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A novel, yet simple, airborne microplastic (MP) sampling approach using global pollen monitoring equipment was applied to identify, characterise and quantify outdoor airborne MPs for the first time. Modification of Burkard spore trap tape adhesive provided particle capture and facilitated downstream spectroscopy analysis. 36 polymer types were identified from a total of 21 days sampling using Burkard spore traps at two locations (United Kingdom and South Africa). MPs were detected in 95 % of daily samples. Mean MP particle levels were 2.0 ± 0.9 MP m -3 (11 polymer types) in Hull (U.K.), during March, 2.9 ± 2.0 MP m -3 (16 types) in Hull in July, and 11.0 ± 5.7 MP m -3 (29 types) in Gqeberha, (S.A.) in August 2023. The most abundant polymer type was nylon (Gqeberha). The approach was compared with two passive sampling methods whereby 27 polymer types were identified and of these, 6 types were above the limit of quantification (LOQ), with poly(methacrolein:styrene) (PMA/PS) the most abundant. Irregularly shaped MPs < 100 µm in length were predominant from all sampling approaches. For the first time, airborne MPs were chemically characterised and quantified using volumetric pollen sampling equipment, representing a viable approach for future airborne MP monitoring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Epigenetic changes that lead to long-term neuroadaptations following opioid exposure are not well understood. We examined how histone demethylase JMJD3 in the nucleus accumbens (NAc) influences heroin seeking after abstinence from self-administration., Methods: Male Sprague Dawley rats were trained to self-administer heroin. Western blotting and quantitative polymerase chain reaction were performed to quantify JMJD3 and bone morphogenetic protein (BMP) pathway expression in the NAc (n = 7-11/group). Pharmacological inhibitors or viral expression vectors were microinfused into the NAc to manipulate JMJD3 or the BMP pathway member SMAD1 (n = 9-11/group). The RiboTag capture method (n = 3-5/group) and viral vectors (n = 7-8/group) were used in male transgenic rats to identify the contributions of D1- and D2-expressing medium spiny neurons in the NAc. Drug seeking was tested by cue-induced response previously paired with drug infusion., Results: Levels of JMJD3 and phosphorylated SMAD1/5 in the NAc were increased after 14 days of abstinence from heroin self-administration. Pharmacological and virus-mediated inhibition of JMJD3 or the BMP pathway attenuated cue-induced seeking. Pharmacological inhibition of BMP signaling reduced JMJD3 expression and H3K27me3 levels. JMJD3 bidirectionally affected seeking: expression of the wild-type increased cue-induced seeking whereas expression of a catalytic dead mutant decreased it. JMJD3 expression was increased in D2 + but not D1 + medium spiny neurons. Expression of the mutant JMJD3 in D2 + neurons was sufficient to decrease cue-induced heroin seeking., Conclusions: JMJD3 mediates persistent cellular and behavioral adaptations that underlie heroin relapse, and this activity is regulated by the BMP pathway., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Patient satisfaction after breast cancer surgery has an impact on body image, sexual function, self-esteem, and quality of life and may differ from the perception of the attending physician. This study aimed to compare the aesthetic outcomes and satisfaction with conservative oncoplastic surgeries, mastectomies, and total breast reconstruction., Methods: We included 760 women diagnosed with invasive breast carcinoma or phyllodes tumors who returned at least 6 months after surgery or radiotherapy at two public hospitals and a private clinic between 2014 and 2022. Data was collected prospectively from patients and retrospectively from their medical records using a specific form after obtaining their informed consent. Aesthetic outcomes and quality of life were assessed using the BREAST-Q©, Harris Scale, and BCCT.core software. Data were evaluated using the SPSS statistical software. Statistical significance was set at p < 0.05. This study was approved by the hospital ethics committees., Results: A total of 405 (53.29%) partial and 355 (46.71%) total reconstructions were included. Patients who underwent partial reconstruction were older and had higher body mass index. Patients who underwent total reconstruction had larger tumors with advanced clinical and pathological stages. Clinical and surgical complications occurred more frequently in the total reconstruction group. A greater number of reparative surgeries and lipofilling procedures were required for total reconstruction. According to the BREAST-Q, the partial reconstruction group showed significantly higher levels of women's satisfaction with their breasts, the surgical outcomes, psychosocial and sexual well-being, provision of information, and the reconstructive surgeon. Only physical well-being was slightly higher in the total reconstruction group. In most cases, the results were rated good or excellent. Physicians considered partial reconstructions to have better results than total reconstructions, although this difference was not perceived by the BCCT.core software., Conclusion: Women who underwent partial breast reconstruction had higher levels of satisfaction in several domains, lower frequency of complications, and required fewer surgeries to complete their reconstruction than women who underwent total reconstruction. Physicians were also more satisfied with the results of partial reconstructions., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest. There are no sources of support for the reported work, including grants, equipment and drugs, and no funding was received for this work from any organization., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adrenergic β2-agonists represent a mainstay in asthma management. Their chronic use has been associated with decreased bronchoprotection and rebound hyperresponsiveness. Here we investigate on the possible therapeutic advantage of a pharmacological association of β2-agonists with montelukast, a highly selective leukotriene receptor antagonist, in modulating bronchial reactivity and controlling asthma features. The study has been conducted in vitro and in vivo and also takes advantage of the synthesis of a salt that gave us the possibility to simultaneously administer in vivo formoterol and montelukast (MFS). In vitro studies demonstrate that montelukast (1) preserves β2-agonist response in isolated bronchi by preventing homologous β2-adrenoceptor desensitization; (2) reduces desensitization by modulating β2-receptor translocation in bronchial epithelial cells. In vivo studies demonstrate that sensitized mice receiving formoterol or montelukast display a significant reduction in airway hyperresponsiveness, but the β2-agonist relaxing response is still impaired. Allergen challenge causes β 2 heterologous desensitization that is further increased by treatment in vivo with formoterol. Conversely MFS not only inhibits airway hyperresponsiveness but it rescues the β2-agonist response. Histological analysis confirms the functional data, demonstrating an enhanced therapeutic efficiency of MSF in controlling also pulmonary metaplasia and lung inflammation. MFS is efficacious also when sensitized mice received the drug by local administration. In conclusion, the data obtained evidenced a therapeutic advantage in the association of β2-agonists with montelukast in the control of asthma-like features and a better rescue bronchodilation response to β2-agonists., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fiorentina Roviezzo reports financial support was provided by Genetic SpA. Fiorentina Roviezzo reports financial support was provided by University of Naples Federico II. Fiorentina Roviezzo reports a relationship with University of Naples Federico II that includes: funding grants. Fiorentina Roviezzo has patent licensed to WO2020245358. The authors declare the following competing financial interest(s): AP, MM, FFi, FFr, GCi, GCa, BS, and FR are listed as authors of the world patent application no. WO2020245358 in the name of GENETIC S.p.A., on the same compounds described in this paper. RP was legal representative of GENETIC S.p.A. at the time the work was carried out. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: We assessed the cost-effectiveness of AI-supported detection of proximal caries in a randomized controlled clustered cross-over superiority trial., Methods: Twenty-three dentists were sampled to assess 20 bitewings; 10 were randomly evaluated supported by an AI-based software (dentalXrai Pro 1.0.4, dentalXrai Ltd, Berlin, Germany) and the other 10 without AI support. The reference test had been established by four independent experts and an additional review. We evaluated the proportion of true and false positive and negative detections and the treatment decisions assigned to each detection (non-invasive, micro-invasive, invasive). Cost-effectiveness was assessed using a mixed public-private-payer perspective in German healthcare. Using the accuracy and treatment decision data from the trial, a Markov simulation model was populated and posterior permanent teeth in initially 31-years old individuals followed over their lifetime. The model allowed extrapolation from the initial detection and therapy to treatment success, re-treatments and, eventually, tooth loss and replacement, capturing long-term effectiveness (tooth retention) and costs (cumulative in Euro). Costs were estimated using the German public and private fee catalogues. Monte-Carlo microsimulations were used and incremental cost-effectiveness at different willingness-to-pay ceiling thresholds assessed., Results: In the trial, AI-supported detection was significantly more sensitive than detection without AI. However, in the AI group, lesions were more often treated invasively. As a result, AI and no AI showed identical effectiveness (tooth retention for a mean (2.5-97.5%) 49 (48-51) years) and nearly identical costs (AI: 330 (250-409) Euro, no AI: 330 (248-410) Euro). 41% simulations found AI and 43% no AI to be more cost-effective. The resulting cost-effectiveness remained uncertain regardless of a payer's willingness-to-pay., Conclusions: Higher accuracy of AI did not lead to higher cost-effectiveness, as more invasive treatment approaches generated costs and diminished possible effectiveness advantages., Clinical Significance: The cost-effectiveness of AI could be improved by supporting not only caries detection, but also subsequent management., (Copyright © 2022. Published by Elsevier Ltd.)

