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Objective: The objective of this study was to determine regional variation in need for mental health care for Aboriginal and Torres Strait Islander adults (18+ years). Methods: Three Australian Indigenous health surveys were analysed, and prevalence rates of high/very high psychological distress (as per the Kessler-5 tool) by the Index of Relative Socio-economic Disadvantage were computed and combined via meta-analysis. These estimates were applied to census population data to estimate regional needs and summed to geographic planning regions. Final estimates were assessed for face validity by comparing with other existing estimates of mental health need. Results: The Index of Relative Socioeconomic Disadvantage had a dose–response relationship with high/very high psychological distress, whereby the more disadvantaged an area, the greater the levels of reported distress. This methodology resulted in varying levels of need within South East Queensland. Conclusions: The approach was found to have good face validity and provides a data-driven method to determine relative levels of need. Implications for Public Health: To ensure equity of mental health service provision, planners should account for variation in levels of need within a catchment. This method may be used throughout Australia to determine regional variation in need for care where other data are lacking to ensure evidence-based investment planning decisions at the local level.

Chemistry is a reproducible science whose pillars - synthesis and analysis - actually comprise a huge collection of highly reproducible experimental methods to synthesize and analyze substances. The historical development of chemistry, furthermore, shows that reproducibility of methods has been the companion of novelty and creative innovation. The “publish or perish” principle dominating global academia since over two decades, however, intrinsically contributes to the publication of non-reproducible research outcomes also in chemistry. A study on reproducibility of chemistry research seems therefore timely, especially now that chemists are slowly but inevitably adopting open science and its tools such as the preprint, open access, and data sharing. We conclude presenting three simple guidelines for enhanced publication of research findings in chemistry.

Background: Despite the well-known efficacy of anti-COVID-19 vaccines in preventing morbidity and mortality, several vaccinated individuals are diagnosed with SARS-CoV-2 breakthrough infection, which might require hospitalisation. This multicentre, observational, and retrospective study aimed to investigate the clinical characteristics and outcomes of vaccinated vs. non-vaccinated patients, both hospitalised with SARS-CoV-2 infection in 3 major hospitals in Northern Italy. Methods: Data collection was retrospective, and paper and electronic medical records of adult patients with a diagnosed SARS-CoV-2 infection were pseudo-anonymised and analysed. Vaccinated and non-vaccinated individuals were manually paired, using a predetermined matching criterion (similar age, gender, and date of hospitalisation). Demographic, clinical, treatment, and outcome data were compared between groups differing by vaccination status using Pearson’s Chi-square and Mann-Whitney tests. Moreover, multiple logistic regression analyses were performed to assess the impact of vaccination status on ICU admission or intra-hospital mortality. Results: Data from 360 patients were collected. Vaccinated patients presented with a higher prevalence of relevant comorbidities, like kidney replacement therapy or haematological malignancy, despite a milder clinical presentation at the first evaluation. Non-vaccinated patients required intensive care more often than their vaccinated counterparts (8.8% vs. 1.7%, p = 0.002). Contrariwise, no difference in intra-hospital mortality was observed between the two groups (19% vs. 20%, p = 0.853). These results were confirmed by multivariable logistic regressions, which showed that vaccination was significantly associated with decreased risk of ICU admission (aOR=0.172, 95%CI: 0.039–0.542, p = 0.007), but not of intra-hospital mortality (aOR=0.996, 95%CI: 0.582–1.703, p = 0.987). Conclusions: This study provides real-world data on vaccinated patients hospitalised with COVID-19 in Northern Italy. Our results suggest that COVID-19 vaccination has a protective role in individuals with higher risk profiles, especially regarding the need for ICU admission. These findings contribute to our understanding of SARS-CoV-2 infection outcomes among vaccinated individuals and emphasise the importance of vaccination in preventing severe disease, particularly in those countries with lower first-booster uptake rates.

Endowed with exceptional chemical and physical properties that make it potentially useful in a wide array of industrial sectors, nanocellulose remains a niche industrial product chiefly manufactured in the form of microfibrillated cellulose for low value utilization in paper and cardboard products. This study first shows that the case of nanocellulose adds to many other cases of overpromising typical of the nanosciences. Hence, it suggests that fulfilling the industrial potential of nanocellulose may benefit from the main lessons learned during the hype technology cycle (attention trigger, peak of inflated expectations, disappointment). Renewed management and research efforts aimed at large-scale production of this bionanomaterial will rather focus on the interdisciplinary approach to green chemistry required to make economically viable the green extraction routes with which to replace current energy-intensive and wasteful fibrillation processes.

Context: The primary lesion in penile cancer is managed by surgery or radiation. Surgical options include penile-sparing surgery, amputative surgery, laser excision, and Moh’s micrographic surgery. Radiation is applied as external beam radiotherapy (EBRT) and brachytherapy. The treatment aims to completely remove the primary lesion and preserve a sufficient functional penile stump. Objective: To assess whether the 5-yr recurrence-free rate and other outcomes, such as sexual function, quality of life, urination, and penile preserving length, vary between various treatment options. Evidence acquisition: The EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane HTA, DARE, HEED), Google Scholar, and ClinicalTrials.gov were searched for publications from 1990 through May 2021. Randomized controlled trials, nonrandomized comparative studies (NRCSs), and case series (CSs) were included. Evidence synthesis: The systematic review included 88 studies, involving 9578 men from 16 NRCSs and 72 CSs. The cumulative mean 5-yr recurrence-free rates were 82.0% for penile-sparing surgery, 83.9% for amputative surgery, 78.6% for brachytherapy, 55.2% for EBRT, 69.4% for lasers, and 88.2% for Moh’s micrographic surgery, as reported from CSs, and 76.7% for penile-sparing surgery and 93.3% for amputative surgery, as reported from NRCSs. Penile surgery affects sexual function, but amputative surgery causes more appearance concerns. After brachytherapy, 25% of patients reported sexual dysfunction. Both penile-sparing surgery and amputative surgery affect all aspects of psychosocial well-being. Conclusions: Despite the poor quality of evidence, data suggest that penile-sparing surgery is not inferior to amputative surgery in terms of recurrence rates in selected patients. Based on the available information, however, broadly applicable recommendations cannot be made; appropriate patient selection accounts for the relative success of all the available methods. Patient summary: We reviewed the evidence of various techniques to treat penile tumor and assessed their effectiveness in oncologic control and their functional outcomes. Penile-sparing as well as amputative surgery is an effective treatment option, but amputative surgery has a negative impact on sexual function. Penile-sparing surgery and radiotherapy are associated with a higher risk of local recurrence, but preserve sexual function and quality of life better. Laser and Moh’s micrographic surgery could be used for smaller lesions.

