Volume 16 - 2022 | https://doi.org/10.3389/fnbeh.2022.831664 Non-motor symptoms are frequently observed in Parkinson’s disease (PD) and precede the onset of motor deficits by years are increasingly considered as a major challenge for patients with PD and their caregivers We recently reported that mice lacking the nuclear factor-κB (NF-κB)/c-Rel protein (c-rel–/– mice) develop an age-dependent PD-like pathology and phenotype characterized by the onset of non-motor symptoms To assess whether c-rel–/– mice also suffer from neuropsychiatric symptoms in this study we tested different cohorts of wild-type (wt) and c-rel–/– mice at 3 and 18–20 months with different behavioral tests Mice lacking c-Rel displayed anxiety and depressive-like behavior starting in the premotor phase at 12 months as indicated by the analysis with the open field (OF) test and the forced swim test with water wheel (FST) A deficit in the goal-oriented nesting building test was detected at 18–20 months these results indicate that c-rel–/– mice recapitulate the onset and the progression of PD-related neuropsychiatric symptoms this animal model may represent a valuable tool to study the prodromal stage of PD and for testing new therapeutic strategies to alleviate neuropsychiatric symptoms Different cohorts of wt and c-rel–/– mice at 3, 6, 12, and 18–20 months of age were tested with the behavioral tasks described below to assess anxiety, depressive-like behavior, apathy, short-term memory, and fine motor deficits. Every cohort of animals was analyzed once with only one behavioral test. The list of mice subjected to the different behavioral tests is reported in Table 1 List of mice/cages used in the behavioral tests The test was performed during the dark phase of the light-dark cycle the time spent by the mice turning the wheel) and maximum and average rpm (revolutions per min) were automatically recorded by a rotation decoder controlled by a software (Ugo Basile ANY-Maze) The task was performed during the light phase Working memory was assessed using a Y-maze [arms 21 cm (long) by 4 cm (wide) with 40-cm walls] (Parrella et al., 2013) the mouse was placed in one of the arms of the maze and allowed to freely explore the environment for 8 min The mouse performance was recorded by a video tracking system (Ugo Basile ANY-Maze) An arm choice was defined as both forepaws and hind paws fully entering the arm Spontaneous alternation behavior (SAB) score was calculated as the ratio of alternations (an arm choice differing from the previous two choices) to the total number of alternation opportunities The novel object recognition test relies on the natural propensity of rodents to explore novel objects, and it has been used to assess short-term spatial memory (Grayson et al., 2015). The maze consists of a black plastic OF box [40 (length) × 40 (width) × 40 (height) cm]. The test is based on the protocol previously described (Parrella et al., 2013) on the first day of the test (habituation day) the mouse was placed into the box and allowed to explore the field for 5 min the habituated mouse was placed again into the box in the presence of two identical non-toxic objects (laboratory flask caps) and was let to freely explore them for 5 min (trial 1) and the time spent exploring the objects was scored considering the exploration of any physical contact with an object and/or approach with obvious orientation to it within 5 cm the mouse was placed back into the arena where one of the familiar objects was replaced by a novel object (ping pong ball) The mouse was allowed to explore the arena for 5 min and its behavior was recorded again by the video tracking system Recognition index (RI) was calculated as the time spent by the animal exploring the novel object to the total time spent exploring both the objects Fine motor deficits were assessed by the adhesive removal test (Fleming et al., 2013) the mouse was restrained by grasping its scruff and one adhesive label was gently placed onto its snout by using a pair of small forceps The time needed by the mouse to remove the adhesive was recorded If the animal did not remove the label within 60 s the trial ended and the adhesive was removed manually by the experimenter Trials where the label fell off were not considered We scored the best result over three trials Statistical analysis was performed with the GraphPad Prism software The value of p < 0.05 was considered significant Comparisons between the two groups were performed using the parametric two-tailed unpaired Student’s t-test or the non-parametric Mann–Whitney test Comparisons among more than two groups were performed using the parametric two-way ANOVA followed by Sidak’s multiple comparison test or the non-parametric Kruskal–Wallis test followed by Dunn’s multiple comparison test The data analyzed using parametric tests were expressed as mean ± standard error of the mean (SEM) while the data analyzed using non-parametric tests were expressed as median ± interquartile range Different cohorts of wild-type (wt) and c-Rel protein (c-rel–/–) mice were tested for anxiety-like behavior in the open field (OF) at 3 (A) Representative track plots of 18–20-month-old wt and c-rel–/– mice at the end of a 5-min OF test The distance travelled by the mice is represented by the purple lines and the average speed calculated in the center of the apparatus (C–E and the number of entries registered in the peripheral area (F–H No significant differences were found between wt and c-rel–/– mice at 3 and 6 months in any of the described parameters c-rel–/– mice covered a higher total distance (B spent less time and walked a lower distance but at a higher speed in the central area (C–E and spent more time and entered more often in the peripheral area (F the differences between wt and c-rel–/– mice became significant for the distance covered in the peripheral area (G remained significant for the time spent and distance covered in the central area and the time spent in the peripheral area (C,D,F and further increased for the total distance covered (B and the number of entries in the peripheral area (H the number of entries in the peripheral area decreased with aging only in wt groups (H: p < 0.0001 we observed an age-dependent decline in the time spent and the distance covered in the peripheral area for both wt and c-rel–/– mice (F,G: p < 0.0001 c-rel–/– 12 months; p < 0.05 c-rel–/– 18–20 months) 3-month-old wt: 12 mice; 3-month-old c-rel–/–: 16 mice; 6-month-old wt: 13 mice; 6-month-old c-rel–/–: 13 mice; 12-month-old wt: 13 mice; 12-month-old c-rel–/–: 15 mice; 18–20-month-old wt: 14 mice; and 18–20-month-old c-rel–/–: 16 mice *p < 0.05; **p < 0.01; ***p < 0.001 ****p < 0.0001 Two-way ANOVA followed by Sidak’s multiple comparison test in (B–D,H); the Kruskal–Wallis test followed by Dunn’s multiple comparison test in (E–G) Data are expressed as mean ± SEM in (B–D,H) or as median ± interquartile range in (E–G) Different cohorts of wt and c-rel–/– mice were tested for depression-like behavior with the FST at 3 The immobility time and latency to immobility are shown (A,B immobility time was observed in 12-month-old (A: p < 0.05 c-rel–/– 12 months) and 18–20-month-old c-rel–/– mice (A: p < 0.01 c-rel–/– 18–20 months; p < 0.0001 c-rel–/– 18–20 months; p < 0.001 18–20-month-old c-rel–/– mice displayed a shorter latency to immobility compared with age-matched wt mice (B c-rel–/– 18–20 months; p < 0.01 3-month-old wt: 13 mice; 3-month-old c-rel–/–: 16 mice; 6-month-old wt: 19 mice; 6-month-old c-rel–/–: 20 mice; 12-month-old wt: 14 mice; 12-month-old c-rel–/–: 14 mice; 18–20-month-old wt: 15 mice; and 18–20-month-old c-rel–/–: 21 mice *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 The Kruskal–Wallis test followed by Dunn’s multiple comparison test Data are expressed as median ± interquartile range In the nest building test, 18–20-month-old c-rel–/– mice took a longer time to open the cellulose bag and build a nest when compared to wt mice and to c-rel–/– mice at younger ages (Figures 3A,B). Nest building performance has been shown to rely on several factors, including cognitive skills, in particular hippocampus function (Jirkof, 2014), and fine motor activities (Paumier et al., 2013) Different cohorts of wt and c-rel–/– mice were tested for apathetic behavior with the nest building test at 3 Cages containing 2–4 mice per cage were used to evaluate the latency to build the nest A small cellulose bag containing corncobs (Mucedola) was placed in the cage (A) Representative images of 18–20-month-old wt and c-rel–/– mice nest building at time 0 and after 3 h following the introduction of bags containing corncobs (B) The latency to build the nest is shown c-rel–/– mice took a longer time to prepare the nest at 18–20 months of age (p < 0.05) the nest building latency of 18–20-month-old c-rel–/– mice was significantly higher than the values scored for c-rel–/– mice at younger ages (p < 0.0001 c-rel–/– 18–20 months; p < 0.05 c-rel–/– 12 months vs 3-month-old wt: 6 cages; 3-month-old c-rel–/–: 6 cages; 6-month-old wt: 5 cages; 6-month-old c-rel–/–: 4 cages; 12-month-old wt: 5 cages; 12-month-old c-rel–/–: 5 cages; 18–20-month-old wt: 7 cages; and 18–20-month-old c-rel–/–: 10 cages; *p < 0.05; ***p < 0.001; ****p < 0.0001 these results indicate that aged c-rel–/– mice did not suffer any impairment in working and short-term spatial memory Two different cohorts of wt and c-rel–/– male mice were tested for working and spatial short-term memory with Y-maze and novel object recognition (NOR) tests at 18–20 months of age spontaneous alternation behavior (SAB) percentage did not vary between wt and c-rel–/– male mice wt: 18 mice; c-rel–/–: 18 mice; p > 0.05 recognition index (RI) did not change between the groups wt: 8 mice; c-rel–/–: 10 mice; p > 0.05 Finally, we tested 18–20-month-old wt and c-rel–/– animals with the adhesive removal test, a task used to evaluate fine motor function in rodents (Fleming et al., 2013). We did not find any significant difference in the time needed to remove the adhesive label between the two experimental groups (Supplementary Figure 3) The results here reported point out clear age-dependent behavioral differences between wt and c-rel–/– mice a finding that aged c-rel–/– mice turned the wheel vigorously as wt points out only a mild motor impairment of the PD model between 12 and 20 months This finding supports the hypothesis that depressive-like behavior may play a role in the abnormal behavior observed in this test The hyperactivity of c-rel–/– mice may be driven by an anxiety status in response to a novel environment (Nakajima et al., 2020). Moreover, hyperactivity was observed in knockout rats for the gene encoding DAT (Leo et al., 2018). Hyperactivity in c-rel–/– male mice was detectable starting at 12 months, an age at which a drop in striatal levels of DAT was observed (Parrella et al., 2019) These findings suggest a possible role of dopamine and DAT dysfunctions in the observed hyperactivity VMAT2 LO mice, a PD animal model lacking VMAT2, the monoamine transporter that we found to be reduced in the striatum of 12-month-old c-rel–/– mice (Parrella et al., 2019), show an age-dependent apathetic behavior in the nest building test similar to that observed in our study (Baumann et al., 2016) the temporal pattern of the LC α-synuclein pathology in c-rel–/– mice correlates with the appearance of anxiety and depressive symptoms The present study shows that a variety of neuropsychiatric symptoms associated with PD, including anxiety, depressive-like behavior, and apathy, are reproduced in the c-rel–/– mice. This animal model, by mimicking the premotor phase and cardinal histopathological features of PD, may contribute to the research on the pathophysiology of PD prodromal stage and to the development of new therapeutic strategies (Cerri and Blandini, 2020) The datasets and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request All animal studies were reviewed and approved by the Animal Welfare Body of the University of Brescia (Organismo Preposto al Benessere degli Animali OPBA) and were in accordance with the Directive 2010/63/EU on the protection of animals used for scientific purposes designed and performed the behavioral studies FDG designed and performed the behavioral studies VP prepared the figures and edited the manuscript All authors contributed to the article and approved the submitted version This work was supported by the Italian Ministry of University and Research PON Program (ARS01_01226) VP receives researcher fellowship from Fondazione Cariplo–Giovani Ricercatori—Research Support GR 2018-0391 The 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 All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher Bruna Bianchi for the assistance in the nest building test The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnbeh.2022.831664/full#supplementary-material Supplementary Figure 1 | Different cohorts of wild-type (wt) and c-Rel protein (c-rel–/–) male mice were tested for depression-like behavior with the FST at 3 The scored parameters did not differ between c-rel–/– and wt mice in any of the considered ages (A–E: p > 0.05) We observed an age-dependent increase of body weight in both wt and c-rel–/– mice (A: p < 0.001 3-month-old c-rel–/–; p < 0.01 18–20-month-old c-rel–/– vs Data are expressed as mean ± SEM 3-month-old wt: 13 mice; 3-month-old c-rel–/–: 16 mice; 6-month-old wt: 19 mice; 6-month-old c-rel–/–: 20 mice; 12-month-old wt: 14 mice; 12-month-old c-rel–/–: 14 mice; 18-month-old wt: 15 mice; and 18-month-old c-rel–/–: 21 mice **p < 0.01; ***p < 0.001; ****p < 0.0001 Two-way ANOVA followed by Sidak’s multiple comparison test in (A,D); the Kruskal–Wallis test followed by Dunn’s multiple comparison test in (B,C,E) Data are expressed as mean ± SEM in (A,D) or as median ± interquartile range in (B,C,E) Supplementary Figure 2 | Two different cohorts of wt and c-rel–/– male mice were tested with Y-maze and novel object recognition (NOR) tests at 18–20 months of age c-rel–/– mice displayed a higher number of arm entries and traveled a longer distance than wt animals Data are expressed as mean ± SEM wt: 18 mice; c-rel–/–: 18 mice rodents were allowed to explore a box containing two identical objects (objects A,B) and the time spent exploring them was recorded No significant difference was found in the time the animals dedicated to exploring the two objects 18–20-month-old wt and c-rel–/– male mice were tested with the adhesive removal test No significant difference was found between the two groups in the time needed to remove the adhesive label wt: 7 mice; c-rel–/–: 7 mice; p > 0.05 Neuropsychiatric Symptoms in Parkinson’s Disease is required for hippocampal long-term synaptic plasticity and memory formation Alvarado-Bolaños Impact of Neuropsychiatric Symptoms on the Quality of Life of Subjects with Parkinson’s Disease Late-onset Parkinsonism in NFkappaB/c-Rel-deficient mice Preliminary Evidence of Apathetic-Like Behavior in Aged Vesicular Monoamine Transporter 2 Deficient Mice Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: critical Interplay in the Pathogenesis of Parkinson’s Disease Factors influencing behavior in the forced swim test A mouse model of non-motor symptoms in Parkinson’s disease: focus on pharmacological interventions targeting affective dysfunctions Transgenic Mice Expressing Human α-Synuclein in Noradrenergic Neurons Develop Locus Ceruleus Pathology and Nonmotor Features of Parkinson’s Disease α-Synuclein and Noradrenergic Modulation of Immune Cells in Parkinson’s Disease Pathogenesis Rodent models of Parkinson’s disease: beyond the motor symptomatology Castagné Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice Google Scholar Emotional manifestations of PD: neurobiological basis In vivo modeling of prodromal stage of Parkinson’s disease Contribution of neuropsychiatric symptoms in Parkinson’s disease to different domains of caregiver burden Anxiety in Parkinson’s disease: identification and management Neuropsychiatric Issues in Parkinson’s Disease Review: sporadic Parkinson’s disease: development and distribution of α-synuclein pathology Characteristics of apathy in Parkinson’s disease (2013) Assessment of sensorimotor function in mouse models of Parkinson’s disease depression and anxiety in Parkinson’s disease PubMed Abstract | CrossRef Full Text | Google Scholar Olfactory deficits cause anxiety-like behaviors in mice Mice expressing the A53T mutant form of human alpha-synuclein exhibit hyperactivity and reduced anxiety-like behavior Assessment of disease-related cognitive impairments using the novel object recognition (NOR) task in rodents Effects of ceftriaxone on the behavioral and neuronal changes in an MPTP-induced Parkinson’s disease rat model Effects of D-cycloserine on MPTP-induced behavioral and neurological changes: potential for treatment of Parkinson’s disease dementia A systematic review of depression and mental illness preceding Parkinson’s disease Burrowing and nest building behavior as indicators of well-being in mice Google Scholar The spectrum of nonmotor symptoms in early Parkinson disease Trans-neuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease NF-κB in Innate Neuroprotection and Age-Related Neurodegenerative Diseases Symptomatology and markers of anxiety disorders in Parkinson’s disease: a cross-sectional study and BDNF Dysregulation in Dopamine Transporter Knock-out Rats A bioinformatics analysis of memory consolidation reveals involvement of the transcription factor c-rel Hippocampus-dependent spatial learning and memory are impaired in growth hormone-deficient spontaneous dwarf rats Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1 c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function Delayed deficits in behavior after transection of the olfactory tracts in hamsters Depression and Parkinson’s disease: current knowledge PubMed Abstract | CrossRef Full Text | Google Scholar selective increases in locomotor activity in a novel environment and paradoxically increased open arm exploration in Neurogranin knockout mice A new behavioral test for antidepressant drugs O’Riordan Regulation of nuclear factor kappaB in the hippocampus by group I metabotropic glutamate receptors Minor hallucinations occur in drug-naive Parkinson’s disease patients NF-κB/c-Rel deficiency causes Parkinson’s disease-like prodromal symptoms and progressive patholo-gy in mice Protein restriction cycles reduce IGF-1 and phosphorylated Tau and improve behavioral performance in an Alzheimer’s disease mouse model Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson’s disease Psychosis-Like Behavior and Hyperdopaminergic Dysregulation in Human α-Synuclein BAC Transgenic Rats The onset of nonmotor symptoms in Parkinson’s disease (the ONSET PD study) Mild In-flammatory Profile without Gliosis in the c-Rel Deficient Mouse Modeling a Late-Onset Parkinsonism Behavioral despair in mice: a primary screening test for antidepressants PubMed Abstract | Google Scholar Diagnostic criteria for psychosis in Parkinson’s disease: report of an NINDS NIMH work group Role of norepinephrine in the pathophysiology and treatment of mood disorders Behavioral phenotyping of Parkin-deficient mice: looking for early preclinical features of Parkinson’s disease Diurnal rhythms in the nest-building behaviour of female mice PubMed Abstract | CrossRef Full Text | Google Scholar Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study Behavioral phenotyping of the MPTP mouse model of Parkinson’s disease Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study doi: 10.1002/1531-8257(200007)15:4<669::aid-mds1011<3.0.co;2-5 Thigmotaxis as an index of anxiety in mice The olfactory bulbectomised rat as a model of depression Psychiatric syndromes in Parkinson’s disease Mood disorders in Parkinson’s disease CrossRef Full Text | Google Scholar The Nonmotor Features of Parkinson’s Disease Google Scholar Locomotor hyperactivity and alterations in dopamine neurotransmission are associated with overexpression of A53T mutant human alpha-synuclein in mice The Role of Sex and Sex Hormones in Neurodegenerative Diseases Chronic and acute LRRK2 silencing has no long-term behavioral effects whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release Long Road to Ruin: noradrenergic Dysfunction in Neurodegenerative Disease PubMed Abstract | CrossRef Full Text | Google Scholar Peptide YY Causes Apathy-Like Behavior via the Dopamine D2 Receptor in Repeated Water-Immersed Mice Simvastatin Improves Behavioral Disorders and Hippocampal Inflammatory Reaction by NMDA-Mediated Anti-inflammatory Function in MPTP-Treated Mice Age-related LRRK2 G2019S Mutation Impacts Microglial Dopaminergic Fiber Refinement and Synaptic Pruning Involved in Abnormal Behaviors [Epub online ahead of print] doi: 10.1007/s12031-021-01896-6 Onset and evolution of anxiety in Parkinson’s disease Olfactory bulbectomy in mice induces alterations in exploratory behavior Fabene PF and Pizzi M (2022) Age-Dependent Neuropsychiatric Symptoms in the NF-κB/c-Rel Knockout Mouse Model of Parkinson’s Disease Copyright © 2022 Parrella, Del Gallo, Porrini, Gussago, Benarese, Fabene and Pizzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Edoardo Parrella, ZS5wYXJyZWxsYUB1bmlicy5pdA== †Present address: Federico Del Gallo Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish CLICK HERE TO SUBSCRIBE TO