Objectives: We aimed to assess the impact of an artificial intelligence (AI)-based diagnostic-support software for proximal caries detection on bitewing radiographs., Methods: A cluster-randomized cross-over controlled trial was conducted. A commercially available software employing a fully convolutional neural network for caries detection (dentalXrai Pro, dentalXrai Ltd.) was randomly employed by 22 dentists, supporting their caries detection on 20 bitewings randomly chosen from a pool of 140 bitewings, with 10 bitewings randomly being supported by AI and 10 not. The reference test had been established by 4 + 1 independent experts in a pixelwise fashion. Caries was subgrouped as enamel, early dentin and advanced dentin caries, and accuracy and treatment decisions for each caries lesion assessed., Results: Dentists with AI showed a significantly higher mean (95% CI) area under the Receiver-Operating-Characteristics curve (0.89; 0.87-0.90) than those without AI (0.85; 0.83-0.86; p<0.05), mainly as their sensitivity was significantly higher (0.81; 0.74-0.87 compared with 0.72; 0.64-0.79; p<0.05) while the specificity was not significantly affected (p>0.05). This increase in sensitivity was found for enamel, but not early or advanced dentin lesions. Higher sensitivity came with an increase in non-invasive, but also invasive treatment decisions (p<0.05)., Conclusion: AI can increase dentists' diagnostic accuracy but may also increase invasive treatment decisions., Clinical Significance: AI can increase dentists' diagnostic accuracy, mainly via increasing their sensitivity for detecting enamel lesions, but may also increase invasive therapy decisions. Differences in the effects of AI for different dentists should be explored, and dentists should be guided as to which therapy to choose when detecting caries lesions using AI support., (Copyright © 2021. Published by Elsevier Ltd.)