The use of biobased polymers or natural inorganic materials in place of synthetic polymers or liquid crystals derived from petroleum to fabricate optical components establishes the concept of “sustainable optics”, at least for what concerns the environmental dimension of sustainability as these polymers are renewable and often biodegradable or compostable. To identify the main obstacles to be addressed prior to industrial uptake of these polymeric resins in the optics industry, we focus on two promising and widely studied biobased polymeric materials, namely nanocellulose and poly(limonene carbonate). The conclusions have implications also for the emerging bioeconomy and the undergoing reshaping of the chemical industry driven by sustainability megatrend.

Greater “emotional fit” with one's cultural group is often associated with positive psychological and relational outcomes. However, the few empirical studies on this link have been limited to the comparison of Anglo-Western, independent, and East Asian, interdependent cultural contexts. In the current paper, we conceptually replicated findings from three studies on the link between emotional fit and well-being in Anglo-Western and East Asian contexts, using different methods and more comprehensive samples. Moreover, we expanded emotional fit research to the understudied Mediterranean region, characterized by an emphasis on “honor” and a distinct blend of independence and interdependence. We collected data from N = 3,097 participants from 12 countries and asked participants to report their emotional experience in 10 hypothetical situations and to rate their well-being in different domains. Our results largely replicated established positive links between emotional fit and well-being in the Anglo-West and East-Asia, as i) experiencing more culturally valued emotions (from which we infer cultural fit) was linked to better general well-being; ii) actual, calculated emotional fit in relationship-focused situations predicted better relational well-being; and iii) only in East Asia calculated emotional fit in culturally central contexts predicted psychological well-being and thriving. Our exploratory analyses on the Mediterranean region showed a non-homogenous pattern: while general well-being was consistently most strongly predicted by the intensity of disengaging emotions, relational and psychological well-being were differentially predicted by calculated emotional fit in relationship-focused situations across different Mediterranean sub-regions. The current work consolidates insights into how our well-being is shaped by the interplay between culture and emotional fit and strengthens evidence that there may be ‘universalism without uniformity’.

Introduction: Adults with congenital heart disease (ACHD) often experience elevated health anxiety. The SMART-3RP is an eight-week, mind-body group resiliency intervention with evidence to reduce health anxiety in other medical populations. The aims of this waitlist-controlled, randomized pilot feasibility trial were to explore (1) feasibility and acceptability of videoconference-delivered SMART-3RP, (2) feasibility and acceptability of remote blood pressure monitoring, and (3) changes in health anxiety, mindfulness, and resiliency. Methods: Participants (N ​= ​12 adults with CHD; Mean age ​= ​41.2 years, SD ​= ​13.8, 100% white, and 75% female) were 1:1 randomized into a pilot from July 2020 to September 2020. Participants completed surveys at baseline, three-month, and six-month follow-up; recorded their blood pressure via a digital health platform four times per week for eight weeks post-randomization (n ​= ​32 total recordings); and completed individual exit interviews. Results: 91% (29/32) of patients screened were eligible; of those, 41% (12/29) enrolled. 83% were retained at three-month follow-up (10/12) and 90% of those (9/10) were retained at six months. Average adherence to blood pressure monitoring was 70% (22/32 recordings completed; SD ​= ​31.9). Effect sizes from baseline to three months suggested greater improvement in the immediate group compared to the waitlist group for health anxiety (Cohen's r ​= ​−.59), mindfulness (r ​= ​−0.44), and resiliency (r ​= ​−0.49). Exit interviews revealed positive experiences with the intervention, benefits of mindfulness skills for coping with anxiety, and suggestions for improvement including further targeting ACHD-specific needs. Conclusions: These findings support the feasibility of conducting a randomized controlled efficacy trial of SMART-3RP for ACHD, and the acceptability and potential utility of SMART-3RP for emotional health in ACHD.

Is the production of the “AnchoisFert” organic fertilizer via the circular economy process based on omega-3 lipid extraction of milled anchovy fillet leftovers with citrus limonene followed by mild drying economically and technically viable? This study answers this question and identifies the main obstacles, chiefly of economic and organizational nature, to be overcome prior to commercialization of this new organic fertilizer. Along with non-variable and proven efficacy, successful competition with conventional organic and inorganic fertilizers requires affordable cost and regular supply. This, inter alia, requires to establish new and mutually beneficial relationship between bioeconomy firms and fish processing companies.

Regardless of multiple efforts carried out across many countries to disseminate the ideas and the practice of open science, most scholars in the early 2020s do not self-archive their research articles and do not publish research papers in preprint form. Having received no education and training on open science, researchers are often puzzled on what to do, in practice, to start reaping the benefits of open science. This study offers a succinct vademecum on how to benefit from the open science approach to scholarly communication, no matter whether in natural or in humanistic and social sciences.

Summary: Vitamin E acetate (VEA) has been strongly linked to outbreak of electronic cigarette (EC) or vaping product use-associated lung injury. How VEA leads to such an unexpected morbidity and mortality is currently unknown. To understand whether VEA impacts the disposition profile of inhaled particles, we created a biologically inspired robotic system that quantitatively analyzes submicron and microparticles generated from ECs in real-time while mimicking clinically relevant breathing and vaping topography exactly as happens in humans. We observed addition of even small quantities of VEA was sufficient to alter size distribution and significantly enhance total particles inhaled from ECs. Moreover, we demonstrated utility of our biomimetic robot for studying influence of nicotine and breathing profiles from obstructive and restrictive lung disorders. We anticipate our system will serve as a novel preclinical scientific research, decision-support tool when insight into toxicological impact of modifications in electronic nicotine delivery systems is desired.

Experimental characterization of high-strength fine wires often arises challenges greater than expected due to the difficulties encountered gripping the wire to the fixtures. To avoid premature breakage within the fixtures, capstan grips are widely utilized, but slippage might occur unless the wire is folded many times around the capstan. Further, estimating the actual elongation of the gauge section might be an issue since wires do not deform in the gauge section only but also within the folded length. This work proposes a simple clamping approach relying on sacrificial tabs made of soft and ductile material allowing to utilize classic wedge-shaped steel jaws to characterize high-strength fine wires without encountering any slippage or break within the gripping region. The suggested tabbing strategy further allows referring to the crosshead motion to evaluate the overall strain in the wire as its deformation concentrates only over the gauge length, hence excluding the use of an extensometer. This is particularly needed in the case of testing in a climatic chamber. On top of the experimental evidence, the proposed tabbing methodology is studied through analytical solutions and finite element analyses, which result in a generalized design tool that can be utilized to choose the best material and dimensions of the sacrificial tabs to correctly test wires other than the ones considered in this work.