THE TDN FOR FREE! Remember Ben with a gift to Thoroughbred aftercare Subscribe for FREE to the Daily PDF or the News Alerts Home » Archive » Top News Europe » Mario Gussago Appointed to Arqana Bloodstock Team Mario Gussago has joined Arqana's bloodstock team Among his duties will be to support the inspection teams in France spent five seasons as a travelling head lad to Marco Botti in England he gained additional experience as an assistant to trainer Roger Varian Said Arqana Bloodstock Director Ludovic Cornuel “We are delighted to welcome Mario to the Arqana bloodstock team His solid experience in racing and with trainers across Europe are important assets to continue to strengthen our team With this recruitment and the forthcoming arrival of Pierre Le Courtois in charge of Management Information Systems Arqana has once again shown its wish to keep improving the quality of its service.” “My experience with trainers in England have given me a solid knowledge of racing and the industry in general,” said Gussago “I am delighted to be able to join the Arqana team which is one of the largest auction houses in Europe where I will now be able to experience the sales from behind the scenes Freddy Powell and Ludovic Cornuel for giving me this opportunity and trusting in me to take up this new challenge.” Not a subscriber? Click here to sign up for the daily PDF or alerts. Copy Article Link Editor / News Stories:editor@thetdn.com Advertising:advertising@thetdn.com Customer Service:customerservice@thetdn.com Click Here to sign up for a free subscription Ciara Kavanagh and Billy Fagan launched a company with a difference and their workshops have been filling up and selling out since February The idea that animates Create & Sip is to host sociable “We wanted to make it a nice social event for people to come to Create & Sip currently hosts two different events: Charm & Sip and Bead & Booze The Charm & Sip workshops allow attendees to create their own custom charm necklace or bracelet while in the Bead & Booze workshops you get to create beaded jewellery With Fagan on the decks and everyone perfecting their custom piece of jewellery there is a bustling atmosphere in the workshops but also individuals looking for something different to do on a Friday night The events are BYOB (Bring Your Own Booze) – but you don’t have to drink “We have a lot of people who come and don’t drink,” says Kavanagh The company originally began hosting events at Flux Studios on Rainsford Street “We just really love this space,” says Kavanagh As Flux Studios recently expanded to the city centre some workshops are held there as well – but they’re mainly in the heart of the Liberties Kavanagh says a lot of the company’s growth “was organic at the start” due to some of their TikTok videos going viral This is how they started selling out their workshops so early on Create & Sip hosts Christmas workshops for companies looking for a unique ‘work-do’ this season Charm & Sip events are held three times a month “We have a couple more ideas of workshops that we are thinking of doing and planning at the minute,” says Kavanagh Don’t miss the latest drinks industry news and insights Sign up for our award-winning newsletters and get insider intel and trends delivered to your inbox every week A new generation of producers in Italy’s premier sparkling wine region are casting off decades of French influence to pursue metodo classico wines with a more genuine sense of place To understand the identity crisis that has long plagued the wine producers in Franciacorta we may as well start with the puzzle of its name According to one of several conflicting accounts upon settling in the region in the year 774 and affectionately dubbed the area “Little France.” the story speaks to the very real challenge the region has faced in establishing its own unique place in the world of sparkling wine when a well-financed cadre of winemaking estates set up shop in this hilly patch of Lombardy with the goal of transforming it into a powerhouse of premium sparkling wine Franciacorta’s identity has revolved around a single imperative: to imitate Champagne Not content merely to adopt the classic Champenoise grapes of Chardonnay and Pinot Noir (Pinot Blanc is allowed as well) and its signature méthode Champenoise of secondary fermentation in bottle the region also lifted Champagne’s famous “Grand Marque” model whereby several large Franciacorta houses historically purchased and blended grapes from across the region to maintain a consistent house style Half a century later, this strategy has catapulted Franciacorta to fame within Italy securing its status as the tipple of choice of Milan’s fashionable elite the category has struggled to gain a foothold in the U.S with prices for Franciacorta rivaling those for Champagne why splurge for the knockoff when you could just buy the real thing we arrive at the crossroads Franciacorta faces today a small but growing cohort of winemakers—some working within the Franciacorta denomination others choosing to opt out of the DOCG—have made it their mission to carve out an alternative path As they collectively cast aside Champagne’s exaggerated influence they’re asking a simple yet revolutionary question: What would it mean to reimagine Franciacorta not as a ready-made style inspired by somewhere else the contours of an alternative Franciacorta paradigm are now coming into view And at a time when authenticity has become the most valuable form of currency among the next generation of wine drinkers the groundbreaking bottles that have emerged from this shift have recently started to claim their rightful place on progressive wine lists and retail shelves across the U.S No one has fought harder to deconstruct the Franciacorta establishment’s outdated logic than Giovanni Arcari, a Lombardy native who, along with his partner Nico Danesi, founded the visionary Arcari + Danesi project in 2006 To finally wean the region off its codependent relationship with Champagne that original analogy never quite added up and the reasons why are twofold: geography and climate Think about it: In the chilly vineyards of Champagne grapes wage an epic battle to achieve ripeness It follows that the set of winemaking practices that form the méthode Champenoise developed in direct response to that struggle using techniques such as refermentation in bottle and added sweetener (dosage) to transform acidic located nearly 1,200 kilometers southeast of Champagne’s capital of Reims and moderated by the warming influence of Lake Iseo Franciacorta’s Brescia province offers growers optimal conditions for evenly and consistently ripening their grapes Franciacorta’s woes derive from a fundamental failure to account for that difference “We here in Italy are still stuck trying to copy [Champagne’s] methodology without looking at the overarching idea of how this technology or winemaking approach fits with our climate or the identity of our territory,” he explains “I fail to see how a wine made using a method that was developed more than a thousand kilometers away could ever be successful for expressing the identity of our land.” much of this progress has come through trial and error we decided to get rid of many things that were considered the dogma of the classic method but which we felt were unnecessary to make great wine here,” explains Tornincasa who has earned a reputation as one of the area’s most restlessly non-programmatic winemakers high-altitude wines from the remote hills of Cellatica were rejected by Valore Italia which evaluates all potential Franciacorta wines for DOCG inclusion as “atypical” (he currently uses the generic VSQ the idea of our wine is to offer something transparent and not driven by style.” Even among the progenitors of this new paradigm there’s no consensus for exactly how to enact that mandate But in what might seem like a twist of irony the course they are pursuing generally follows a minimalist playbook that will be familiar to anyone versed in the grower rebellion that recently upended the balance of power in Champagne that signals return to more virtuous (read: organic or biodynamic) farming using ambient yeasts for the primary fermentation and investigating alternative ways to kickstart the secondary fermentation have even replaced the cane sugar historically used in the liqueur de tirage with grape must of the same vintage rather than picking early to keep Champagne-like acidity levels they focus upon harvesting physiologically ripe grapes that eliminate any need for dosage—hence the latest wave of zero-dosage bottlings that emphasize the nuances of grape and soil it’s all part of the larger mission of figuring out what “here” is supposed to taste like “We have a very recent history,” she observes but we’ve only been making sparkling wine since the 1960s We need time to understand what we have and how to express it.” Perhaps the most exciting aspect of this experimentation is the counterpoint it provides to the conventional notion of Franciacorta as a homogenous wine Shaped by five different periods of glacial activity the Franciacorta zone consists of an incredibly complex tapestry of soil types the Franciacorta consortium has made conscious efforts to highlight this diversity including an elaborate zoning study first launched in 1992 But as Italian wine expert Ian d’Agata explains in Italy’s Native Wine Grape Terroirs “identifying a terroir effect in Franciacorta’s wine can be difficult in most cases because the majority of estates blend together grapes from many different communes.” The small-scale producers driving change in the region today are challenging that notion both in theory and in practice Their efforts to excavate the identities of their respective subzones provide a fresh opportunity to pick apart distinctions between Franciacorta’s various communes—even if current DOCG regulations preclude them from printing such place names on the label It’s largely this restriction that prompted Alessandra Divella along with fellow defectors Nicola Gatta and Antonio Tornincasa to declare her independence from the Franciacorta denomination altogether she bottles her vivid lineup of zero-dosage bottlings under the village name of Gussago A lesser-known subzone in Franciacorta’s cooler not far from the rugged Campi di Cellatica where Cà del Vént is perched the area has lately emerged as a creative laboratory for Franciacorta’s new guard “It’s very important to me that my wines show their connection to the land where I work,” Divella says “Unlike the better-known parts of the region with a higher elevation and a very particular set of Jurassic limestone soils that give the minerality and acidity I look for.” That