Growth hormone-releasing peptide-6 (GHRP-6) is part of a group of small synthetic peptides with potent GH-releasing activity that have gained attention in the last two decades by virtue of their cyto- and cardioprotective effects. Despite numerous preclinical studies highlighting the potential cardiovascular benefits of GHRP-6, confirmation of clinical efficacy is still awaited. Recent advances in transdermal drug delivery systems have been made to address challenges related to the poor skin permeation rate of peptides by using pain-free microneedle (MN) devices. Accordingly, highly sensitive and validated analytical methods are required for the potential clinical translation of MN-based peptides. The ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) methods developed in this study aimed to quantify GHRP-6 in biological matrices (plasma, skin) and dissolving polymeric MNs. UHPLC/MS-MS method detection limits of 0.1, 1.1, 0.9 and 1.5 ng/mL were achieved in neat solution, plasma, MN polymer solution, and skin matrices, respectively. Method validation also involved assessment of precision, accuracy, limits of quantification, linearity of matched calibration curves (R 2  > 0.990), extraction recovery, matrix effect, stability studies, selectivity, and carry-over effect. Additionally, quality control samples were analyzed at three concentration levels to determine recovery (85-109%) and accuracy/bias (3.2-14.7%). Intra- and inter-day precision were within the range of acceptance (RSDs of 3.0-13.9% and 0.4-14.5%, respectively). The validity and applicability of such methods were successfully demonstrated for transdermal GHRP-6 delivery using GHRP-6-loaded MN patches applied to pig skin., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Since January 2020, the COVID-19 pandemic has dominated the media and exercises pressure on governments worldwide. Apart from its effects on economies, education systems and societies, the pandemic has also influenced climate change research. This paper examines the extent to which COVID-19 has influenced climate change research worldwide during the first wave at the beginning of 2020 and how it is perceived to exploit it in the future. This study utilised an international survey involving those dedicated to climate change science and management research from Academia, Government, NGOs, and international agencies in 83 countries. The analysis of responses encompasses four independent variables: Institutions, Regions, Scientific Areas, and the level of economic development represented by the Human Development Index (HDI). Results show that: (1) COVID-19 modified the way the surveyed researchers work, (2) there are indicators that COVID-19 has already influenced the direction of climate change and adaptation policy implementation, and (3) respondents perceived (explicitly concerning the COVID-19 lockdowns of March-April 2020), that the pandemic has drawn attention away from climate policy. COVID- 19 has influenced the agenda of climate change research for more than half of the respondents and is likely to continue in the future, suggesting that the impacts on their research will still be felt for many years. The paper concludes by outlining critical implications for policy-making., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background: Right ventricle (RV) dilatation and dysfunction are established criteria for intervention in severe tricuspid regurgitation (TR); however thresholds to support intervention are lacking. New measures of RV function such as RV shortening (RVS) and effective RV ejection fraction (eRVEF) may be earlier markers of RV dysfunction., Purpose: to compare the prognostic impact of different parameters of RV function and to describe cut-off values of RV size/function and TR severity of poor prognosis., Methods: Consecutive patients evaluated in the Heart Valve Clinic with significant TR (severe, massive or torrential TR) undergoing a CMR study were included. In addition to parameters of biventricular volume and function, RVS and eRVEF were assessed. A combined endpoint of hospital admission due to right heart failure and cardiovascular mortality was defined., Results: 75 patients were included (age 75 ± 8 years, female 75%). During a median follow-up of 3 years (IQR: 1.4-3.9 years), 39% experienced the endpoint. Cut-off values of worse prognosis were: RVS ≥ -14%, eRVEF ≤34%, RVEF ≤58%, RV-EDV ≥100 ml/m2, TR regurgitant fraction (TRF) ≥40% and TR volume ≥ 42 ml. RVS and eRVEF identified higher rates of RV dysfunction than RVEF. After adjustment for age and LVEF, both eRVEF ≤34% (HR: 5.29 [2.25-12.4]) and RVS ≥ -14% (HR: 3.46 [1.13-9.17]) were significantly associated with outcomes. Among all parameters of RV function, eRVEF was the strongest predictor of outcomes, incremental to RVEF (ΔC-statistic 0.139 [0.040-0.237], p = 0.005). Patients with eRVEF ≤34% and RV-EDV ≥100 ml/m2 or eRVEF ≤34% and TRF ≥40% had the worst prognosis (p < 0.01 for both)., Conclusion: RVS and eRVEF identify higher rates of RV dysfunction beyond RVEF. Among all measures, eRVEF held the strongest association with outcomes, incremental to RVEF., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Toxoplasma gondii and Cryptosporidium parvum are protozoan parasites that are highly prevalent and opportunistically infect humans worldwide, but for which completely effective and safe medications are lacking. Herein, we synthesized a series of novel small molecules bearing the diacyl urea scaffold and related structures, and screened them for in vitro cytotoxicity and antiparasitic activity against T. gondii and C. parvum. We identified one compound (GMG-1-09), and four compounds (JS-1-09, JS-2-20, JS-2-35 and JS-2-49) with efficacy against C. parvum and T. gondii, respectively, at low micromolar concentrations and showed appreciable selectivity in human host cells. Among the four compounds with efficacy against T. gondii, JS-1-09 representing the diacyl urea scaffold was the most effective, with an anti-Toxoplasma IC 50 concentration (1.21 μM) that was nearly 53-fold lower than its cytotoxicity IC 50 concentration, indicating that this compound has a good selectivity index. The other three compounds (JS-2-20, JS-2-35 and JS-2-49) were structurally more divergent from JS-1-09 as they represent the acyl urea and acyl carbamate scaffold. This appeared to correlate with their anti-Toxoplasma activity, suggesting that these compounds' potency can likely be enhanced by selective structural modifications. One compound, GMG-1-09 representing acyl carbamate scaffold, depicted in vitro efficacy against C. parvum with an IC 50 concentration (32.24 μM) that was 14-fold lower than its cytotoxicity IC 50 concentration in a human intestinal cell line. Together, our studies unveil a series of novel synthetic acyl/diacyl urea and acyl carbamate scaffold-based small molecule compounds with micromolar activity against T. gondii and C. parvum that can be explored further for the development of the much-needed novel anti-protozoal drugs., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although effective and low-cost urate-lowering therapy has been available for decades, inequities in gout management exist. Despite high impact of disease, rates of urate-lowering therapy prescription are low in women, in African-Americans in the United States, in Māori (Indigenous New Zealanders), and in Pacific peoples living in Aotearoa/New Zealand. Social determinants of health, barriers to accessing the health care system, health literacy demands, stigmatization, and bias contribute to inequities in gout burden and management. Approaches that focus on building health literacy and delivering culturally safe care lead to improved outcomes in gout, and offer important solutions to achieve health equity., Competing Interests: Disclosure A.G. Guillén and L. Te Karu have no disclosures. J.A. Singh has received consultant fees from Crealta/Horizon, MediSYS, Fidia, UBM LLC, Trio health, Medscape, WebMD, Clinical Care options, Clearview health care partners, Putnam associates, Focus forward, Navigant consulting, Spherix, Practice Point communications, the National Institutes of Health, and the American College of Rheumatology (ACR). J.A. Singh owns stock options in Amarin pharmaceuticals and Viking therapeutics. J.A. Singh is on the speaker’s bureau of Simply Speaking. J.A. Singh is a member of the executive of OMERACT, an organization that develops outcome measures in rheumatology and receives arms-length funding from 12 companies. J.A. Singh serves on the Food and Drug Administration Arthritis Advisory Committee. J.A. Singh is the chair of the Veterans Affairs Rheumatology Field Advisory Committee. J.A. Singh is the editor and the Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. J.A. Singh previously served as a member of the following committees: member, the ACR Annual Meeting Planning Committee and Quality of Care Committees; the Chair of the ACR Meet-the-Professor, Workshop, and Study Group Subcommittee; and the cochair of the ACR Criteria and Response Criteria subcommittee. N. Dalbeth has received fees from Janssen, AbbVie, CymaBay, AstraZeneca, Crealta, Takeda, Kowa, Horizon, Hengrui, Dyve Biosciences, Arthrosi, Selecta, bpac, the Health Research Council of New Zealand, UpToDate, Oxford University Press, the Pharmaceutical Society of New Zealand, the Spanish Society for Rheumatology, the Asia Pacific Gout Consortium, and the ACR. Her institution has received research grants from the Health Research Council of New Zealand, the Auckland Medical Research Foundation, PHARMAC, AstraZeneca, and Amgen., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aim of the current review was to assess whether there was an association between obesity and higher levels of hospitalization, poor outcomes and mortality due to the disease of novel coronavirus (COVID-19)., Methodology: A systematic review of articles on the novel coronavirus, containing information on obesity and its association with COVID-19 morbidity and mortality. In the bibliographic research, four databases were used, with the terms ['COVID-19'] AND ['hospitalization'] AND ['obesity'] AND ['mortality']. Studies published from 12/01/2019 until 05/01/2020 were included. The research contains inclusive criteria targeting studies of humans adults infected by Sars-Cov-2, with or without comorbidities. This research was selected from publications in Spanish and English languages., Results: 96 articles were identified, 15 being presented in two databases. Twenty articles were included, with a population total estimated from 1 to 7671 patients, with a prevalence of obesity ranging from 13.3% to 68.6%. The association of obesity and mortality has been observed in at least 4 studies, that 85.3% of the population was hospitalized. Among 19 of the 20 studies, more severe forms of the disease were observed and in 14 of them, higher rates of complications among obese people infected with the new coronavirus. Limitation differences in the definition of obesity was observed among publications, of which obesity was considered from a body mass index >25 kg/m²., Conclusions: In the current review, obesity and overweight were represented an unfavorable factor for infection of novel coronavirus, where the higher the BMI the worse the outcomes. This occurred by worsening the infection itself, as well as increasing the prevalence of hospitalizations, worst outcomes and greater lethality; especially when co-occurring with other chronic conditions and in the elderly as well. Given this evidence, greater attention is suggested to the obese and overweight population in the face of the current pandemic., (Copyright © 2020 Asia Oceania Association for the Study of Obesity. All rights reserved.)

