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Canine parvovirus type 2 (CPV-2) is one of the most relevant pathogens associated with enteritis in dogs and is frequently reported in association with the detection of other pathogens in faeces. In this study the concomitant presence of Canine circovirus (CanineCV) and Canine adenovirus (CAdV) DNA in faecal or intestine samples of 95 dogs with parvovirus enteritis sampled in Italy (1995–2017) was investigated and the viruses identified were genetically characterised. Potential correlations with the antigenic variant of CPV-2 and with signalment data and outcome were evaluated. Twenty-eight of 95 (29.5%) CPV-2 infected dogs tested positive to other viruses: 7/28 were also positive to CanineCV, 1/28 to CAdV-1, 18/28 to CAdV-2, 1/28 to CanineCV and CAdV-2, and 1/28 to CAdV-1 and CAdV-2. The frequency of CAdV DNA detection and coinfections was significantly higher in purebred dogs compared to mixed breed ones (P = 0.002 and 0.009, respectively). The presence of coinfection was not associated with any other relevant data available, including CPV-2 variant and final outcome. The detection of CanineCV in a dog sampled in 2009 allowed to backdating its circulation in dogs. The eight CanineCV completely sequenced were phylogenetically related to the CanineCV identified in dogs, wolves and a badger from Europe, USA, Argentina and China. Nine CAdV were partially sequenced and phylogenetic analysis showed a separate branch for the oldest CAdV-2 identified (1995). From the results obtained in this study population, CanineCV and CAdV coinfections in dogs with parvoviral enteritis did not result in more severe disease. Supplementary Information The online version contains supplementary material available at 10.1007/s11259-021-09850-y.

Background: Pyothorax in cats is routinely managed, at least initially, with thoracic tube placement associated with systemic antimicrobial administration. Traditionally, large-bore trocar-type thoracostomy tubes have preferentially been used for the drainage of thick material from the pleural space. In recent years, the use of small-bore wire-guided thoracic drains has increased in both small animals and in humans. Few studies have highlighted the efficacy of small-bore wire-guided thoracostomy tubes. Aim: The purpose of this study was to describe the use of small-bore wire-guided thoracostomy tubes in feline pyothorax in terms of efficacy, safety and outcome. Methods: Cats with pyothorax managed with small-bore thoracostomy tubes (2015-2018) were retrospectively studied. The number of drains inserted, the need for anesthesia and analgesia for chest tube placement and maintenance, and related major and minor complications were reviewed. Clinical data, diagnostic results, treatment and outcome were recorded. Results: Ten cats were enrolled. Thoracostomy tube placement was unilateral in 7/10 cats despite the presence of bilateral effusion in 9/10 cats, and required sedation (8/10) or anesthesia (2/10). Three cats experienced minor complications during the chest tube insertion, including self-limiting pneumothorax (1/3) and malpositioning (2/3). One cat had a major complication (non functional malposition) requiring reposition of the drain. Pain management was adequately achieved using opioids (8/10) or opioids plus nonsteroidal anti-inflammatory drugs (NSAIDs) (2/10). Partial chest tube occlusion occurred in 3 cases and it was resolved with lavage. In one case, the occlusion was complete, requiring drain removal. Three/10 cats were treated medically, combining thoracostomy tubes and antibiotics while 7/10 cats underwent surgery. All the cats survived. Conclusion: Small-bore thoracostomy tubes represent a safe and effective option for the initial management of feline pyothorax. In fact, mainly minor complications were reported during insertion and usage. The small-bore thoracostomy tubes were well tolerated by the cats with a satisfactory performance in terms of exudate drainage in most cases. The combined use of a small-bore thoracostomy drain together with the common practice of surgical treatment might have resulted in the successful management of the cases presented.

Friedreich’s ataxia (FA) is a neurodegenerative disease caused by the epigenetic repression of the Frataxin gene modulating mitochondrial activity in the brain, which has a diffuse phenotypic impact on patients’ motor behavior. Therefore, with current gold-standard clinical scales, it requires 18–24 month-long clinical trials to determine if disease-modifying therapies are at all beneficial. Our high-performance monitoring approach captures the full-movement kinematics from human subjects using wearable body sensor networks from a cohort of FA patients during their regular clinical visits. We then use artificial intelligence to convert these movement data using universal behavior fingerprints into a digital biomarker of disease state. This enables us to predict two different ‘gold-standard’ clinical scores (SCAFI, SARA) that serve as primary clinical endpoints. Crucially, by performing gene expression analysis on each patient their personal Frataxin gene expression levels were poorly, if at all, correlated with their clinical scores – fundamentally failing to establish a link between disease mechanism (dysregulated gene expression) and measures to quantify it in the behavioral phenotype. In contrast, our wearable digital biomarker can accurately predict for each patient their personal FXN gene expression levels, demonstrating the sensitivity of our approach and the importance of FXN levels in FA. Therefore, our data-derived biomarker approach can not only cross-sectionally predict disease and their gene expression levels but also their longitudinal disease trajectory: it is sensitive and accurate enough to detect disease progression with much fewer subjects or shorter time scales than existing primary endpoints. Our work demonstrates that data-derived wearable biomarkers have the potential to substantially reduce clinical trial durations and a first in-human demonstration of reconstructing FXN gene expression levels from behavioral data alone.