tension is tangible in her racy Blanc de Blancs fermented in equal parts concrete tank and used barrique and aged 30 months on the lees a savory blend of Pinot Noir and Chardonnay that walks a tightrope between ripe orchard fruit and a faintly oxidative edge (a result of the reserve wine that constitutes 25 percent of the blend) Daniele Gentile and Gigi Nembrin of Corte Fusia are crafting terroir-driven Francicaorta wines from four small parcels that had largely been abandoned during the shift to commercial production it’s very important to emphasize that we don’t want to make the greatest Franciacorta—we want to make a great Franciacorta from Monte Orfano,” Gentile says contrasting the “power and salinity” that characterize the zone from the “softer more floral quality” of the wines that “come from closer to the lake.” the project plans to release the first of a series of site-specific bottlings they started producing in 2014 which will highlight three separate vineyards planted at different elevations on the hill of Monte Orfano There’s just one caveat: “The wines will need to have imaginary names because we’re not allowed to use the name “This type of work is still very avant-garde here in Franciacorta.” If this next generation of metodo classico producers has ushered in a new era for Franciacorta the good news for wine drinkers on this side of the Atlantic is that industry professionals have started to notice At E&R Wine Shop in Portland Laura Bartram and Ed Paladino—two of the category’s earliest champions—have assembled one of America’s most comprehensive selections of Franciacorta’s new wave “It’s not always easy to introduce people to these wines,” Bartram admits they immediately understand that these are among the greatest sparkling wines in the world.” Having struggled to find metodo classico wines that fit the parameters of the natural-leaning, Italian-centric wine list at Manhattan’s Altro Paradiso sommelier Amanda Smeltz (the restaurant’s former wine director) recalls her first encounter with Alessandra Divella’s examples in 2019 which quickly became staples of the beverage program there they were immediately palpable as extremely high-quality super elegant sparkling wines that offered such clear expressions of their grape varieties,” she says but I also wouldn’t have guessed Franciacorta because they’re so different from so much of the Franciacorta to which I had been exposed.” If there was once a time when Franciacorta popped up almost exclusively in Italian restaurants, that’s also changing. At San Francisco’s three-star Michelin restaurant Quince Nicola Gatta’s 60 Lune rosé—refined for a remarkable 60 months on the lees—currently graces the pages of the wine program alongside many of the hottest names in Champagne It’s yet another testament to the category’s expanding relevance But if the message is that these Italian examples have the capacity to keep company with highly coveted grower Champagnes such as Selosse or Prévost that’s ultimately a reflection of the fact that they’re just as unique the public wants to drink something for what it is not because it’s an alternative version of something else,” Quince general manager and sommelier Matt Cirne explains “These producers are trying to make wines that actually reflect the identity of Franciacorta That’s why I’m able to represent them on the list.” Don’t miss the latest drinks industry news and insights—delivered to your inbox every week and California—including one AVA that has already been approved—have exciting potential for the U.S As vines are pulled and grapes left unpicked across California fruit-forward profile of classic Provence rosé calls for reductive winemaking but some producers are turning to a more oxidative approach to add complexity to their wines There’s no right way to space a vineyard but winemakers and researchers nonetheless have strong—and often opposing—views on the best way to approach vine density Learn more about how Provi simplifies the complex process of ordering and promoting wholesale alcohol between buyers SevenFifty Daily is an award-winning online magazine about the business and culture of the beverage alcohol industry covering all three tiers of the alcohol industry Please upgrade your browser to improve your experience wine-producers and Consortium members reveal their favourite places and hidden gems in the Franciacorta region Whether you’re travelling close to home or further afield recommendations from locals often lead to surprising and rewarding discoveries we’ve asked some of the region’s local experts for their favourite touring itineraries and places to visit between Brescia and Lake Iseo in order to make your trip to the Franciacorta region even more enjoyable Our list of routes exploring the region’s art, natural landscapes, and food and ine starts with suggestions from Silvano Brescianini, President of the Franciacorta Consortium who chooses the evocative Torbiere del Sebino (peat bogs) as “an ideal place for a walk while a visit to the old Maglio di Ome forge is also interesting as it represents an important piece of iron-working history in our valleys Also worth exploring is the secluded route from Ome to Monticelli as well as the road from Timoline to Provaglio I would suggest that visitors to our region sample the three very different types of cuisine served here which include recipes inspired by lake fish produce from Rovato market and typical spit-roasted dishes from Gussago” A visit to the Stella di Gussago sanctuary, “a peaceful and restful place”, is one of the first recommendations offered by Riccardo Scalvinoni, the chef at Il Colmetto restaurant which has been awarded a Michelin Green star: “Franciacorta has a longstanding arts and crafts tradition and my advice is to stop and talk to people who work here the roads that wend their way through the Monterotondo and Borgonato vineyards are among the most beautiful in the region while interesting places to visit include the Olivetana di San Nicola abbey in Rodengo Saiano and the botanical gardens in Ome where you can enjoy a pleasant stroll among the conifer trees” the region’s natural landmarks are of particular geo-historical interest: “From Monte Alto and the Madonna del Corno concentric arches can be seen on the hills that mark the limit reached by different ice ages The Mindel glacial stage (480 000-350 000 years ago) has left a moraine deposit on which the villages of Erbusco Cazzago San Martino and Paderno Franciacorta stand today; the frontal moraine of the Riss ice age (240 000-150 000 years ago) includes the villages of Corte Franca and Provaglio d’Iseo while the Wurm ice age (120 000-11 000 years ago) resulted in the moraine between Clusane Geological history and a unique microclimate are distinctive features of this geographical region and according to Camilla Alberti, President of the Franciacorta Wine Route these natural features can be admired at the Gaina waterfalls in Monticelli Brusati and from the fitness trail on the Monte della Madonna: “Here after walking through woodlands of oak and sweet chestnuts you reach the 14C Santuario della Madonna della Rosa which stands at the most panoramic point on the Monte della Madonna hill I would suggest the old Valeriana road which follows the meanders of the Gandovere stream into the Ome region a historic hamlet with historic mills that have been in operation since the 12C The route continues into the Parco delle Querce di Ome as far as Fratta and Fontana which is home to the 15C Church of San Zenone” Alberti concludes by saying “we have invested heavily in marketing and signage for the Wine Route – we’ve mapped out six cycling itineraries and the same number of hiking routes all of which can be downloaded from the franciacorta.wine website As part of the Bergamo Brescia 2023 Capital of Culture project we are also creating a programme that will showcase the artistic and cultural heritage of the region in association with the ‘Terra della Franciacorta’ organisation” also recommends exploring the Sebino peat bog as well as a visit to the Vino Ricci Curbastro museum and a cycle ride along the route from Brescia to Paratico: “Following the old Roman road you’ll enjoy scenic views as well as discover an area steeped in Roman renowned for its production of wooden vessels which play such an important role in the lake’s history I should mention that Monte Isola is also famous for gastronomic products such as salami extra-virgin olive oil and dried sardines” Giornalista dal 2004 con Laurea e Master in Storia e Relazioni Internazionali presso la LSE visita i sette continenti e approfondisce ogni giorno la sua passione per cucina hotellerie di charme e tradizioni del territorio italiano From listening bars to neighbourhood restaurants explore all the top recommendations from Chishuru’s Adejoké Bakare One of the most prominent chefs serving Indian cuisine talks India and his New York these splurge-worthy hotels have the design and prestige to rival even that most historic of city landmarks The first hotel on this list is just 20 minutes from Florence From vineyards to infinity pools and farm-to-table restaurants every one of these 14 Tuscan classics is within two hours of the city With its range of innovative solutions to facilitate more mindful travel that has less of an impact on the environment – including state-of-the-art tyres for cars which remains an invaluable source of reliable advice – MICHELIN contributes to making each and every one of your journeys more enjoyable From Michelin-starred and Bib Gourmand restaurants to charming residences nestled in the beautiful Italian countryside the MICHELIN Guide helps make your travels even more special From the Cantieri Riva boatyard to roads that wind their way through vineyards and historic villages the region between Brescia and Lake Iseo celebrates the past present and future of cars and boats alike you’ll find centres of excellence and extraordinarily scenic routes many of which are dotted with top-quality Michelin-starred restaurants The intoxicating nuances of Franciacorta wines over the centuries and a strong wine tradition in a region with a unique microclimate Not only is the Franciacorta region home to excellent food and wine beautiful vineyards and charming tourist sights dotted between Brescia and the shores of Lake Iseo it also boasts a rich artistic heritage and a vibrant arts and crafts tradition white and rosé wines include many different grape varieties and methods of production and provide the perfect accompaniment to the region’s cuisine It has been suggested that the unusual name of this region lying between Brescia and Lake Iseo is a reference to France (Francia in