Objectives: We aimed to apply deep learning to detect caries lesions of different radiographic extension on bitewings, hypothesizing it to be significantly more accurate than individual dentists., Methods: 3686 bitewing radiographs were assessed by four experienced dentists. Caries lesions were marked in a pixelwise fashion. The union of all pixels was defined as reference test. The data was divided into a training (3293), validation (252) and test dataset (141). We applied a convolutional neural network (U-Net) and used the Intersection-over-Union as validation metric. The performance of the trained neural network on the test dataset was compared against that of seven independent using tooth-level accuracy metrics. Stratification according to lesion depth (enamel lesions E1/2, dentin lesions into middle or inner third D2/3) was applied., Results: The neural network showed an accuracy of 0.80; dentists' mean accuracy was significantly lower at 0.71 (min-max: 0.61-0.78, p < 0.05). The neural network was significantly more sensitive than dentists (0.75 versus 0.36 (0.19-0.65; p = 0.006), while its specificity was not significantly lower (0.83) than those of the dentists (0.91 (0.69-0.98; p > 0.05); p > 0.05). The neural network showed robust sensitivities at or above 0.70 for both initial and advanced lesions. Dentists largely showed low sensitivities for initial lesions (all except one dentist showed sensitivities below 0.25), while those for advanced ones were between 0.40 and 0.75., Conclusions: To detect caries lesions on bitewing radiographs, a deep neural network was significantly more accurate than dentists., Clinical Significance: Deep learning may assist dentists to detect especially initial caries lesions on bitewings. The impact of using such models on decision-making should be explored., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Liposomal bupivacaine (LB), as an extended-release local anesthetic, may provide lasting pain control and therefore decrease the need for narcotics in the immediate postoperative period., Objectives: The aim of this study was to evaluate whether transversus abdominis plane (TAP) block with LB decreased the use of postoperative narcotics compared with regular bupivacaine (RB) and no TAP block in patients undergoing weight loss procedures., Setting: A large, metropolitan, university-affiliated, tertiary hospital., Methods: Patients undergoing laparoscopic Roux-en-Y gastric bypass, sleeve gastrectomy, or sleeve-to-bypass conversion over 1 year were randomized to receive TAP block using LB, TAP block with RB, or no block in a double-blind, randomized controlled trial. The outcomes measured were postoperative use of opiates, pain score, length of stay, time to ambulation, and nausea. Data were analyzed using χ 2 test and analysis of variance F test., Results: Two hundred nineteen patients were included in the study. Fentanyl patient-controlled analgesia usage was not significantly different between the groups (LB 351.4 versus RB 360.7 versus no TAP block 353.9, P = .97) at 48 hours post operation. The pain scores (scale 1-10) were similar among the groups with the mean for the LB group at 4.3, and RB and no TAP block groups both at 4.7 (P = .35). The type of block or lack of block did not significantly impact the length of stay, time to ambulation, or presence of nausea., Conclusion: The LB TAP block did not significantly reduce the total opiate pain medication consumption nor did it reduce pain scores among bariatric surgery patients., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The prevalence of hyperuricemia has increased substantially in recent decades. It has been suggested that it is an independent risk factor for weight gain, hypertension, hypertriglyceridemia, metabolic syndrome (MetS), and cardiovascular disease. Results from epidemiological studies conducted in different study populations have suggested that high consumption of dairy products is associated with a lower risk of developing hyperuricemia. However, this association is still unclear. The aim of the present study is to explore the association of the consumption of total dairy products and their subtypes with the risk of hyperuricemia in an elderly Mediterranean population with MetS., Methods and Results: Baseline cross-sectional analyses were conducted on 6329 men/women (mean age 65 years) with overweight/obesity and MetS from the PREDIMED-Plus cohort. Dairy consumption was assessed using a food frequency questionnaire. Multivariable-adjusted Cox regressions were fitted to analyze the association of quartiles of consumption of total dairy products and their subtypes with the prevalence of hyperuricemia. Participants in the upper quartile of the consumption of total dairy products (multiadjusted prevalence ratio (PR) = 0.84; 95% CI: 0.75-0.94; P-trend 0.02), low-fat dairy products (PR = 0.79; 95% CI: 0.70-0.89; P-trend <0.001), total milk (PR = 0.81; 95% CI: 0.73-0.90; P-trend<0.001), low-fat milk (PR = 0.80; 95% CI: 0.72-0.89; P-trend<0.001, respectively), low-fat yogurt (PR = 0.89; 95% CI: 0.80-0.98; P-trend 0.051), and cheese (PR = 0.86; 95% CI: 0.77-0.96; P-trend 0.003) presented a lower prevalence of hyperuricemia. Whole-fat dairy, fermented dairy, and yogurt consumption were not associated with hyperuricemia., Conclusions: High consumption of total dairy products, total milk, low-fat dairy products, low-fat milk, low-fat yogurt, and cheese is associated with a lower risk of hyperuricemia., Competing Interests: Declaration of Competing Interest Mena-Sánchez G declares no conflicts of interest. Babio N declares that she has received payments from Danone S.A. for scientific and technical consulting but not for the preparation of this study. She is one of the members of the Scientific Advisory Board of the EU program for the promotion of milk and milk products within the framework of appropriate dietary practices. Becerra-Tomás N declares no conflicts of interest. Miguel Ángel Martínez-González, Andrés Díaz-López, Dolores Corella, Maria Dolores Zomeño, Dora Romaguera, Jesús Vioque, Ángel M. Alonso-Gómez, Julia Wärnberg, J. Alfredo Martínez, Luís Serra-Majem, Ramon Estruch, Rosa Bernal, José Lapetra, Xavier Pintó, Josep A. Tur, José Lopez-Miranda, Naomi Cano-Ibáñez, Jose Juan Gaforio, Pilar Matía-Martín, Lidia Daimiel, José Luis Llisterri Caro, Josep Vidal, Clotilde Vázquez, Emili Ros, Ana Garcia Arellano, Antoni Palau, Rebeca Fernández-Carrión, Alejandra Pérez-Vega, Marga Morey, Manoli García de la Hera, Jessica Vaquero-Luna, Francisco J. Carmona-González, Itziar Abete, Jacqueline Álvarez-Pérez, Rosa Casas, José Carlos Fernández-García, José Manuel Santos-Lozano, Emili Corbella, Antoni Sureda, Miguel Ruiz Canela, Rocio Barragán, Albert Goday, Marian Martín, María Consuelo Altozano Rodado, Estefanía Toledo, Montse Fitó declare no conflicts of interest. Salas-Salvadó J reports that he has served on the Board of and received grant support through his institution from the International Nut and Dried Fruit Council; has served as a member of the Danone S.A. Advisory Board; has received personal consulting fees from Danone, Font Vella Lanjaron, Nuts for Life, and Eroski; and has received grant support through his institution from the Nut and Dried Fruit Foundation and Eroski., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Dietary uptake is a key step in conveying both toxic mercury (Hg; particularly as highly bioavailable methylmercury, MeHg) and essential dietary biochemicals, such as polyunsaturated fatty acids (PUFA), across trophic levels within aquatic food webs. Using stable isotopes and fatty acids we evaluated the role of food sources in size-fractioned plankton and littoral macroinvertebrates for the bioaccumulation of total Hg and MeHg in six oligotrophic and one mesotrophic Swedish lakes with differing concentrations of dissolved organic carbon (DOC). We found that the consumption of both algal and terrestrial diets (assessed by PUFA and long-chain saturated fatty acids, respectively) predicted >66% of the Hg concentration variability in meso- (100-500 μm) and macrozooplankton (>500 μm) in oligotrophic lakes. In the mesotrophic lake, total Hg bioaccumulation in higher trophic level biota, carnivorous macroinvertebrates was also significantly related to terrestrial diet sources (R 2  = 0.65, p < 0.01). However, lake pH and DOC correlated to total Hg bioaccumulation and bioconcentration across all lakes, suggesting the consumption of different diet sources is mediated by the influence of lake characteristics. This field study reveals that using dietary biomarkers (stable isotopes and fatty acids) together with the physico-chemical lake parameters pH and nutrients together improve our ability to predict Hg bioaccumulation in aquatic food webs. Fatty acids used as dietary biomarkers provide correlative evidence of specific diet source retention in consumers and their effect on Hg bioaccumulation, while pH and nutrients are the underlying physico-chemical lake parameters controlling differences in Hg bioaccumulation between lakes., (Copyright © 2019. Published by Elsevier B.V.)