The main purpose of this study is to analyze how reorganization of public research organizations and shrinking public research lab budgets affect the evolution of research activity and scientific productivity. This study focuses on a case study of National Research Council of Italy (CNR), one of largest European public research organizations, to identify evolution of research activities and dynamics of scientific production from 2000 to 2019. The statistical analysis suggests that, in line with the origin of the CNR, scientific research focuses mainly on research fields of natural sciences, such as chemical, life and physical sciences, with an increasing role of scientific research in energy, engineering and mathematics. The study also shows a high intensity of collaboration of the CNR within international research networks. A key finding of this study is to show, for the first time, that although uncertain reforms and reductions of public funds, scientific productivity is growing. This novel result can be explained with self-determination of scholars as a vital determinant supporting scientific production that outclasses shrinking public research lab budgets and organizational deficiencies. The management and research policy implications of this study can be generalized to support an efficient organizational and managerial behavior, and higher scientific productivity of public research institutes in contexts of reduced public funding and market turbulence.

Removing one key barrier to the industrial uptake of green chemistry and nanocatalysis in the fine and specialty chemical industry requires to fill an ongoing “talent shortage” via expanded chemistry education. In this study we show how the use of hybrid sol-gel catalysts to synthesize fine chemicals and active pharmaceutical ingredients in flow chemistry reactors illustrates new ideas to reshape chemistry education based on recent research outcomes, visualization and digital tools. Aiming to expand the knowledge base, skills and competencies that comprise the aforementioned new professional talent in catalysis and green chemistry currently in high demand, we identify several lessons learned from the industrial and academic utilization of these materials.

From professors overwhelmed by anxiety-driven e-mails from students, through faculty and administrative staff wasting valued time on e-mail minutia, misuse of electronic mail in the academy has become ubiquitous. After a brief overview of the unique features of e-mail communication, this study provides guidelines to plan new educational activities on purposeful utilization of electronic mail in university and research centres of the digital era. The overall aim is to prioritize scholarly deep work by focusing on teaching and research work, freeing working time wasted on unproductive use of e-mail.

Objective: To analyze the scientific literature on dietary changes in preterm children during the first years of life. Data source: The PubMed database was used for article selection. The texts were analyzed according to their objectives, research design, and research group characteristics. The following were selected to comprise the criteria: (1) publications in the period from 1996 to 2014; (2) participation of infants and children from birth to 10 years of age; (3) development of oral motor skills necessary for feeding; (4) development of the feeding process; and (5) feeding difficulties during childhood. Summary of the findings: There were 282 studies identified, of which 17 were used in the review, and five more articles were identified through the reference list of selected articles, totaling 22 references. Conclusion: Very low birth weight preterm newborns are more likely to have feeding problems in early postnatal stages and during childhood when compared with full-term infants. Monitoring the feeding of these infants after hospital discharge is strictly recommended in an early intervention program aiming at better development of feeding skills. Resumo: Objetivo: Analisar a literatura científica sobre alterações alimentares em crianças prematuras durante os primeiros anos de vida. Fonte dos dados: A base de dados do Pubmed foi a percursora para a seleção dos artigos. Os textos foram analisados quanto aos seus objetivos; desenhos da pesquisa; características do grupo pesquisa e foram selecionados os seguintes temas para compor os critérios: (1) publicações no período de 1996 a 2014; (2) participação de bebês e crianças, do nascimento até os 10 anos de idade; (3) desenvolvimento das habilidades motoras orais necessárias para a alimentação; (4) desenvolvimento do processo de alimentação e (5) dificuldades alimentares durante a infância. Síntese dos dados: foram identificados 282 estudos, destes 17 foram utilizados e 5 artigos foram identificados por meio da lista de referência bibliográfica dos artigos selecionados, totalizando 22 referências bibliográficas. Conclusão: A revisão permitiu concluir que recém-nascidos pré-termo muito baixo peso (RNPTMBP) são mais propensos a apresentarem problemas de alimentação nos estágios iniciais pós-natal e durante a infância quando comparados com crianças a termo. O monitoramento da alimentação após a alta hospitalar é estritamente recomendado em um programa de intervenção precoce com vistas ao melhor desenvolvimento das habilidades alimentares. Keywords: Development of feeding skills, Infant feeding, Feeding problems, Infants and preterm infants, Palavras-chave: Desenvolvimento das habilidades alimentares, Alimentação infantil, Problemas de alimentação, Bebês e crianças prematuras

Squamous cell carcinoma (SCC) of the penis is a rare cancer in the industrialized countries, including the United States. Risk factors for these cancers include inflammatory conditions as well as infection with the human papilloma virus (HPV). Treatment modalities are based on TNM staging and may include surgical management or chemoradiation. Patients with local or some regional disease can have a favorable prognosis; however, with extranodal metastasis, survival decreases sharply. Here, we present a case of long-term disease-free survival in a patient with widely metastatic SCC of the penis.

Exposure therapy is a well-studied and highly efficacious treatment for phobic disorders. Although the neurobiological model of fear is well underpinned by various studies, the mechanisms of exposure therapy are still under discussion. Partly, this is due to the fact that most neurophysiological methods like fMRI are not able to be used in the natural therapeutic settings.The current study used in situ measurements of cortical blood oxygenation (O2Hb) during exposure therapy by means of functional near-infrared spectroscopy. 37 subjects (N = 30 completers) underwent exposure therapy during 5 adapted sessions in which subjects were exposed to Tegenaria Domestica (domestic house spider – experimental condition) and Dendrobaena Veneta/ Eisenaia hortensis (red earthworm – control condition).Compared to the control condition, patients showed higher O2Hb levels in the anticipation and exposure phase of spider exposure in areas of the cognitive control network (CCN). Further, significant decreases in O2Hb were observed during the session accompanied by reductions in fear related symptoms. However, while symptoms decreased in a linear quadratic manner, with higher reductions in the beginning of the session, CCN activity decreased linearly. Further, higher anxiety at the beginning of session one was associated with increased O2Hb in the CCN. This association decreased within the following sessions.The current study sheds light on the neuronal mechanisms of exposure therapy. The results are discussed in light of a phase model of exposure therapy that posits a role of cognitive control in the beginning and routine learning at the end of the therapy session.