Italian) although another interpretation favours the idea that the area was once a corte franca or a free zone exempt from the payment of taxes to the monks who cultivated the land here Non-members can add the privileges at checkout through our 30 day free trial By continuing I accept the Terms & Condition and Privacy Policy. I would like to receive Newsletter from MICHELIN Guide Save lists of your favorite restaurants & hotels Whether you\u2019re travelling close to home or further afield we\u2019ve asked some of the region\u2019s local experts for their favourite touring itineraries and places to visit between Brescia and Lake Iseo in order to make your trip to the Franciacorta region even more enjoyable Our list of routes exploring the region\u2019s art, natural landscapes, and food and ine starts with suggestions from Silvano Brescianini, President of the Franciacorta Consortium who chooses the evocative Torbiere del Sebino (peat bogs) as \u201can ideal place for a walk produce from Rovato market and typical spit-roasted dishes from Gussago\u201d A visit to the Stella di Gussago sanctuary, \u201ca peaceful and restful place\u201d, is one of the first recommendations offered by Riccardo Scalvinoni, the chef at Il Colmetto restaurant which has been awarded a Michelin Green star: \u201cFranciacorta has a longstanding arts and crafts tradition where you can enjoy a pleasant stroll among the conifer trees\u201d He continues: \u201cIn terms of touring options an increasing number of travellers are looking for natural landscapes and one of the region\u2019s most delightful routes leads to Iseo via Campiani and then over the hills that separate Gussago from Rodengo Saiano After crossing Monte Delma and heading to Fantecolo you can climb up to the Madonna del Corno overlooking Provaglio d\u2019Iseo\u201d the region\u2019s natural landmarks are of particular geo-historical interest: \u201cFrom Monte Alto and the Madonna del Corno Cazzago San Martino and Paderno Franciacorta stand today; the frontal moraine of the Riss ice age (240 000-150 000 years ago) includes the villages of Corte Franca and Provaglio d\u2019Iseo Geological history and a unique microclimate are distinctive features of this geographical region and according to Camilla Alberti, President of the Franciacorta Wine Route these natural features can be admired at the Gaina waterfalls in Monticelli Brusati and from the fitness trail on the Monte della Madonna: \u201cHere which is home to the 15C Church of San Zenone\u201d Alberti concludes by saying \u201cwe have invested heavily in marketing and signage for the Wine Route \u2013 we\u2019ve mapped out six cycling itineraries and the same number of hiking routes we are also creating a programme that will showcase the artistic and cultural heritage of the region in association with the \u2018Terra della Franciacorta\u2019 organisation\u201d as well as a visit to the Vino Ricci Curbastro museum and a cycle ride along the route from Brescia to Paratico: \u201cFollowing the old Roman road you\u2019ll enjoy scenic views as well as discover an area steeped in Roman renowned for its production of wooden vessels which play such an important role in the lake\u2019s history extra-virgin olive oil and dried sardines\u201d Many of the factors that make Franciacorta special are already known being in a region that claims to be ‘pre-Alpine’ is fiercely continental but has two mitigating factors: Lake Iseo to the north and Monte Orfano to the south The proximity of the lake has a huge mitigating effect on temperatures in both summer and winter Evidence of this lies in Franciacorta’s typically Mediterranean vegetation which includes both wild and naturalised plant species along with those that are easy to cultivate In the growing period for the vines (April to October) the average rainfall is 500-600 mm approximately two thirds of the annual total The Franciacorta area is triangular in shape with an apex in the north that touches the southern shores of Lake Iseo we can quite clearly make out the morainic amphitheatre formed during the Ice Age thanks to a large glacier coming from Val Camonica which divided into two branches immediately after the basin of the lake with a small one to the east and a much larger and more important one to the west On the northwest side lies Paratico and Capriolo with their higher altitudes The first glacial branch from this side includes Clusane are part of a different glacial configuration which shelters Franciacorta from the humidity of the Padana valley quite different from the morainic origin of the rest of Franciacorta Here the style of wine is tighter and chalkier The morainic origin of the other parts of the region is equally crucial Morainic soils mean that pH values are not as high as in Champagne and acidity is almost half of the level obtainable in the Champagne region This means that sparkling wines in Franciacorta are made with a focus on extracting the purest expression possible from the grapes Soils in the region are rich in sand and silt and typically lacking in clay often with considerable thickness and high permeability types and colours are scattered everywhere and for centuries they have been used for constructing villas the characteristic stone walls that surround houses and vineyards One of the basic characteristics of Franciacorta’s moraine-originating soils is an enormous wealth of added minerals which are different to those derived only from the rocks found there and form the basis for the area’s high-quality viticulture Wines tasted and rated by Decanter contributor Aldo Fiordelli Colline della Stella winery is in the extreme east of Franciacorta on old terraced vineyards planted on chalky soil the talented Andrea Arici produces some of the tightest and most mineral pas dosé sparkling wines in Franciacorta Bright straw colour in the glass with pinprick bubbles Zesty in acidity and lightly tannic on a rich toasted finish Barone Pizzini’s vineyards are located in the northwest heartland of Franciacorta The grapes are harvested in Provaglio D’Iseo The latter stands out for its northern position and its altitude Animate was the first Franciacorta to be blended with Erbamat the late-maturing grape rediscovered in the region hints of apricot and acacia honey give way to fresh green apple and a mineral finish fresh on the palate and well-balanced at the end with a tight-knit texture this Chardonnay-based wine comes from the heart of Franciacorta and is part of the Antinori stable Zesty acidity is finely grained with lemon flavour expressing an incredibly long mousse with a toasty finish and lemon curd flavour and compared to other villages within the region it’s higher in altitude with limestone soil Faccoli is famously the first to start the harvest every year classic profile with restrained strawberry fruit and candied strawberries smoky woodland and mouth-filling chalky minerality Creamy mousse and silky finish with good body Pietta Firearms is celebrating its 60th year in business, having become an industry leader in manufacturing refined, historical firearm reproductions and quality, innovative, modern firearms. The company made its humble start in 1963—in Gussago, Italy—when Giuseppe Pietta made a commitment to produce guns as authentic and true-to-original as possible. Customer experience was, and still is, the primary focus, a key to the firm’s longevity and success. “We are incredibly fortunate to have this opportunity to deepen our roots in an amazing industry,” said Alessandro Pietta, one of Giuseppe’s two sons who are now running the company. “The entrepreneurial and artistic spirit of our father still runs deep through all of us at Pietta Firearms. We’re honored to continue to carry on the tradition, legacy and achievements set forth by him.” “We are proud of our history, not only for all that Pietta has accomplished as the leader in manufacturing to the highest standard, but because we have always operated from a foundation of best-in-class replica firearms expertise,” said Alberto Pietta, the other brother at the firm’s helm. “We look forward to continuing to serve our customers by providing exceptional firearms the world can trust.” The two brothers have stayed responsive to customer needs, but their investment in the future and creativity has allowed Pietta to grow into a world authority on replica and traditional firearms. The company not only produces exceptional single-actions and blackpowder revolvers, but modern firearms as well. With a history that spans more than six decades, Pietta Firearms preserves its founder’s legacy as one of the leaders in both single-action and blackpowder revolvers. Long respected for its world-leading military small arms, Heckler & Koch, through its American factory and engineers, has taken the pulse of U.S. shooters—and the new Concealed Carry 9 mm Luger micro pistol is poised to quicken it. Read today's "The Armed Citizen" entry for real stories of law-abiding citizens, past and present, who used their firearms to save lives. Despite a slight decline in demand for new firearms, the industry’s economic impact rose from $90.5 billion in 2023 to $91.7 billion in 2024. Since its inception, Kahr Arms has been most well-known for its single-stack line of concealed-carry pistols, but, in 2025, the company is moving into the double-stack market with its new Premium X Series. Henry's Special Products Division has officially released its first line of unique offerings in its HUSH series of suppressor-ready lever-action rifles. Built primarily from thick 6061 aircraft-grade aluminum, the Multi Cal. Steady Rest from Ransom Intl. is an incredibly robust and stable gun rest designed for use with pistols and long guns alike. Volume 10 - 2023 | https://doi.org/10.3389/fcvm.2023.1235178 This article is part of the Research TopicApproaches to Personalized Medicine in Acute Heart FailureView all 5 articles Acute heart failure (AHF) represents a common clinical scenario that requires prompt evaluation and therapy and that is characterized by a high risk of mortality or subsequent rehospitalizations The pathophysiology leading to AHF decompensation is still not fully understood Significant activation of inflammatory pathways has been identified in patients with AHF and it has been hypothesized that systemic inflammation has a role in AHF pathogenesis Several inflammatory mediators and cytokines such as high sensitivity C-reactive protein soluble suppression of tumorigenicity 2 and galectin-3 have been shown to play a role in the pathogenesis development and worsening of this condition with an independent prediction of adverse outcomes This manuscript reviews the prevalence and prognostic value of