Cancer is a leading cause of death worldwide, and its incidence is continually increasing. Although anticancer therapy has improved significantly, it still has limited efficacy for tumor eradication and is highly toxic to healthy cells. Thus, novel therapeutic strategies to improve chemotherapy, radiotherapy and targeted therapy are an important goal in cancer research. Macroautophagy (herein referred to as autophagy) is a conserved lysosomal degradation pathway for the intracellular recycling of macromolecules and clearance of damaged organelles and misfolded proteins to ensure cellular homeostasis. Dysfunctional autophagy contributes to many diseases, including cancer. Autophagy can suppress or promote tumors depending on the developmental stage and tumor type, and modulating autophagy for cancer treatment is an interesting therapeutic approach currently under intense investigation. Nutritional restriction is a promising protocol to modulate autophagy and enhance the efficacy of anticancer therapies while protecting normal cells. Here, the description and role of autophagy in tumorigenesis will be summarized. Moreover, the possibility of using fasting as an adjuvant therapy for cancer treatment, as well as the molecular mechanisms underlying this approach, will be presented.

Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the p.R357X and p.G217R both abolish the ability of TBK1 to phosphorylate 2 of its kinase targets, IRF3 and optineurin, and to undergo phosphorylation. They both inhibit binding to optineurin and the p.G217R, within the TBK1 kinase domain, reduces homodimerization, essential for TBK1 activation and function. Finally, we show that the proportion of TBK1 that is active (phosphorylated) is reduced in 5 lymphoblastoid cell lines derived from patients harboring heterozygous missense or in-frame deletion TBK1 mutations. We conclude that missense mutations in functional domains of TBK1 impair the binding and phosphorylation of its normal targets, implicating a common loss of function mechanism, analogous to truncation mutations., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Repair of hernias with loss of domain in obese patients can lead to acute respiratory failure., Objectives: The objective of this study was to analyze preoperative progressive pneumoperitoneum (PPP) in increasing abdominal cavity volume and its impact on respiratory function., Setting: The study was conducted at the University Hospital, State University of Londrina, Brazil, which is a referral center for the treatment of obesity. The patients were hospitalized for the duration of the study., Methods: Sixteen obese patients were evaluated. Computed tomography was used to determine hernia sac volume (HSV) and abdominal cavity volume (ACV). Respiratory function was evaluated by measuring vital capacity and forced expiratory volume in the first second (FEV-1). All data were obtained before PPP, on the day before surgery, and on the second postoperative day. PPP was performed daily with insufflation of CO 2 ., Results: The number of insufflations was 12. The average of total volume inflated was 5.7 L. The HSV was 2953 cm 3 before PPP and 1935 cm 3 after PPP. The average ACV increased from 8898 to 11,317 cm 3 after PPP. The relationship between HSV and ACV was 38.2% before and 16.3% after PPP. There was a favorable improvement in respiratory function with an increase in vital capacity from 1875 to 2760 mL and an increase in FEV-1 from 1060 to 1670 mL after PPP. Respiratory function tests after surgery showed values of 2600 and 1560 mL, respectively, for cavity volume and FEV-1. There were no postoperative respiratory complications., Conclusions: This technique can be used safely in the surgical preparation of obese patients with hernias with loss of domain, reducing the relation between HSV and ACV and avoiding pulmonary complications., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

