oil, shows a highly linear dependence of the logarithm of the shift separation in the CC bond upon the number of bonds separating this from the ester moiety. Both the linearity of this dependence, and the observation that it does not change sign upon reversal of the ester grouping, rule out the ‘electric field effect’ as an explanation, but are semi-quantitatively consistent with a remarkably simple, ‘σ-inductive’ through-bond mechanism. Semi-empirical MO calculations support this conclusion. The attenuation factor is 1.75 per saturated C–C bond in each class of compound, although the actual shift separations, for a given chain length, vary up to twofold with changes in the polarizing group and with (Z)–(E) isomerism at the CC bond. Other series of compounds show the same attenuation factor.

The major objective of this study was to determine the chemical structure of long-chain esters present in lower-grade olive oil. The classes of esters composing the hexanediethyl ether (99∶1) extract of the wax fraction from a pomace olive oil were: (i) esters of oleic acid with C1−C6 alcohols, (ii) esters of oleic acid with long-chain aliphatic alcohols in the range C22−C28 and (iii) benzyl alcohol esters of the very long-chain saturated fatty acids C26 and C28. The analysis and the structure assignments were carried out by gas chromatography coupled with mass spectrometry and by comparison with synthetic authentic model compounds. This work provided precise data on the chemical nature of the wax esters present in olive oil and should represent a means to detect adulteration of higher-grade olive oil with less expensive pomace olive oil and seed oils.

Background: Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. Methods: Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C0: 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C0: 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. Results: Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms. Conclusions: Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.

To understand mechanisms of osmoprotection, the composition of sugars and related compounds were analyzed in extracts of fully hydrated and desiccated leaves of the desiccation-tolerant resurrection plant Myrothamnus flabellifolia. During the dehydration process the concentrations of fructose and glucose decrease, whereas sucrose, arbutin and glucopyranosyl-β-glycerol increase. The substances were identified by GC-MS and NMR-analyses. This is the first report of large amounts of glucopyranosyl-β-glycerol in higher plants which may act as an osmoprotectant. Significant levels of the nonreducing sugar trehalose were present in all samples tested.

Curie-point pyrolysis mass spectra were obtained from a variety of extra-virgin olive oils, prepared from various cultivars using several mechanical treatments. Some of the oils were adulterated (according to a double-blind protocol) with different amounts of seed oils (50-500 ml of soya, sunflower, peanut, corn or rectified olive oils per litre of mixed oil). Canonical variates analysis indicated that the major source of variation between the pyrolysis mass spectra was due to differences between the cultivars. rather than whether the oils had been adulterated. However, artificial neural networks could be trained (using the back-propagation algorithm) successfully to distinguish virgin oils from those which had been adulterated.

A series of asymmetric 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates characterized by the presence of a 3,3-diphenyl-propylamino moiety in one of the ester groups were synthesized. They exhibited remarkable antihypertensive activity in spontaneously hypertensive rats as well as affinity for the 1,4-dihydropyridines binding site labelled by 3 H -nitrendipine in the calcium channel. Introduction of this bulky and lipophilic amine confers to the whole series an elevated level of antihypertensive activity and a long duration of action, a structure-dependent modulation of the activity being found only in the subset characterized by the presence of a branched propylene bridge between the ester and the amino groups. The presence of the amino group is essential for oral activity. Out of this series, compound 9u (Rec 15/2375-lercanidipine) was selected for clinical development and obtained marketing authorization as an antihypertensive in several countries.

The main components of the chloroform-soluble epicuticular waxes from olive tree leaves (Olea europaea cvs Coratina and Cipressino), were triterpene oleanolic and betulinic acids and triterpenols sitosterol, α- and β-amyrin, uvaol and erythrodiol. The waxes of both cultivars contain the ubiquitous wax classes of alkanes, alcohols, aldehydes, fatty acids and alkyl esters. Methyl phenyl esters and 2-phenyl-ethanol-1-esters were both present in low amounts in cv. Coratina whilst cv. Cipressino contained only the former class of compounds. Furthermore cv. Coratina contained triacylglycerols that were missing in cv. Cipressino wax.

The chloroform-soluble waxes of green and black olive fruits ( Olea europaea cv Coratina) contain alkanes (C 23 –C 33 ), saturated and unsaturated alkyl esters (C 38 –C 56 ), aldehydes (C 24 –C 30 ), methyl phenyl esters, triacylglycerols, alcohols (C 22 –C 28 ), fatty acids (C 16 –C 28 ), and pentacyclic triterpenols and triterpenoid acids. Oleanolic acid and triacylglycerols are the major components. Uvaol and erythrodiol, present in substantial amount in wax from green olives, were present only in trace amounts in that from black olives.

Craterostigma plantagineum, a resurrection plant, displays extreme desiccation tolerance; dehydrated leaves and ABA-treated calli resume a normal metabolic state upon rehydration. Samples of calli and leaves of C. plantagineum were analysed for the major classes of compounds such as sugars, fatty acids, amino acids and derivatives, and phytosterols. Calli solutes are characterized by large amounts of glutamine and tyramine, triterpene acids and colneleic acid, an inhibitor of lipoxygenase. Among the sugars extracted from calli, sucrose, together with its hydrolytic products, predominates, while maslinic, ursolic and oleanolic acids are the most important triterpenes. In leaves the most common triterpene alcohols were campesterol, stigmasterol and β-sitosterol. Almost 50% of the weight of the lyophilized material consisted of 2-octulose, a sugar present as a minor component in a limited spectrum of plant species. Acquisition of desiccation tolerance in ABA-treated and desiccated calli was accompanied by an increase of fatty acids, accumulation of colneleic acid and by the disappearance of glucose and fructose. The most relevant biochemical effect of desiccation on leaves was the conversion of 2-octulose into sucrose.