systemic inflammation in AHF as well as the potential role of anti-inflammatory therapies focusing on available evidence from clinical trials and ongoing studies we discuss the role of inflammatory biomarkers in AHF their prognostic value and the potential utility of targeting precise phenotypes to improve outcomes We also summarize the results of most important clinical trials of therapies targeting inflammatory processes in the AHF setting and explore future directions in this field Numerous studies have confirmed the presence of a sterile inflammation state (without concomitant infections) in ADHF with high levels of several inflammatory cytokines at hospital admission detected in some patients with AHF varies in different studies and according to different AHF presentation Inflammatory biomarkers in acute heart failure these studies suggest that signs of systemic inflammation are frequently observed among patients with AHF potentially with higher levels in patients with more severe clinical presentation (i.e. cardiogenic shock) as compared to those with less severe phenotypes a large glycoprotein synthesized by mesothelial cells has been validated as a reliable indicator of congestion and inflammation in patients with AHF The prognostic role of inflammatory markers in both chronic and acute HF is well known (26, 61) several studies have been conducted with the aim of evaluating whether the decreasing levels of these markers in response to anti-inflammatory therapies In a multi-marker prognostic analysis in AHF, higher GDF-15 concentrations were associated with worse prognosis in AHF independently of BNP, in both patients with HFrEF and HFpEF. Patients discharged with both BNP and GDF-15 above the mean had a multivariate adjusted HR of 2-year death of 4.33 (95% CI 2.07–90.6, P < 0.001) when compared with the reference category (both BNP and GDF-15 below the mean) (75) CA125 exhibited a stronger correlation with congestion compared to NT-proBNP The study also found that the combination of these biomarkers improved the accuracy of evaluating congestion levels in AHF patients allowing for a more precise and reliable diagnosis and potentially aiding in better treatment decisions These findings suggest that CA125 could be used as a valuable biomarker for assessing the severity and prognosis of AHF providing clinicians with useful information for patient management and treatment strategies Therefore, available evidence suggests that different biomarkers involved in inflammatory pathways (CRP, IL-6, IL-1 axis, Galectin-3, MPO, GDF-15 and CA-125) have a strong prognostic impact in patients with AHF, and their increased circulating levels secondary to enhanced systemic inflammation are associated with worse outcomes and may represent interesting therapeutic targets (Figure 1) Systemic inflammation has been proved to be frequently enhanced during AHF with high levels of different inflammatory biomarkers identified in relevant subset of patients Such biomarkers have also been involved in key pathophysiological pathways leading to HF decompensation These pro-inflammatory cytokines allow the crosstalk between the heart and multiple peripheral organ systems The main effectors of inflammations are the lymphatic tissue cells which also activate fibroblasts and lead to the formation of collagen Kidney and gut are targets of these negative effects soluble suppression of tumorigenesis-2; GAL 3 Studies evaluating anti-inflammatory therapies in heart failure Finally, levosimendan was associated to a significant decrease in circulating pro-inflammatory cytokines and also a reduction in soluble apoptosis mediators demonstrating that this medication has a positive effect on reducing inflammation and cell death processes in patients with decompensated advanced HF (84) although preliminary evidence suggests the safety of anti-inflammatory therapy in the AHF setting no definitive proof of efficacy has been demonstrated in patients with AHF and concomitant systemic inflammation Some studies testing anti-inflammatory therapy in AHF are ongoing Beyond the randomized Dexamethasone Versus Prednisone in Heart Failure Patients Hospitalized With Exacerbation of Chronic Obstructive Pulmonary Disease trial (NCT02237820) that is focused on HF patients hospitalized with exacerbation of COPD other studies are specifically focusing on the impact on anti-inflammatory strategies in AHF The Recently Decompensated Heart failure Anakinra Response 2 Trial (REDHART2) planned to enrol 102 patients with recently decompensated HF (before hospital discharge) LVEF ≤ 40% and hsCRP >2 mg/L that are randomized 2:1 to anakinra 100 mg for 24 weeks or placebo (NCT03797001) The primary objective is to determine whether sustained anakinra treatment determines an improvement in aerobic exercise capacity with peak VO2 change at 24 weeks as primary endpoint The ongoing Randomized Double-blind Trial to Study the Benefit of Colchicine in Patients With Acutely Decompensated Heart Failure (COLICA) study is randomizing 278 patients with ADHF and either reduced or preserved LVEF to colchicine 0.5 mg or placebo initiated within the first 24 h of hospitalisation and administered for 8 weeks (NCT04705987) The primary objective of the study is the reduction of NT-proBNP after 2 months of treatment evidence of systemic inflammation is not needed to be enrolled in the COLICA trial The Effect of Short-Term Prednisone Therapy on C-Reactive Protein Change in Emergency Department Patients With Acute Heart Failure and Elevated Inflammatory Marker (CORTAHF) trial is including 120 patients with AHF evaluated at the ED randomized 1:1 to prednisone 40 mg for 7 days plus standard therapy or standard therapy alone (NCT05668676) prednisone therapy is initiated in the ED and continued up to 7 days The primary endpoint is change in CRP from baseline to day 7 and other clinical and functional outcomes will be evaluated as secondary endpoints The multicenter, randomized, open-label, controlled study to evaluate the efficacy and safety of corticoSTEROids added to standard therapy in patients with Acute Heart Failure (STERO-AHF) pilot trial will enrol 120 patients hospitalized for AHF, irrespective of LVEF, with documented diuretic resistance (according to current guidelines) (5) and with evidence of sustained systemic inflammation (CRP ≥ 20 mg/L) (NCT05809011) Patients will be randomized 1:1 to or standard-of-care plus corticosteroid therapy for up to 7 days (single-bolus intravenous dexamethasone 20 mg on day 1 followed by oral prednisone 1 mg/kg daily—maximum 60 mg daily—from day 2 to day 7) or standard-of-care alone The two primary endpoints are diuretic response defined as absolute body weight change from baseline to day 8 (or to discharge or to the occurrence of death) per 40 mg total dose of administered intravenous furosemide or equivalent defined as a hierarchical composite of all-cause death or change in patient-reported dyspnea (quantified by the visual analogue scale) from baseline to day 8 (or to discharge or to the occurrence of death) these ongoing studies will help defining the role of pharmacological or interventional anti-inflammatory therapies in patients with AHF episodes Different inflammatory pathways can be implicated in different HF stages also including the specific setting of AHF Inflammation can be both a cause and consequence of HF decompensation and seems to play a pathogenetic and prognostic role with several inflammatory mediators and cytokines up-regulated and associated with worse prognosis in patients with AHF Despite numerous studies validating the association between specific inflammatory biomarkers and AHF results from clinical trials have proven conflicting results with some recent trials showing encouraging preliminary findings but without definitive and convincing evidence supporting the use of anti-inflammatory therapies in this setting Managing inflammation is still a clinical challenge in AHF and ongoing studies will help defining the role of different anti-inflammatory pharmacological approaches (corticosteroids anti-IL-1 therapy) in improving AHF outcomes All authors listed have made a substantial and intellectual contribution to the work and approved it for publication MP has received personal fees from Abbot Vascular MA reports speaker fees from Abbott Vascular and Medtronic MM has received consulting honoraria as a member of trial committees or advisory boards for Abbott Vascular 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 The reviewer MM declared a past co-authorship with the authors MM Mode of presentation and mortality amongst patients hospitalized with heart failure A report from the first euro heart failure survey Acute heart failure: more questions than answers Evidence-based management of acute heart failure Roadmap for the management of heart failure patients during the vulnerable phase after heart failure hospitalizations: how to implement excellence in clinical practice 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC Clinical phenotypes and outcome of patients hospitalized for acute heart failure: the ESC heart failure long-term registry Euroheart failure survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population Impact analysis of heart failure across European countries: an ESC-HFA position paper Is acute heart failure a distinctive disorder Long-term survival and life expectancy following an acute heart failure hospitalization in Australia and New Zealand Temporal trends in mortality and readmission after acute heart failure: a systematic review and meta-regression in the past four decades Early and short-term intensive management after discharge for patients hospitalized with acute heart failure: a randomized study (ECAD-HF) Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial Sotagliflozin in patients with diabetes and recent worsening heart failure Inflammation across universal definition of heart failure stages: the CASABLANCA study Inflammation in human heart failure: major mediators and therapeutic targets Reappraising the role of inflammation in heart failure Inflammation and heart failure: a two-sample mendelian randomization study Inflammation in heart failure: causal determinant or bystander CrossRef Full Text | Google Scholar Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the vesnarinone trial (VEST) C-reactive protein and interleukin-6 in cardiogenic shock—insights from the CardShock study Pathophysiology and clinical evaluation of acute heart failure PubMed Abstract | CrossRef Full Text | Google Scholar Long-term prognostic value of inflammatory biomarkers for patients with acute heart failure: construction of an inflammatory prognostic scoring