The os acetabuli is thought to arise from unfused secondary ossification centers or as rim fractures in the setting of dysplastic hips or hips with femoroacetabular impingement. Resection of a large os acetabuli can lead to structural instability of the joint, and in these cases, osteoplasty of the impingement, reduction and internal fixation of the osseous fragment, and labral repair have been described in the literature. Anchor fixation for labral repair in the surrounding zone of the osteosynthesis might bring some technical problems. We aim to describe a technical modification improving labral lesion treatment while addressing the rim fracture. The addition of a suture to the screw addresses both lesions because it simultaneously has the function of a screw and an anchor. A suture-on-screw technique for os acetabuli fixation helps surgeons to gain versatility and is more cost-effective for the patients and health services.

The aim of the present study was to analyze in vivo the role of zinc finger protein SNAI1 (SNAI1) on renal fibrosis. Unilateral ureteral obstruction injury was induced in Snai1 knockout mice. Snai1 gene deletion was, however, only partial and could therefore not be correlated to reduced fibrosis. Expression of SNAI1 protein and epithelial-mesenchymal transformation markers was then assessed in human chronic allograft nephropathy biopsy specimens. Significant up-regulation of SNAI1 protein was detected within cytoplasm of proximal tubules localized, for some of them, near foci of fibrosis and tubular atrophy. No concomitant epithelial-mesenchymal transformation could, however, be demonstrated analyzing the expression of the fibroblast markers vimentin, α-smooth muscle actin, and S100A4. SNAI1 cytoplasmic up-regulation was particularly evident in biopsy specimens obtained from calcineurin inhibitor-treated patients, which might be because of, as suggested by in vitro experiments, a decrease of the proteasome chimotrypsin activity. Deeper analysis on chronic allograft nephropathy biopsy specimens suggested that SNAI1 cytoplasmic up-regulation was preceded by a transient increase of phosphorylated heat shock protein 27, p38 mitogen-activated protein kinase, and glycogen synthase kinase 3β. Concomitant down-regulation of the polyubuquitinylated conjugates was detected in SNAI1 + tubules. Altogether, these results might suggest that calcineurin inhibitor-induced tubular SNAI1 protein cytoplasmic accumulation, possibly because of impaired SNAI1 proteasomal degradation and nuclear translocation, might be a sign of a diseased profibrotic epithelial phenotype., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Cigarette smoking is an important risk factor for disease onset and progression among the major chronic diseases accounting for most morbidity and mortality in the world. Our objective was to identify characteristics associated with tobacco use among patients with multiple chronic conditions (MCC)., Methods: This cross-sectional study was implemented at the Center HIPERDIA Minas Juiz de Fora, Brazil, which manages patients with high cardiovascular risk, hypertension, diabetes mellitus and chronic kidney disease., Results: Of 1558 participants, 12% were current smokers; 41% former smokers and 47%, never smokers. In univariate analyses, current smoking was associated with gender, age, physical activity, alcohol use, depressive symptoms, overweight, and atherosclerosis. In multinomial analyses, multiple chronic conditions were associated with the current or previous use of tobacco; COPD and atherosclerotic disease were more prevalent among patients who were current smokers., Conclusions: Cigarette smoking was as prevalent in this high population as in the general population. Smokers had worse clinical profiles compared to former smokers or never smokers. Aggressive smoking cessation support should yield considerable health benefits and health care cost savings within patients with MCC, especially, those with high cardiovascular risk., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

In order to evaluate the performance, carcass characteristics and meat quality of culled ewes finished in pasture or exclusivelywith grain, 41 culled Polwarth ewes, were assigned to six treatments: RY (ryegrass pasture), RYGO (ryegrass and whole grain oats), RYGM (ryegrass and whole grain maize), GM (whole grain maize), GO (whole grain oats), GS (whole grain sorghum). The finishing systemof the ewes influenced weight gain,wherein the GM and GS treatments increased daily weight gain. The GO treatment decreased the dressing percentage. Nonetheless, a*, h*, pH, cooking loss and tenderness were similar across dietary treatments. Using principal component analysis, the variables C18:2n6, h*, n6/n3, TBARS, total lipids, L* and b* were assigned as characteristics of meat from the feedlot animals, while the pasture finishing system produced meat with higher CLA and n-3 fatty acids but lower TBARS values indicating lipid stability.

Fetal exposure to illicit drugs is a worldwide problem, since many addicted women do not stop using it during pregnancy. Cocaine consumed in powdered (snorted or injected) or smoked (crack cocaine) form are harmful for the baby and its side effects are not completely known. Meconium, the first stool of a newborn, is a precious matrix usually discarded, that may contain amounts of substances consumed in the last two trimesters of pregnancy. Analyzing this biological matrix it is possible to detect the unaltered molecule of cocaine (COC) or its metabolite benzoylecgonine (BZE) and pyrolytic products anhydroecgonine methyl ester (AEME) and anhydroecgonine (AEC). A liquid chromatography mass spectrometry (LC-MS) method was validated for meconium samples after solvent extraction, followed by direct injection of 10μL. Linearity covered a concentration range of 15 to 500ng/mg with a lower limit of quantification (LLOQ) of 15ng/mg for all analytes. Matrix effect was evaluated and showed adequate results. Detection of illicit substances usage can be crucial for the baby, since knowing that can help provide medical care as fast as possible. The method proved to be simple and fast, and was applied to 17 real meconium samples., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the efficacy, safety, and tolerability of lacosamide in adults with LGS in the clinical setting., Method: The present report is a retrospective, open-label treatment study carried out from June 2013 to December 2014 at the National Institute of Colombia. Lacosamide was introduced as add-on therapy. All caregivers were instructed to initiate lacosamide at low doses (25-50 mg) and gradually increasing it every 2 weeks. The efficacy was evaluated based on the reduction in the rate of each countable type of seizure. We also evaluated the retention rate for lacosamide as the number of days with lacosamide during follow-up. The tolerability was evaluated base on account the adverse events., Results: We found that lacosamide only improves the seizure rate in three out of 19 patients with LGS, in two of them by more than 50%. The highest seizure reduction rate was observed in the focal and tonic-clonic seizures. The most commonly reported adverse events were worsening of seizures, aggressiveness and irritability. Nine patients (47.4%) showed worsening of their behavior during the treatment with lacosamide., Conclusion: Lacosamide can exacerbate both, the tonic and astatic seizures, and the encephalopathy associated with this epileptic syndrome. However, it is interesting to consider the likelihood of suppression of generalized tonic-clonic and focal seizures. That is why; lacosamide could be an option after carefully balancing risks and benefits in each individual case., (Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Astrocytes play a critical role during the development and the maintenance of the CNS in health and disease. Yet, their lack of accessibility from fetuses and from the brain of diseased patients has hindered our understanding of their full implication in developmental and pathogenic processes. Human pluripotent stem cells (PSCs) are an alternative source to obtain large quantities of astrocytes in vitro, for mechanistic studies of development and disease. However, these studies often require highly pure populations of astrocytes, which are not always achieved, depending on the PSC lines and protocols used. Here, we describe the generation and characterization of human PSC reporter lines expressing TagRFP driven by the ABC1D region of the human GFAP promoter, as new cellular model for generating homogenous population of astrocytes generated from CNS regionally defined PSC-derived neural progenitors. GFA(ABC1D)::TagRFP-expressing astrocytes can be purified by fluorescent-activated cell sorting and maintain a bright expression for several additional weeks. These express canonical astrocyte markers NF1A, S100β, CX43, GLAST, GS and CD44. These new cellular models, from which highly pure populations of fluorescence-expressing astrocytes can be obtained, provide a new platform for studies where pure or fluorescently labeled astrocyte populations are necessary, for example to assess pro-inflammatory cytokine and chemokine release in response to specific treatment, and uptake and degradation of fluorescently labeled pathogenic proteins, as reported in this study., (Copyright © 2015. Published by Elsevier B.V.)