Behavioral disorders affect millions of people worldwide. Hypertension contributes to both the development and progression of brain damage and cognitive dysfunction and could represent the most powerful modifiable risk factor for cerebral vessel dysfunction and consequent behavioral impairment. Tomato contains antioxidants and bioactive molecules that might play an important role in the prevention of cardiovascular and brain diseases. The effects of the combined gel and serum from Lycopersicum esculentum L. var. “Camone” tomatoes and those of purified tomato glycoalkaloids (tomatine) and an antihypertensive drug (captopril) were investigated in male spontaneously hypertensive rats (SHRs) and compared with normotensive Wistar Kyoto (WKY) rats. Body weight, systolic blood pressure, behavioral parameters, as well as brain susceptibility to oxidative stress and brain cytokine contents, were assessed. Treating hypertensive rats with tomato gel/serum or captopril for four weeks caused a significant reduction in blood pressure, decreased locomotor activity and increased grooming behavior, the last two parameters were also significantly affected by tomatine treatment. Brain slices obtained from hypertensive rats treated with tomato gel/serum were more resistant to oxidative stress and contained lower levels of inflammatory cytokines than vehicle-treated ones. In contrast, tomatine treatment had no effect. In conclusion, the tomato-derived gel/serum can be considered a dietary supplement able to drive in vivo blood pressure towards healthier values and also control some central effects such as behavior and brain oxidative stress.

Dysfunctional mitochondria characterise Parkinson’s Disease (PD). Uncovering etiological molecules, which harm the homeostasis of mitochondria in response to pathological cues, is therefore pivotal to inform early diagnosis and therapy in the condition, especially in its idiopathic forms. This study proposes the 18 kDa Translocator Protein (TSPO) to be one of those. Both in vitro and in vivo data show that neurotoxins, which phenotypically mimic PD, increase TSPO to enhance cellular redox-stress, susceptibility to dopamine-induced cell death, and repression of ubiquitin-dependent mitophagy. TSPO amplifies the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signalling, forming positive feedback, which represses the transcription factor EB (TFEB) and the controlled production of lysosomes. Finally, genetic variances in the transcriptome confirm that TSPO is required to alter the autophagy–lysosomal pathway during neurotoxicity.

Auditory neural impairment is a key clinical feature of Friedreich’s Ataxia (FRDA). We aimed to characterize the phenotypical spectrum of the auditory impairment in FRDA in order to facilitate early identification and timely management of auditory impairment in FRDA patients and to explore the relationship between the severity of auditory impairment with genetic variables (the expansion size of GAA trinucleotide repeats, GAA1 and GAA2), when controlled for variables such as disease duration, severity of the disease and cognitive status. Twenty-seven patients with genetically confirmed FRDA underwent baseline audiological assessment (pure-tone audiometry, otoacoustic emissions, auditory brainstem response). Twenty of these patients had additional psychophysical auditory processing evaluation including an auditory temporal processing test (gaps in noise test) and a binaural speech perception test that assesses spatial processing (Listening in Spatialized Noise-Sentences Test). Auditory spatial and auditory temporal processing ability were significantly associated with the repeat length of GAA1. Patients with GAA1 greater than 500 repeats had more severe auditory temporal and spatial processing deficits, leading to poorer speech perception. Furthermore, the spatial processing ability was strongly correlated with the Montreal Cognitive Assessment (MoCA) score. To our knowledge, this is the first study to demonstrate an association between genotype and auditory spatial processing phenotype in patients with FRDA. Auditory temporal processing, neural sound conduction, spatial processing and speech perception were more severely affected in patients with GAA1 greater than 500 repeats. The results of our study may indicate that auditory deprivation plays a role in the development of mild cognitive impairment in FRDA patients.