system Meta-analysis of soluble suppression of tumorigenicity-2 and prognosis in acute heart failure Inflammation and long-term mortality in acute congestive heart failure Pathophysiology and therapeutic approaches to acute decompensated heart failure PubMed Abstract | CrossRef Full Text | Google Scholar Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition Inflammation in heart failure: JACC state-of-the-art review and tissue damage markers in patients with acute heart failure with and without cardiorenal syndrome type 1 injury and failure in acute heart failure: from pathophysiology to diagnosis and management A review on behalf of the acute heart failure committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) The pathophysiology of acute heart failure–is it all about fluid accumulation Inflammatory pathways in heart failure with preserved left ventricular ejection fraction: implications for future interventions High-sensitivity C-reactive protein in acute heart failure: insights from the ASCEND-HF trial Association between C-reactive protein levels at hospital admission and long-term mortality in patients with acute decompensated heart failure C-reactive protein level on admission and time to and cause of death in patients hospitalized for acute heart failure Effect of systemic corticosteroid therapy for acute heart failure patients with elevated C-reactive protein PubMed Abstract | CrossRef Full Text | Google Scholar From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection Inflammation—cause or consequence of heart failure or both Gene expression and levels of IL-6 and TNFα in PBMCs correlate with severity and functional class in patients with chronic heart failure Quantifying inflammation using interleukin-6 for improved phenotyping and risk stratification in acute heart failure Interleukin-6 and outcomes in acute heart failure: an ASCEND-HF substudy The additive prognostic value of serial plasma interleukin-6 levels over changes in brain natriuretic peptide in patients with acute heart failure Clinical and prognostic significance of sST2 in heart failure Distribution and clinical correlates of the interleukin receptor family member soluble ST2 in the framingham heart study in cardiomyocytes and myocardial infarction Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (recently decompensated heart failure anakinra response trial) Interleukin-1 blockade in acute decompensated heart failure: a randomized The interleukin-1 axis and risk of death in patients with acutely decompensated heart failure Galectin-3 in cardiac remodeling and heart failure PubMed Abstract | CrossRef Full Text | Google Scholar Myeloperoxidase inhibition improves ventricular function and remodeling after experimental myocardial infarction Dynamics of growth differentiation factor 15 in acute heart failure Oxidative stress and inflammation in the evolution of heart failure: from pathophysiology to therapeutic strategies Impact of sacubitril/valsartan on surfactant binding proteins lung function tests and heart failure biomarkers: hemodynamic or pleiotropism Impact of sacubitril/valsartan on circulating microRNA in patients with heart failure Surfactant proteins changes after acute hemodynamic improvement in patients with advanced chronic heart failure treated with levosimendan Biomarkers of inflammation in heart failure: from risk prediction to possible treatment targets C-reactive protein and N-terminal pro-brain natriuretic peptide levels correlate with impaired cardiorespiratory fitness in patients with heart failure across a wide range of ejection fraction Diagnostic and prognostic value of serum C-reactive protein in heart failure with preserved ejection fraction: a systematic review and meta-analysis Long-term trajectories of high-sensitivity C-reactive protein level among patients with acute heart failure Higher C-reactive protein predicts worse prognosis in acute heart failure only in noninfected patients Inflammation and cardio-renal interactions in heart failure: a potential role for interleukin-6 Time-course of changes in the levels of interleukin 6 in acutely decompensated heart failure Interleukin-6 and B-type natriuretic peptide are independent predictors for worsening of heart failure in patients with progressive congestive heart failure J Heart Lung Transplant Off Publ Int Soc Heart Transplant Prognostic role of pro- and anti-inflammatory cytokines and their polymorphisms in acute decompensated heart failure Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (pro-brain natriuretic peptide investigation of dyspnea in the emergency department) study Utility of amino-terminal pro-brain natriuretic peptide and apelin for the evaluation of patients with acute heart failure and long-term mortality in patients with acutely decompensated heart failure Use of myeloperoxidase for risk stratification in acute heart failure Growth differentiation factor 15 (GDF-15) in patients admitted for acute heart failure: results from the RELAX-AHF study Towards a multi-marker prognostic strategy in acute heart failure: a role for GDF-15 CA 125 secretion by peritoneal mesothelial cells Peripheral venous congestion causes inflammation Immunomodulation and immunopharmacology in heart failure Colchicine and the heart: pushing the envelope Association of colchicine use for acute gout with clinical outcomes in acute decompensated heart failure Prednisone adding to usual care treatment for refractory decompensated congestive heart failure Cardiac outcome prevention effectiveness of glucocorticoids in acute decompensated heart failure: cOPE-ADHF study CORT-AHF Study: effect on outcomes of systemic corticosteroid therapy during early management acute heart failure Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure Metra M and Pagnesi M (2023) Inflammation in acute heart failure Received: 5 June 2023; Accepted: 30 October 2023;Published: 17 November 2023 © 2023 Garofalo, Corso, Tomasoni, Adamo, Lombardi, Inciardi, Gussago, Di Mario, Metra and Pagnesi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Marco Metra bWFyY28ubWV0cmFAdW5pYnMuaXQ= Matteo Pagnesi bS5wYWduZXNpQGdtYWlsLmNvbQ== †These authors have contributed equally to this work located off Thomas Street in The Liberties is set to become the second Dublin city alleyway to close due to improper use The laneway is easy to miss as it is so narrow – however it allows pedestrians to cut through it and emerge onto Hanbury Lane The laneway stands between two popular Irish food shops It also provides access to a residential building which shares the laneway with the two businesses. says the space is often occupied by drug users we shouldn’t even be walking through that.” Not only is the laneway posing a sanitation issue “They sometimes sit and have their backs against our door and that’s a fire safety issue,” says Milian Both the adjacent businesses were broken into through their side doors located in the laneway There is no definitive date yet for the closure of the laneway to the public. Dublin City Council appealed this month for representations or objections relating to the closure of Swan Alley High travel demand and hefty fuel prices have resulted in the cost of flights to Europe rising by up to 53 per cent Some Italians living in Melbourne decided to put off travelling until next year Benedetta Ferrara is a local news reporter for Il Globo and La Fiamma from 46th in 2024 to 49th place in 2025 in the Press Freedom Index drawn up every year by Reporters Sans Frontières (Reporters Without Borders - RSF) Researcher and lecturer Flavia Marcello explores the fascist influence on the architecture of Rome the race for the fourth Champions League qualifying spot from Italy’s Serie A has become even tighter Napoli didn’t allow flares and delays to affect their performance as Antonio Conte’s side ground out a 1-0 win at Lecce to take firm control of Serie A in Italy Fiorentina have lost the first leg of their UEFA Conference League semifinal tie 2-1 away to Real Betis Inter Milan’s Serie A title defence is on the line with the busy champions chasing a fresher Napoli side who have the finishing line in sight Carlo Ancelotti has turned down the Brazil job and is mulling a mega offer to coach Saudi Arabia Spanish sports daily ‘Marca’ said Wednesday British director Ken Loach has blasted plans to tear down much of Milan’s iconic San Siro stadium to make room for a new home for Inter and AC Milan Barcelona and Inter Milan have delivered a thrilling 3-3 draw in the first leg of their Champions League semi-final One of the pillars of Italian culture is the union between music and wine Nicholas ‘Nick’ Renfree-Marks is somewhat of an expert on both Italian Mario Gussago has joined Arqana's bloodstock department after spending time working with trainers Marco Botti and Roger Varian in Newmarket The 31-year-old told Racing Post Bloodstock about his route into the industry Can you tell us about your background and how you got into racing I come from a non-racing family but I’ve followed Mario Baratti since a young age while he was an amateur jockey In 2012 I joined him in Newmarket and started working for Marco Botti while Mario was his assistant my love for racing started growing exponentially and I decided I would never leave this world You have worked at a wide range of racing operations around the globe as I was dealing on a daily basis with owners for the first couple of years as one of the stable members and after as a manager I’ve been in close contact with different farriers and vets so that helps me to understand the morphology and the anatomy of the horse Every single one of them has been part of my formation I was travelling head person for nearly three years at Marco's so I learned so much about the logistics and the organisation of trips abroad and the care of the horses during their training routine For the last two years I’d been lucky enough to follow Roger Varian at the sales What made you want to move from the racing side to the sales side I started speaking with Roger during 2019 to come up with a plan and he put me in contact with a lot of people to find the best solution but after a few months we sat down and we both thought that sales was a very good option because I really enjoyed shadowing him and it really suits my profile Can you tell us more about what you'll be doing in your new role at Arqana At the moment I’m learning every aspect of the company because Arqana deals with every type of horse I’ll be more focussed on the horses in training as I have come straight out of a racing yard but learning about Arqana’s parameters on how to judge a young horse as well You must have worked with some very good racehorses in your