During the last decades, Raman spectroscopy has grown to an established analytical technique in archaeometry, art analysis and conservation science. Mobile Raman instruments were designed to be used for in situ characterisation and identification of inorganic and organic materials in art and archaeometry. This research paper aims to point out several aspects that need to be considered when selecting a mobile Raman spectrometer for in situ archaeometrical studies. We describe an approach to evaluate these parameters and apply this to a dual laser portable Raman spectrometer. Twofold characterisation of mobile Raman instrumentation for art analysis: (i) investigation of spectroscopic characteristics such as (amongst others) spectral resolution, spectral window, signal to noise ratio and limit of detection; (ii) evaluation of specific properties that are useful for mobile studies in archaeometry. These include options for easy positioning and focussing, the ability to reduce laser power on the surface of the art object and the working distance between the probehead and the artefact. Finally, the research was completed with field tests by studying the pigments of a mediaeval wall painting., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Physiological shortening of the atrioventricular (AV) interval with increasing heart rate is well documented in normal human beings and is an established component of dual-chamber pacing for bradycardia., Objectives: To assess the effect of exercise on optimal AV delay and the impact of a patient-specific rate-adaptive AV delay (RAAVD) on exercise capacity in patients with heart failure following cardiac resynchronization therapy., Methods: Phase 1: We performed iterative AV optimization at rest and exercise in 52 cardiac resynchronization therapy patients in atrial-sensed mode (mean age 71.6 ± 9.2 years, 25% females). Phase 2: Subsequently, 20 consecutive volunteers from this group (mean age 69.2 ± 9.6 years, 15% females) underwent cardiopulmonary exercise testing with RAAVD individually programmed ON (RAAVD-ON) or OFF (RAAVD-OFF)., Results: Phase 1: In 94% of the patients, there was a marked reduction (mean 50%) in optimal AV delay with exercise. The optimal resting vs exercise AV delay was 114.2 ± 29 ms at a heart rate of 64.4 ± 7.1 beats/min vs 57 ± 31 ms at a heart rate of 103 ± 13 beats/min (P < .001). No patients required an increase in AV delay with exercise, and 3 (6%) showed no change. Phase 2: With RAAVD-ON, significantly better exercise times were achieved (8.7 ± 3.2 minutes) compared with RAAVD-OFF (7.9 ± 3.2 minutes; P = .003), and there was a significant improvement in Vo(2)max (RAAVD-ON 16.1 ± 4.0 vs RAAVD-OFF 14.9 ± 3.7 mL/(kg · min); P = .024)., Conclusions: There was a dramatic reduction in optimal AV delay with physiological exercise in the majority of this heart failure cardiac resynchronization therapy cohort. Replicating this physiological response with a programmable RAAVD translated into a 10% improvement in exercise capacity., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

In situ microcosm study investigated both the kinetics of plant material mass loss and qualitative and quantitative aspects of DNA content by researching leaf degradation of two specific varieties of tomato (Admiro and Palmiro) in freshwater column incubated for 40 days. A two-compartment first order model fitted both tomato dry matter and DNA content mass loss well. The composite half-decrease times were, respectively, 1.13 ± 0.51 and 1.16 ± 0.47 days for Palmiro and Admiro. The composite half-disappearance times of total DNA in Palmiro and Admiro tomato leaves were, respectively, 0.92 ± 0.31 and 0.88 ± 0.26 days. Genomic analysis indicates that before having been released, a significant amount of DNA may be degraded in plant tissues decomposing in water column. The results of this study confirm the hypothesis that release of plant DNA in aquatic environments can be caused by intracellular nuclease activities in the plants cells and by enzymatic degradation of cell structures by residual microbial activities in leaves., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The aim of this work was to quantify the biopolymers associated to esterase enzymes and identify bacterial respiratory activity in four cores collected in Suruí Mangrove, Guanabara Bay - RJ. Biopolymer concentration was 1000 times lower than previously reported in the literature, indicating the need for creating and establishing eutrophication indicative rates and records compatible with tropical coastal systems. The biochemical representative relationships in the cores were equivalent to those from studies on coastal marine environments made in the Northern Hemisphere. The esterase enzymes in the sediment proved efficient in the mineralization of biopolymers, even with preferentially anaerobic metabolic physiology. Despite the lack of incipient geomicrobiological studies, the results highlighted the possible application of microbiology to a better understanding of geological processes., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Regulated exocytosis involves calcium-dependent fusion of secretory vesicles with the plasma membrane with three SNARE proteins playing a central role: the vesicular synaptobrevin and the plasma membrane syntaxin1 and SNAP-25. Cultured bovine chromaffin cells possess defined plasma membrane microdomains that are specifically enriched in both syntaxin1 and SNAP-25. We now show that in both isolated cells and adrenal medulla slices these target SNARE (t-SNARE) patches quantitatively coincide with single vesicle secretory spots as detected by exposure of the intravesicular dopamine beta-hydroxylase onto the plasmalemma. During exocytosis, neither area nor density of the syntaxin1/SNAP-25 microdomains changes on the plasma membrane of both preparations confirming that preexisting clusters act as the sites for vesicle fusion. Our analysis reveals a high level of colocalization of L, N and P/Q type calcium channel clusters with SNAREs in adrenal slices; this close association is altered in individual cultured cells. Therefore, microdomains carrying syntaxin1/SNAP-25 and different types of calcium channels act as the sites for physiological granule fusion in "in situ" chromaffin cells. In the case of isolated cells, it is the t-SNAREs microdomains rather than calcium channels that define the sites of exocytosis.