Bone metastasis of non-seminomatous germ cell tumors (NSGCT) of the testes is a rare event and even more uncommon at initial presentation. Generally, bone lesions are discovered in the presence of concurrent retroperitoneal lymph node or visceral disease. However, in this case, a 37 years old male complaining of a growing testicular mass was found to have isolated bone metastasis with associated caudaequina syndrome without apparent abnormal findings on initial computed tomography (CT) scans. Continued neurologic symptoms prompted further evaluation with magnetic resonance imaging (MRI), which demonstrated multiple sites of bone metastasis without evidence of retroperitoneal lymph node or visceral organ involvement. This case represents a rare clinical presentation and disease manifestation of NSGCT.

Driven by the rapid uptake of battery electric vehicles, Li-ion power batteries are increasingly reused in stationary energy storage systems, and eventually recycled to recover all the valued components. Offering an updated global perspective, this study provides a circular economy insight on lithium-ion battery reuse and recycling.

The elucidation of toxicity determinants of multi-walled carbon nanotubes (MWCNT) is still incomplete. Functionalization with carboxyl groups is, however, commonly used to mitigate MWCNT toxicity, although the rationale for the mitigating effect has not been fully clarified yet. In this work, two optimized chemical vapor deposition methods were employed to obtain MWCNT of comparable length but different diameter, which were subsequently functionalized. For MWCNT of diameter larger than 40 nm, no detrimental effects on cell viability of macrophages were observed, while mild cytotoxicity was recorded for diameters between 15 and 40 nm, with a mitigating effect of functionalization. To investigate the factors responsible for the mitigation, we used the thinnest MWCNT preparation on different cell models, evaluating several endpoints, such as viability, production of nitric oxide (NO), expression of pro-inflammatory markers, the Trans-Epithelial Electrical Resistance (TEER), and clonogenic activity. Substantial mitigation of the changes caused by pristine MWCNT was observed not only with carboxyl- but also with amino-functionalized MWCNT, suggesting that negative or positive surface charge was not the main factor responsible for the effect. Instead, either functionalized preparation exhibited a stronger tendency to agglomerate that was strictly dependent on the presence of proteins. Moreover, we found that either carboxyl- or amino-functionalized MWCNT adsorbed a larger amount of serum proteins than pristine counterparts, with a distinctive pattern for each type of MWCNT. We propose, therefore, that the formation of larger agglomerates, dependent upon different protein coronae, contributes to mitigate the biological effects of functionalized MWCNT in protein-rich biological media. Keywords: Carbon nanotubes, Macrophages, Airway epithelium, Inflammation, Functionalization, Agglomeration, Protein corona

The relevance of extracellular vesicles (EV) as mediators of cardiac damage or recovery upon Ischemia Reperfusion Injury (IRI) and Remote Ischemic PreConditioning (RIPC) is controversial. This study aimed to investigate whether serum-derived EV, recovered from patients with Acute Coronary Syndrome (ACS) and subjected to the RIPC or sham procedures, may be a suitable therapeutic approach to prevent IRI during Percutaneous-Coronary-Intervention (PCI). A double-blind, randomized, sham-controlled study (NCT02195726) has been extended, and EV were recovered from 30 patients who were randomly assigned (1:1) to undergo the RIPC- (EV-RIPC) or sham-procedures (EV-naive) before PCI. Patient-derived EV were analyzed by TEM, FACS and western blot. We found that troponin (TnT) was enriched in EV, compared to healthy subjects, regardless of diagnosis. EV-naive induced protection against IRI, both in-vitro and in the rat heart, unlike EV-RIPC. We noticed that EV-naive led to STAT-3 phosphorylation, while EV-RIPC to Erk-1/2 activation in the rat heart. Pre-treatment of the rat heart with specific STAT-3 and Erk-1/2 inhibitors led us to demonstrate that STAT-3 is crucial for EV-naive-mediated protection. In the same model, Erk-1/2 inhibition rescued STAT-3 activation and protection upon EV-RIPC treatment. 84 Human Cardiovascular Disease mRNAs were screened and DUSP6 mRNA was found enriched in patient-derived EV-naive. Indeed, DUSP6 silencing in EV-naive prevented STAT-3 phosphorylation and cardio-protection in the rat heart. This analysis of ACS-patients' EV proved: (i) EV-naive cardio-protective activity and mechanism of action; (ii) the lack of EV-RIPC-mediated cardio-protection; (iii) the properness of the in-vitro assay to predict EV effectiveness in-vivo., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Neuregulin1 (Nrg1) and its receptors ErbB are crucial for heart development and for adult heart structural maintenance and function and Nrg1 has been proposed for heart failure treatment. Infarct size is the major determinant of heart failure and the mechanism of action and the role of each ErbB receptor remain obscure, especially in the post-ischemic myocardium. We hypothesized that Nrg1 and ErbB are affected at transcriptional level early after ischemia/reperfusion (I/R) injury, and that the protective postconditioning procedure (PostC, brief cycles of ischemia/reperfusion carried out after a sustained ischemia) can influence this pathway., Methods and Results: The Langendorff's heart was used as an ex-vivo model to mimic an I/R injury in the whole rat heart; after 30min of ischemia and 2h of reperfusion, with or without PostC, Nrg1 and ErbB expression were analysed by quantitative real-time PCR and Western blot. While no changes occur for ErbB2, ErbB4 and Nrg1, an increase of ErbB3 expression occurs after I/R injury, with and without PostC. However, I/R reduces ErbB3 protein, whereas PostC preserves it. An in vitro analysis with H9c2 cells exposed to redox-stress indicated that the transient over-expression of ErbB3 alone is able to increase cell survival (MTT assay), limiting mitochondrial dysfunction (JC-1 probe) and apoptotic signals (Bax/Bcl-2 ratio)., Conclusions: This study suggests ErbB3 as a protective factor against death pathways activated by redox stress and supports an involvement of this receptor in the pro-survival responses., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ischemic heart disease remains the leading cause of death worldwide. Ischemic pre-, post-, and remote conditionings trigger endogenous cardioprotection that renders the heart resistant to ischemic-reperfusion injury (IRI). Mimicking endogenous cardioprotection by modulating genes involved in cardioprotective signal transduction provides an opportunity to reproduce endogenous cardioprotection with better possibilities of translation into the clinical setting. Genes and signaling pathways by which conditioning maneuvers exert their effects on the heart are partially understood. This is due to the targeted approach that allowed identifying one or a few genes associated with IRI and cardioprotection. Genes critical for signaling pathways in cardioprotection include protectomiRs (e.g., microRNA 125b*), ZAC1 transcription factor, pro-inflammatory genes such as cycloxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), antioxidant enzymes such as hemoxygenase (HO)-1, extracellular and manganese superoxidase dismutases (ec-SOD and Mg-SOD), heat shock proteins (HSPs), growth factors such as insulin like growth factor (IGF)-1 and hepatocyte growth factor (HGF), antiapoptotic proteins such as Bcl-2 and Bcl-xL, pro-apoptotic proteins such as FasL, Bcl-2, Bax, caspase-3 and p53, and proangiogenic genes such as TGFbeta, sphingosine kinase 1 (SPK1), and PI3K-Akt. By identifying the gene expression profiles of IRI and ischemic conditioning, one may reveal potential gene targets responsible for cardioprotection. In this manuscript, we review the current state of the art of gene therapy in cardioprotection and propose that gene expression analysis facilitates the identification of individual genes associated with cardioprotection. We discuss signaling pathways associated with cardioprotection that can be targeted by gene therapy to achieve cardioprotection., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background Aims: The presence of ectopic tissues in the pathologic artery wall raises the issue of whether multipotent stem cells may reside in the vasculature itself. Recently mesenchymal stromal cells (MSC) have been isolated from different human vascular segments (VW MSC), belying the previous view that the vessel wall is a relatively quiescent tissue., Methods: Resident multipotent cells were recovered from fresh arterial segments (aortic arches, thoracic and femoral arteries) collected in a tissue-banking facility and used to establish an in situ and in vitro study of the stemness features and multipotency of these multidistrict MSC populations., Results: Notch-1+, Stro-1+, Sca-1+ and Oct-4+ cells were distributed along an arterial wall vasculogenic niche. Multidistrict VW MSC homogeneously expressed markers of stemness (Stro-1, Notch-1 and Oct-4) and MSC lineages (CD44, CD90, CD105, CD73, CD29 and CD166) whilst they were negative for hematopoietic and endothelial markers (CD34, CD45, CD31 and vWF). Each VW MSC population had characteristics of stem cells, i.e. a high efflux capability for Hoechst 33342 dye and the ability to form spheroids when grown in suspension and generate colonies when seeded at low density. Again, VW MSC cultured in induction media exhibited adipogenic, chondrogenic and leiomyogenic potential but less propensity to osteogenic differentiation, as documented by histochemical, immunohistochemical, molecular and electron microscopy analysis., Conclusions: Overall, these findings may enlighten the physiopathologic mechanisms of vascular wall diseases as well as having potential implications for cellular, genetic and tissue engineering approaches to treating vascular pathologies when these are unresponsive to medical and surgical therapies.