time During my time at Marco Botti's I came across some great racehorses so it's very difficult to pick from five years the gentle grey who won back to back Prix Royal-Oaks as I used to look after him and he was my first winner at Ascot in the Group 2 Summer Mile Then there's Euro Charline for her story going to win the Beverly D at three and finishing second behind Belardo in the Lockinge who was a Grade 1 winner in the Natalma Stakes at Woodbine on my last trip for Marco Dylan Mouth was the first winner who I travelled back to Italy with Picking only a few from three years at Roger’s is very difficult as well as I’ve worked with so many well-bred horses Defoe was the stable’s star who unfortunately suffered a fatal injury while Daahyeh was the first Royal Ascot winner I was involved with when winning the Albany Stakes I travelled Angel Power to Rome last November to win one of the most historic Italian races and Fujaira Prince is a gentleman of a horse who won the Ebor last year There are many others from both experiences that I keep in my memory; every horse stays in your mind for small things when you spend every day with them You must have spent plenty of time in Newmarket I’ve lived there for eight years so I’ve gained very good friends and I'll miss the surroundings; I found it a beautiful place to live Newmarket gives you a feeling that everything is very close in the world Everything passes through there at least once a year - racing breeding - so I think I will miss that feeling Italian breeding and racing have both seemed to be in decline for many years Do you have any optimism about it for the future but I know there still are young people that are interested in the game and I hope they will try to get closer and think of ways to bring the sport back up collectively because we have a very important tradition that can’t go to waste Hopefully in the future we'll hear again about the good Italian races with new generations of breeders and trainers A horse in training that I would follow this year has to be from Roger’s and I'd say it has to be Zaajirah the son of Dubawi who did very well last year as a first-season sire I can’t see why he won’t improve his stats Balko Des Flos tops Goffs sale at £110,000 The breeding legacy of the great Sheikh Hamdan Listed-winning We Are Ninety tops Tattersalls Online March Sale at 75,000gns 'It gives us great pleasure' - meet the keen young couple behind Ashbrooke Stud First-season sires in Brocklesby and Ghaiyyath's brother among Doncaster entries Published on 25 March 2021inNews Copyright © 2025 Spotlight Sports Group Limited or its licensors The Italian presence in Australia goes back hundreds of years James Matra and Antonio Ponto were aboard the Endeavour with Captain James Cook on his voyage of discovery in 1770 .. specialising in stories of cultural interest to the local community Live & Breathe Pilates studio in Portobello was set up 12 years ago before the Pilates craze started and continues to thrive to this day with booked and busy weekly schedules With the Pilates industry becoming increasingly popular in recent years owner of Live & Breathe Pilates and long-time Pilates instructor herself The main pieces of apparatus used are the reformer it’s a common misconception that mat work will help you build up strength to use the above apparatus “The whole point of the apparatus is to help you with mat work,” says Grey The reformers have multiple levels of resistance using springs “We would have many people who would come in who would have an expectation that it’s all about how heavy the spring is but a lot of the times the lighter the spring the more challenging the exercise,” she says Another misconception is that the heavier the resistance on your reformer is the less support the reformer gives you – this allows people to build up their balance over time “The reformer is only a part of the whole Pilates repertoire,” Grey says The goal is to be able to support all your body weight on a mat without the help of other apparatus Pictured: Some reformers alongside the mats used at Live & Breathe Pilates is another piece of apparatus particularly used for rehabilitation or athletic conditioning purposes. Pilates is for all people of all ages – Live & Breathe Pilates even offer sessions for pregnant and post-natal women “We want it to be an exercise programme that works for all stages of life,” Grey says To begin doing Pilates at Live & Breathe you will be asked to complete an initial assessment to familiarise yourself with the equipment even if you’ve done Pilates before elsewhere Classes at Live & Breathe Pilates are run in accordance with your level of familiarity with Pilates “We teach a lot based on technique and figuring out what each client needs,” Grey says “We’re a very international family – we have Irish probably based on how Pilates portrayed in the media it was “designed initially for boxers and training of the military during the second World War” The monthly Sunday market with the crazy name – Le Zeitgeist Bohemia Flea Market – started two years ago in Stoneybatter at the Educate Together National School Le Zeitgeist market has been in its Phibsborough location for the past year and is a great hit with not only the customers but the merchants and we’ve been coming since then,” says Colm Durham who sells in Le Zeitgeist with Aquarius Sea Jewels – their stand features earrings and necklaces decorated with colourful sea glass and it’s great when you meet other traders – you share ideas and help each other for different markets.” who attended the market with his t-shirt brand Field and Greene agrees that the market has been useful to grow his brand due to the location and amount of footfall While many other markets around the area can be very expensive Aine and Molly Hughes also had a stall at the market selling clothes They are unsure of the name of their brand but are fairly curtained they’ll name it ‘Cute Hoorders’ and they said that they would probably come back to Le Zeitgeist again if they were to attend another market in the future “We are a new business in the sense that we haven’t done this before so if in future we accumulate loads [of clothes] again and we want to sell it we’d probably be back to this market because it’s great and it’s busy,” Aine says Kelly’s Yard is a mixed indoor and outdoor venue – those with vintage items have shelter without worrying about their goods getting damaged by the Irish weather those situated outdoors have gazebos to protect them from potential weather mishaps Le Zeitgeist market continue to encourage businesses to attend the flea market by contacting them through their email. New and returning businesses are welcome. Details about the markets, including date and location, can be found through their Facebook and Instagram pages The Sale of Alcohol Bill which was published by the Department of Justice in October 2022 gave businesses hope that Ireland could follow in the rest of Europe’s footsteps by allowing for extended nightlife opening hours pubs would be permitted to stay open until 12.30am and nightclubs would be permitted to open until 6am pubs close at 11.30pm from Monday to Thursday Nightclubs can also only serve alcohol until 2.30am Despite the potential change being capable of bringing in lots of business venues and promoters are divided on whether this drastic change would actually be a positive increased drug usage and an increase in other anti-social behaviour as nights get longer Keiron Black, booker and venue manager at The Grand Social “It’s great that people want to stay out that late […] but I don’t think it’ll work well for venues or promoters.” Black also expressed concerns for health and safety “I’d expect there would be more of a drug culture than a simple drinking culture you’d have to double up on staff and security costs.” Steve Manning from Hidden Agenda Manning says the potential new opening hours could be beneficial for up and coming artists in the locality “Longer hours give more opportunities for local DJs and local collectives.” Though this would be a drastic change for Ireland Manning adds: “we’ve got the earliest closing times in Europe – we’re not asking for anything unique or new.” Bloom Lane has been unofficially named ‘Italian Quarter’ due to an urbanisation project by Mick Wallace which saw the founding of multiple Italian businesses in Bloom Lane back in 2004 in the same vicinity who all cater to the same cuisine the businesses that still stand since the opening of Italian Quarter are thriving Renato Papillo, co-owner of ‘Sfuso’ a hybrid Italian restaurant says that the area is good for business and competition isn’t an issue it gives some identity to the area,” says Papillo ‘Sfuso’ is understandably a popular establishment as they provide the true Italian experience with an impressive wine collection and authentic deli the wine collection is even more impressive there’s nobody in the middle between us and the producer.” says Renato ‘Sfuso’ faced challenges through COVID like many other businesses before it was a proper wine bar with a full menu Then we changed it a little bit to a different concept.” Right across the lane, you can find ‘Bar Italia’ which is owned by David Izzo has been the only owner ever since the restaurant opened ‘Bar Italia’ has an extensive but impressive authentic Italian menu Izzo agrees that there are no issues with competition amongst the different businesses especially since Bar Italia provides authentic Italian dishes none of that creamy-chicken-carbonara nonsense. Bar Italia doesn’t entertain the Irish interpretation of Italian food – you definitely won’t find pepperoni pizza and chips here “Italian food is such a broad world which is so misinterpreted.” says David A fascinating aspect of Bar Italia is that whenever David has a new chef it’s up to the chef to adjust the menu to suit his cooking style therefore you can see authentic cuisine from Rome on the menu Despite the great cuisine seen in Italian Quarter today there used to be many more Italian businesses when the concept first launched “We’re not really an Italian Quarter anymore now we’re just two restaurants,” says Izzo They’ve been replaced by business such as ‘Eyemazy’ and a shisha bar “I’m happy to keep [calling it Italian Quarter] because we get business out of that but it’s not really an Italian quarter anymore we don’t want to lose our status,” says David Though the number of Italian businesses in Italian Quarter has diminished over the years Both businesses featured have an extensive but high-quality menu – especially in terms of wine It’s hard to imagine that they’d go out of business anytime soon as they bring such a refreshing