Emergency Medicine (EM) is a developing specialty in Peru, as is the case in many other countries around the world. The nation's first residency training program was started in 1993 at the Universidad Nacional Mayor de San Marcos (UNMSM). This description of the development, organization, challenges, and goals of the EM specialty in Peru is based on personal experience and communication with other specialists in the country.

The auxiliary Ca(v)beta subunit is essential for functional expression of high-voltage activated Ca(2+) channels. Here, we describe a lure sequence designed to sequester the Ca(v)beta subunits in transfected bovine chromaffin cells. This sequence is composed of the extracellular and transmembrane domains of the alpha chain of the human CD8, the I-II loop of Ca(v)2.1 subunit, and EGFP. We showed that expressing the CD8-I-II-EGFP sequence in chromaffin cells led to a >50% decrease in overall Ca(2+) current density. Although this decrease involved all the Ca(2+) channel types (L, N, P/Q, R), the proportion of each type supporting the remaining current was altered. A similar effect was observed after transfection when measuring the functional role of Ca(2+) channels in catecholamine release by chromaffin cells: global decrease of release and change of balance between the different channel types supporting it. Possible explanations for this apparent discrepancy are further discussed.

A series of tropane-3-spiro-4'(5')-imidazolines was synthesized and studied by 1H and 13C NMR spectroscopy, and the crystal structure of 2'-(1H-indol-3-yl)tropane-3-spiro-4'(5')-imidazoline hydrochloride 5(6)f was determined by X-ray diffraction. In CD3OD solution, compounds 5(6)a-f display the same preferred conformation. The pyrrolidine and piperidine rings adopt an envelope conformation flattened at N8 and a distorted chair conformation puckered at N8 and flattened at C3, respectively, with the N-substituent in the equatorial position with respect to the piperidine ring. This conformation is similar to that observed for compound 5(6)f in the solid state. From binding studies on the compounds synthesized, compound 5(6)d demonstrated the ability to efficiently displace the binding of [3H]GR65630 to bovine brain area postrema membranes to an extent comparable to MDL 72222. In the von Bezold-Jarisch reflex, compound 5(6)d was equipotent with metoclopramide. It is, therefore, likely that the imidazoline ring may provide a useful bioisosteric replacement for the carbonyl group in 5-HT3 antagonists.

The purpose of this study was to identify the possible effect of enteroviruses on placental tissue. Seventy-eight pregnant women were studied throughout their pregnancy: enteroviral infection was detected by faecal viral isolation and seric neutralization of previously identified virus in cell culture. In 19 cases of confirmed maternal infection, placentae were examined grossly, by optical microscopy, immunohistochemical and electron microscopic methods. Ten term placentae from women included in the study, with no clinical, serological or virological evidence of enteroviral infection, were used as control, and examined by gross and optical microscopy. In 17 specimens (echovirus-coxsackievirus) an haematogenous placentitis was suspected on the basis of gross observation. Microscopic lesions were similar to those found in other viral infections, with specific features. The nature of the inflammatory reaction pointed to the presence of an acute type of haematogenous placentitis, not present in placentae of the control group. The authors (AA) comment on the results and present the hypotheses about the available data: (1) maternal enteroviremia and faecal virus shedding without placental invasion, placentary damage being an unspecific consequence of infection; (2) direct virus-induced injury is not the only possible cause for the lesions: (3) placental enteroviral infection occurred with placental pathology but the virus did not cross the organ as the newborn had no signs of infection.

Three groups of placentae from 27 cases of cytomegalovirus infection were examined morphologically and by specific immunofluorescence. Placentae in Group 1 (four cases) had a mean gestational age of 24.5 +/- 2.5 weeks; those in Group 2 (11 cases) had a mean gestational age of 36.4 +/- 2.7 weeks; those in Group 3 (12 cases) had a mean gestational age of 40 +/- 1.8 weeks. A tendency towards increased placental weight was observed. In 23 cases, a haematogenous placentitis was suspected on gross examination. Some specific features were detected on light microscopy. In Group 1 the lesions were represented by pronounced dysmaturity of villous structures, diffuse reparative villitis and intervillitis allied to an abundance of cytomegalic cells and areas of necrosis and calcification. In Group 2 a chronic active process was indicated by the presence of vascular involvement, proliferative-necrotic and reparative villitis and fresh villous necrosis; cytomegalic cells were scarce. In Group 3 placentae there was a predominance of villous plate lesions similar to those found in the septicaemic phase of maternal infections; necrotizing, proliferative and, rarely, reparative villitis was present; cytomegalic cells were rare. We may conclude that placental morphology needs to be substantiated by special laboratory techniques for the detection of cytomegalovirus infection.

Two groups of placentae from 18 cases of maternal rubella were examined morphologically and virologically. Placentae in Group I (four cases) had a mean gestational age of 21 +/- 1.9 weeks, whilst those in Group 2 (14 cases) had a mean gestational age of 38 +/- 2.8 weeks. A tendency to hypoplasia was observed. The microscopic lesions were similar to those found in other viral infections but in each group some specific features were noted. Only placentae of Group I showed nodules of villi agglutinated by fibrin. This lesion suggested recent maternal infection. Attention is drawn to the presence of abnormal areas of lobular rarefaction due to dysmaturity of villous stem and terminal villi. This aspect was more diffuse and accentuated in Group 2 placentae. Villitis of reactive, necrotic, proliferative and reparative types was seen only in placentae of Group 2. Devastating villitis was not observed. Inclusions in placental cells suggested rubella infection. The lesions were non-specific and hence stress the need for virological examination of the placenta, immunofluorescence studies and electron microscopy to confirm the diagnosis.