New cell sorting methodologies, which are simple, fast, non-invasive, and able to isolate homogeneous cell populations, are needed for applications ranging from gene expression analysis to cell-based therapy. In particular, in the forefront of stem cell isolation, progenitor cells have to be separated under mild experimental conditions from complex heterogeneous mixtures prepared from human tissues. Most of the methodologies now employed make use of immunological markers. However, it is widely acknowledged that specific markers for pluripotent stem cells are not as yet available, and cell labelling may interfere with the differentiation process. This work presents for the first time gravitational field-flow fractionation (GrFFF), as a tool for tag-less, direct selection of human hematopoietic stem and progenitor cells from cell samples obtained by peripheral blood aphaeresis. These cells are responsible to repopulate the hemopoietic system and they are used in transplantation therapies. Blood aphaeresis sample were injected into a GrFFF system and collected fractions were characterized by flow cytometry for CD34 and CD45 expression, and then tested for viability and multi-differentiation potential. The developed GrFFF method allowed obtaining high enrichment levels of viable, multi-potent hematopoietic stem cells in specific fraction and it showed to fulfil major requirements of analytical performance, such as selectivity and reproducibility of the fractionation process and high sample recovery.

Background and Aim: The beneficial effects of exercise in reducing the incidence of cardiovascular diseases are well known. Several studies have demonstrated that forced exercise (FE) could activate a stress response similar to a restrain stress. Previous studies suggest that heart protection to ischemic events would be improved by an omega 3 free fatty acid (omega3-FFA)-enriched diet. Here, we investigate the impact of stressful FE and an omega 3-FFA-enriched diet on cardiac tolerance to ischemic events over one month., Methods and Results: Twenty-four Wistar rats were randomly assigned to one of the following protocols: 1) Sedentary (SED) animals who were regularly fed; 2) sedentary animals who were given 1ml/day of fish oil for one month; 3) FE+omega3-FFA rats who were given 1ml/day of fish oil and forced to run on a motorized wheel for 30min every day, both for one month; and 4) FE animals were forced to exercise as group 3 and fed with a regular diet. At the end of the treatments an isolated heart preparation was performed. After a 30min global ischemic event and 2h reperfusion, hearts of sedentary-omega3 animals recovered about 37% of left ventricular developed pressure, whereas FE, omega3+FE and CTRL-SED animals recovered only about 15%, 5% and 8% respectively. Similarly, heart infarct size was significantly lower in sedentary-omega3 animals compared to animals in the three other groups., Conclusions: Results indicate that one month of treatment with an omega3-FFA-enriched diet improves cardioprotection upon ischemic events, whereas FE leads to a reduced heart tolerance to ischemic events, which cannot be reversed by an omega3-FFA diet.

Background Aims: Bone marrow (BM)- and adipose tissue (AT)-derived mesenchymal stromal cells (MSC) are currently under evaluation in phase III clinical trials for inflammatory bowel disease and other intestinal disease manifestations. The therapeutic efficacy of these treatments may derive from a combination of the differentiation, trophic and immunomodulatory abilities of the transplanted cells. We investigated intestinal tissues as sources of MSC: such cells may support tissue-specific functions and hold advantages for engraftment and contribution in the gastrointestinal environment., Methods: Intestinal specimens were collected, and the mucosa and submucosa mechanically separated and enzymatically digested. Mesenchymal stromal populations were isolated, expanded and characterized under conditions commonly used for MSC. The differentiation potential, trophic effect and immunomodulatory ability were investigated. Results We successfully isolated and extensively expanded populations showing the typical MSC profile: CD29+, CD44+, CD73+, CD105+ and CD166+, and CD14(-), CD34(-) and CD45(-). Intestinal mucosal (IM) MSC were also CD117+, while submucosal cultures (ISM MSC) showed CD34+ subsets. The cells differentiated toward osteogenic, adipogenic and angiogenic commitments. Intestinal-derived MSC were able to induce differentiation and organization of intestinal epithelial cells (Caco-2) in three-dimensional collagen cultures. Immunomodulatory activity was evidenced in co-cultures with normal heterologous phytohemagglutinin-stimulated peripheral blood mononuclear cells. Conclusions Multipotent MSC can be isolated from intestinal mucosal and submucosal tissues. IM MSC and ISM MSC are able to perform trophic and immunomodulatory functions. These findings could open a pathway for novel approaches to intestinal disease treatment.

Nitric oxide (NO) participates in the control of contractility and heart rate, limits cardiac remodeling after an infarction and contributes to the protective effect of ischemic pre- and postconditioning. Low concentrations of NO, with production of small amounts of cGMP, inhibit phosphodiesterase III, thus preventing the hydrolysis of cAMP. The subsequent activation of a protein-kinase A causes the opening of sarcolemmal voltage-operated and sarcoplasmic ryanodin receptor Ca(2+) channels, thus increasing myocardial contractility. High concentrations of NO induce the production of larger amounts of cGMP which are responsible for a cardiodepression in response to an activation of protein kinase G (PKG) with blockade of sarcolemmal Ca(2+) channels. NO is also involved in reduced contractile response to adrenergic stimulation in heart failure. A reduction of heart rate is an evident effect of NO-synthase (NOS) inhibition. It is noteworthy that the direct effect of NOS inhibition can be altered if baroreceptors are stimulated by increases in blood pressure. Finally, NO can limit the deleterious effects of cardiac remodeling after myocardial infarction possibly via the cGMP pathway. The protective effect of NO is mainly mediated by the guanylyl cyclase-cGMP pathway resulting in activation of PKG with opening of mitochondrial ATP-sensitive potassium channels and inhibition of the mitochondrial permeability transition pores. NO acting on heart is produced by vascular and endocardial endothelial NOS, as well as neuronal and inducible synthases. In particular, while in the basal control of contractility, endothelial synthase has a predominant role, the inducible isoform is mainly responsible for the cardiodepression in septic shock.

Ischemic preconditioning (IP) triggers cardioprotection via a signaling pathway that converges on mitochondria. The effects of the inhibition of carnitine palmitoyltransferase I (CPT-I), a key enzyme for transport of long chain fatty acids (LCFA) into the mitochondria, on ischemia/reperfusion (I/R) injury are unknown. Here we investigated, in isolated perfused rat hearts, whether sub-chronic CPT-I inhibition (5 days i.p. injection of 25 mg/kg/day of Etomoxir) affects I/R-induced damages and whether cardioprotection by IP can be induced after this inhibition. Effects of global ischemia (30 min) and reperfusion (120 min) were examined in hearts harvested from Control (untreated), Vehicle- or Etomoxir-treated animals. In subsets of hearts from the three treated groups, IP was induced by three cycles of 3 min ischemia followed by 10 min reperfusion prior to I/R. The extent of I/R injury under each condition was assessed by changes in infarct size as well as in myocardial contractility. Postischemic contractility, as indexed by developed pressure and dP/dt(max), was similarly affected by I/R, and was similarly improved with IP in Control, Vehicle or Etomoxir treated animals. Infarct size was also similar in the three subsets without IP, and was significantly reduced by IP regardless of CPT-I inhibition. We conclude that CPT-I inhibition does not affect I/R damages. Our data also show that IP affords myocardial protection in CPT-I inhibited hearts to a degree similar to untreated animals, suggesting that a long-term treatment with the metabolic anti-ischemic agent Etomoxir does not impede the possibility to afford cardioprotection by ischemic preconditioning.

The radical gas nitric oxide (NO) is implicated in an enormous number of biological function both in physiological and pathological conditions. Often it is not clear if it plays a deleterious or beneficial role. Here briefly, are analyzed some of the reasons of this multitude of effects. Emphasis is given to factors influencing NO formation and to the type and quantity of radicals formed by nitric oxide synthase. In particular, a comparison between the biological effects of nitroxyl anion (HNO/NO(-)) and nitric oxide NO(.) is considered. These redox siblings often exhibit orthogonal behavior in physiological and pathological conditions. In the light of the multitude of effects of NO, the role of this gas, their siblings and their derivatives in cardiac ischemic preconditioning scenario is more extensively analyzed.

Ischemic preconditioning increases the velocity of vasodilatation and reduces the total hyperemic flow (THF) of a subsequent coronary reactive hyperemia (CRH). The increase in the velocity of vasodilatation has been shown to depend on an up-regulation of the endothelial release of nitric oxide, while the reduction of THF is attributed to an adenosine A(1) receptor-mediated mechanism. We investigated whether the changes in CRH induced by preconditioning ischemia (PI) can still be obtained after blockade of mitochondrial ATP-sensitive K(+) channels by sodium 5-hydroxydecanoate (5-HD), and whether the blockade per se affects the pattern of CRH. In anesthetized goats, flow was recorded from the left circumflex coronary artery (LCCA). CRH was obtained with the occlusion of LCCA for 15 s. PI was obtained by 2 cycles of 2.5 min of LCCA occlusion with a 5 min interval of reperfusion between the two occlusions. CRH was studied before and after i.v. administration of 5-HD (20 mg/kg), as well as in the presence of 5-HD after PI. Following 5-HD, the pattern of CRH remained unchanged. After 5-HD and PI, velocity of vasodilatation and total hyperemic flow of CRH showed the same changes as in previous studies after PI alone. It was concluded that the blockade of mitochondrial ATP-sensitive K(+) channels, which is reported to prevent myocardial protection, does not affect CRH and does not prevent PI from increasing the velocity of vasodilatation and reducing THF. These results demonstrate that the changes induced in CRH by preconditioning are independent of the opening of the mitochondrial ATP-sensitive K(+) channels.

Barbiturates induce reduction of myocardial contractility and metabolism, whereas ketamine exerts a sympathomimetic effect that can mask its direct depressant effect on contractility. However, it is unclear whether barbiturates, which interfere with the cytochrome P-450 pathway, or ketamine, which inhibits nitric oxide synthesis, also alter the responsiveness of the coronary vessels to vasodilator stimuli. We hypothesized that the parameters of coronary reactive hyperemia (CRH), which reflect both the degree of myocardial metabolism and vascular reactivity, could be modified by the type of anesthesia used. In two groups of goats, anesthesia was induced either using ketamine plus nitrous oxide or pentobarbital alone. To record coronary flow an electromagnetic flow-probe was placed around the left circumflex coronary artery. In the ketamine group (n = 14) and in the pentobarbital group (n = 16) CRH was studied using the indices of myocardial metabolism and vascular dilator responsiveness. In the pentobarbital group all of the indices of myocardial metabolism were lower than in the ketamine group (i.e. the excess to debt flow ratio was 2.3+/-0.8 vs. 4.6+/-2.4; p< 0.001). Yet, some indices of vascular responsiveness (time derivative of coronary flow and the peak to basal flow ratio) were not different in the two groups. Moreover, the duration of the reactive hyperemia was shorter in the ketamine than in the pentobarbital group (118+/-47 vs. 153+/-45 s, p<0.05). It is suggested that pentobarbital decreases the indices of CRH related to metabolic activity, whereas ketamine reduces the duration of the hyperemic response, which suggests an impairment of endothelial function.

In many species one or more brief coronary occlusions limit the injuries which a subsequent ischemia-reperfusion can produce in the myocardium. A similar protection has been observed in the majority of organ systems. A first period or window of protection can lasts up to 3 hours and is followed by a second window of protection (SWOP) which begins about 24 hours after the brief coronary occlusions and lasts about 72 hours. Increase of the release of endogenous agents such as adenosine and nitric oxide (NO) may be responsible for both windows through the activation of a protein-kinase C (PKC) which in turn activates ATP sensitive potassium (K+(ATP)) channels. Nitric oxide is also reported to act directly on K+(ATP) channels. Recently, it has been suggested that the channels involved in the protection are mitochondrial rather than sarcolemmal. In SWOP the origin of NO is attributed to the activity of an inducible NO-synthase. Free oxygen radicals released during preconditioning are likely to take part in the delayed protection through the production of peroxynitrite which activates PKC and through the increase of the activity of antioxidant enzymes such as Mn superoxide-dismutase. The production of heat shock proteins is considered a marker rather than a mechanism of SWOP.

The response of the coronary vasculature to an experimental manoeuvre of step-like decrease of the perfusion pressure has been investigated with a model. The coronary vasculature was simulated using a 'windkessel' scheme. Proximal resistance and compliance were assumed to be pressure-independent. The distal resistance, on the contrary, was controlled by a feed-back loop which accounts for the smooth muscle activation induced by the pressure variation. Three more parameters were introduced, and namely the smooth muscle activation time constant and the pressure-induced and flow-induced gains. The parameter values were assessed by comparing the model predicted coronary flow with the one actually measured in animals.

The aim of this study was the quantitative evaluation of the myotatic reflex in a group of 26 patients affected by stationary spastic paresis (6: hemiparesis; 5: paraparesis; 8: tetraparesis; 7: multiple sclerosis) before and after a treatment of hydro-kinesy therapy. The treatment was carried out in an indoor pool containing warm (32 degrees C) sea water and consisted of active and passive motion exercises, coordination exercises and immersion walking. The measured parameters were: (i) the peak input force (FpH) measured by means of an instrumented hammer with which the patellar tendon was hit; and (ii) the peak value of the corresponding reflex force of the quadriceps femoris (FpQ) measured by means of a load cell connected to the subject's ankle. The peak values of the reflex response (FpQ) were found to increase as a function of the intensity of the imposed stimulus and to reach a plateau between 15 and 30 N of FpH. A Student's t test applied to the paired values of FpQ (as measured at plateau conditions) on both the lower limbs, before and after therapy, showed no significant changes due to the treatment in the four groups of subjects. However, if all subjects were grouped regardless the type of illness: 1) the average reflex response of the affected limb (the one characterized before therapy by the higher FpQ values) was found to decrease following the treatment (75.1+/-26.7 N pre therapy and 69.1+/-29.3 N post therapy, p = 0.07, n = 26); and 2) the effect of the treatment was found to be significantly larger (p = 0.04, n = 26) on the affected limb (delta FpQ = 6.07+/-16.5 N) as respect with the contra lateral one (delta FpQ = -0.16+/-12.1 N).

Since its discovery over 20 years ago as an intercellular messenger, nitric oxide (NO), has been extensively studied with regard to its involvement in the control of the circulation and, more recently, in the prevention of atherosclerosis. The importance of NO in coronary blood flow control has also been recognized. NO-independent vasodilation causes increased shear stress within the blood vessel which, in turn, stimulates endothelial NO synthase activation, NO release and prolongation of vasodilation. Reactive hyperemia, myogenic vasodilation and vasodilator effects of acetylcholine and bradykinin are all mediated by NO. Ischemic preconditioning, which protects the myocardium from cellular damage and arrhythmias, is itself linked with NO and both the first and second windows of protection may be due to NO release. Exercise increases NO synthesis via increases in shear stress and pulse pressure and so it is likely that NO is an important blood flow regulatory mechanism in exercise. This phenomenon may account for the beneficial effects of exercise seen in atherosclerotic individuals. Whilst NO plays a protective role in preventing atherosclerosis via superoxide anion scavenging, risk factors such as hypercholesterolemia reduce NO release leading the way for endothelial dysfunction and atherosclerotic lesions. Exercise reverses this process by stimulating NO synthesis and release. Other factors impacting on the activity of NO include estrogens, endothelins, adrenomedullin and adenosine, the last appearing to be a compensatory pathway for coronary control in the presence of NO inhibition. These studies reinforce the pivotal role played by the substance in the control of coronary circulation.

During the myocardial protection induced by ischemic preconditioning a reduction in myocardial metabolism occurs due to activation of the A1 adenosine receptors. This study investigates whether preconditioning changes both resting coronary flow and the magnitude of coronary reactive hyperemia and whether A1 adenosine receptors are involved in the observed changes. Experiments were performed in 14 goats (30-50 kg body weight). After the animals were anesthetized with ketamine, an electromagnetic flow-probe was used to record blood flow in the left circumflex coronary artery. Distal to the probe, an occluder was placed to produce ischemic preconditioning and reactive hyperemia. Preconditioning was obtained with two periods of 2.5 min of coronary occlusion separated from each other by 5 min of reperfusion. Coronary reactive hyperemia was obtained with 15 s of occlusion of the artery before and after preconditioning. In a group of goats before preconditioning 0.2 mg kg(-1) of 8-cyclopentyl-dipropylxanthine (CPX), an A1 adenosine receptor blocker, were given intravenously. In all animals ischemic preconditioning did not alter resting coronary flow, but, in the absence of A1 adenosine receptor blockade, reduced the reactive hyperemic response. The total hyperemic flow and the excess/debt flow ratio were reduced by about 25% and 30% respectively. The A1 adenosine receptor blockade "per se" did not cause any change in the resting flow and in the parameters of the reactive hyperemia. Unlike what observed in the absence of blockade, after CPX ischemic preconditioning was unable to reduce total hyperemic flow and the excess/debt flow ratio. The results suggest that ischemic preconditioning reduces the coronary hyperemic response by decreasing the myocardial metabolism through the activation of the A1 adenosine receptors.

The effects of Bitis gabonica venom have been studied in several animal species, including the monkey, dog, rabbit, rat and guinea pig. Further information has been provided by observations on the effects of snake bite in man. Bitis gabonica venom exerts a number of cytotoxic and cardiovascular effects: cytotoxic effects include widespread hemorrhage, caused by the presence of two hemorrhagic proteins. These hemorrhagins bring about separation of vascular endothelial cells and extravasation of blood into the tissue spaces. Metabolic alterations include decreased oxygen utilization by tissues and increased plasma glucose and lactate concentrations. Metabolic non-compensated acidosis has also been seen in the rat as a consequence of the cytotoxicity of the venom. Cardiovascular effects include disturbances in atrio-ventricular conduction and reduction in amplitude and duration of the action potential brought about by a decreased calcium membrane conductance. A progressive decrease in myocardial contractility can also be attributed to the decreased calcium conductance, which together with the severe acidosis may cause death in experimental animals. A severe, though reversible, vasodilatation was observed after envenomation due to unidentified compounds in the venom. In man, envenomation causes a variable clinical picture depending on the time course and severity of envenomation. Frequently seen effects include hypotension, hemorrhage at the site of the bite and elsewhere and disseminated intravascular coagulation. Envenomation can be satisfactorily treated with antivenom.

Ischemic preconditioning can be obtained with brief coronary occlusions. It has been studied in different animal species including dogs, pigs, rabbits and rats. The suggested duration of the occlusions ranges from four periods of 5 min, separated from each other by 5 min of reperfusion, to one period of 2.5 min. In addition to the reduction of the size of a subsequent infarction, preconditioning is responsible for the attenuation of the ischemia-reperfusion injury. The protection has a short duration and does not exceed two hours. Myocardial, neural and endothelial factors are involved in preconditioning. The myocardial component includes an increased release of adenosine with activation of A1 adenosine receptors, the activation of a protein-kinase C and possibly of antioxidant enzymes. The neural component includes a reduction in the release of noradrenaline from the postganglionic sympathetic fibers and a reduced myocardial sensitivity to noradrenaline. The increased myocardial release of adenosine, together with the reduced adrenergic activity, is consistent with the reduction in myocardial metabolism which has been observed after preconditioning. The coronary vascular endothelium is concerned in an increased release of nitric oxide which seems to be responsible for a prevention of reperfusion arrhythmias. In addition to the protective effect exerted on the myocardium, ischemic preconditioning seems to be responsible for a change in the coronary responsiveness to short periods of occlusion followed by release. This change in responsiveness is mainly represented by a greater velocity of the increase in flow occurring in the coronary reactive hyperemia.

The effect of the inhibition of the endothelial release of nitric oxide (NO) on the hyperaemia which follows a 10 s coronary occlusion was studied in anaesthetized dogs. Aortic blood pressure was kept constant during the experiments using an arterial reservoir connected with the femoral arteries. The blood flow in the left circumflex coronary artery was recorded with an electromagnetic flow probe. A 10 s coronary occlusion was performed before and after intracoronary infusion of Nitro-L-arginine (LNNA), at the dose of 100 mg in 20 min. The effect of LNNA in preventing the release of NO by the endothelium was demonstrated by the reduced coronary hyperaemia which follows the intracoronary infusion of acetylcholine. After LNNA the baseline coronary flow was not altered. Following the release of the coronary occlusion the peak amplitude of the reactive hyperaemia was not significantly changed, while the duration was reduced to almost a half of the control. The results suggest that in the intact dog NO is not important in the regulation of the baseline coronary vasomotor tone. It may also be argued that the peak amplitude of the hyperaemia is not significantly affected by LNNA either because the inhibition of the release of nitric oxide is counteracted by a greater production of adenosine, or because a mechanism not affected by nitric oxide (e.g. a myogenic mechanism) is involved in the reactive hyperaemia. In contrast the reduction of the duration of the hyperaemia after the inhibitor may depend on a reduced effect of the shear stress of the blood on the endothelium during the reactive hyperaemia.

The mechanical and electrical effects of the venom of Bitis nasicornis were studied on the guinea-pig Langendorff and left atrial myocardium preparations. While Langendorff preparations were treated with individual doses of 0.1, 0.6 and 1.4 mg, isolated left atria were treated using concentrations of 2.0, 20 and 200 micrograms/ml of venom in the perfusion solution. In the Langendorff preparation, transient increases in left ventricular systolic pressure (LVSP) and heart rate (HR) were seen after 0.1 mg of venom. When 0.6 mg of venom was given, the increases were followed by decreases, while 1.4 mg doses simply induced decreases in LVSP and HR. After both 0.6 and 1.4 mg doses the decreases were accompanied by increases in left ventricular diastolic pressure. In addition to these mechanical effects, transient increases in HR with atrio-ventricular blocks, ventricular extrasystoles and tachycardia were observed after each dose. In the left atrium the 2 micrograms/ml venom concentration produced an increase, followed by a decrease, in the maximum tension developed, which was only seen to decrease with higher concentrations of 20 and 200 micrograms/ml of venom. A dose dependent significant reduction in the action potential duration was observed for the doses of 0.6 and 1.4 mg in the ventricle and for all three concentrations in the atrium.

The acid-base and metabolic effects of Bitis gabonica venom administered intravenously to the anaesthetised rabbit were studied. Doubling doses of venom from 0.125 mg/kg to 1.0 mg/kg were used. Venom caused progressive and significant increases in plasma glucose and plasma lactate levels although oxygen consumption only became significantly lower after the fourth dose. Standard base excess (SBE) became significantly more negative after the third dose of venom and the fall in pH became significant at the same point. The results indicate that venom induces a metabolic acidosis in the rabbit and because the acidosis occurs in the absence of any fall in arterial PO2, it cannot be considered a consequence of impaired pulmonary ventilation. The reduction in oxygen uptake is likely to occur at a cellular level with a shift from aerobic to anaerobic metabolism hence the increase in plasma lactate levels. However, the magnitude of the acidosis is unlikely to be the principal cause of death under experimental conditions.