Background: Three different phenotypes of septic shock based on changes in blood pressure and lactate are recognized in people. Dysoxic shock, representing the combination of fluid-refractory hypotension and hyperlactatemia, is characterized by greater disease severity and mortality compared to cryptic shock (hyperlactatemia alone) and vasoplegic shock (hypotension with normal blood lactate). Little is known about septic shock and specifically its phenotypes in cats.Objective: To analyze the characteristics and prognostic implications of three septic shock phenotypes in cats with sepsis.Methods: Cats with septic shock were prospectively included. Septic shock was defined by the presence of hypotension (mean blood pressure 4 mmol/L) and classified in three subgroups: dysoxic shock, vasoplegic shock and cryptic shock. Clinical and clinicopathological variables including APPLEfast and APPLEfull scores, occurrence of multi-organ dysfunction syndrome (MODS; presence of at least two dysfunctional organs simultaneously) and outcome were compared among subgroups. Cats with sepsis showing normal blood pressure and lactate concentrations hospitalized during the study period were included as uncomplicated sepsis, and compared to cats with septic shock for selected variables. Length of hospital stay and mortality were evaluated in the whole study population. Odds ratios for mortality were calculated using logistic regression analysis. Significance was set at P < 0.05.Results: The study enrolled 48 cats with uncomplicated sepsis and 37 cats with septic shock (dysoxic shock n = 17; vasoplegic shock n = 11; cryptic shock n = 7). Cats with dysoxic shock had significantly higher APPLEfast and APPLEfull scores compared to vasoplegic and cryptic shock. Mortality rates were not significantly different among cryptic (57%), dysoxic (65%) and vasoplegic shock (91%), while MODS occurrence was significantly lower in cats with cryptic shock (57%) compared to patients affected by dysoxic (94%) and vasoplegic (100%) shock. Cats with septic shock had higher frequency of MODS and greater mortality rate than cats with uncomplicated sepsis.Conclusion: Despite similar in-hospital mortality, cats with dysoxic and vasoplegic shock are characterized by having higher occurrence of multi- organ dysfunction compared to cats affected by cryptic shock. Results from this study suggest novel means of identifying high-risk subgroups of septic cats.

Background Urine neutrophil gelatinase‐associated lipocalin (NGAL) is a promising biomarker of acute kidney injury (AKI) in dogs. Objectives To evaluate the utility of urinary NGAL for characterizing AKI according to volume responsiveness, presence of inflammation and sepsis, and prognosis. Animals Dogs with AKI (n = 76) and healthy controls (n = 10). Methods Prospective study. Clinical and clinicopathologic data including absolute urine NGAL concentration (uNGAL) and NGAL normalized to urine creatinine concentration (uNGALC) were measured upon admission. Dogs were graded according to International Renal Interest Society (IRIS) AKI guidelines and compared based on AKI features: volume‐responsive (VR‐) AKI vs. intrinsic (I‐) AKI based on IRIS criteria; VR‐AKI and I‐AKI based on urine chemistry; inflammatory versus noninflammatory; septic versus nonseptic; and survivors versus nonsurvivors. Nonparametric statistics were calculated, and significance set at P

Heinz bodies (HBs) are known to interfere with automated hematology in cats, particularly with the white blood cell (WBC) count. We evaluated the influence of feline HBs on the complete blood count (CBC) results obtained using a flow cytometry–based analyzer. We retrospectively selected cats with circulating HBs and reviewed the results of their CBCs, including red blood cell (RBC) indices, basophil/lobularity (Baso) WBC count (WBCB), peroxidase (Perox) WBC count (WBCP), and cytograms. Based on the presence or absence of HB-related artifacts in their Baso cytogram, cats were grouped into Baso-HBs and HBs groups, respectively, for comparison. The WBCB and WBCP were compared to manual counts of WBCs carried out on blood smears at 400× (MC-WBC). We included 32 cats in our study: 9 of 32 were in the Baso-HBs group, and 23 of 32 were in the HBs group. Baso-HBs cats had a significantly increased HB percentage ( p < 0.001), WBCB ( p < 0.001), difference between WBCB and WBCP ( p < 0.001), lymphocyte count ( p < 0.001), mean corpuscular hemoglobin concentration ( p < 0.001), and difference between calculated and measured erythrocyte hemoglobin concentrations ( p < 0.001) compared to HBs cats. In Baso-HBs cats, the WBCB was significantly higher than the WBCP ( p = 0.02); no significant difference was detected between the WBCP and the MC-WBC ( p = 0.88). Evaluation of automated CBC results raised the suspicion of HB-related interference when using a hematology analyzer in cats; hence, blood smear examination remains essential in routine practice.

Background: Little information is available in spinocerebellar ataxias (SCAs) regarding pelvic organ symptoms. The aim of this study was to characterize the lower urinary tract (LUT) and bowel dysfunction in autosomal dominant spinocerebellar ataxias. Methods: Patients with confirmed SCAs attending a tertiary care service were approached about LUT and bowel complaints, and completed validated questionnaires: urinary symptom profile (USP), QualiveenShort form, International Prostate Symptom Score, and Neurogenic Bowel Dysfunction Score. SCA3 and SCA7 patients with urological complaints additionally underwent urodynamic studies (UDS). Patients’ characterization included demographic, clinical (Scale for the Assessment and Rating of Ataxia (SARA), Inventory of Non-Ataxia Signs (INAS)), and genetic variables. Descriptive and comparative analyses were performed. Results: Fifty-one patients participated: SCA1 (n = 4), SCA2 (n = 11), SCA3 (n = 13), SCA6 (n = 17), and SCA7 (n = 6). The prevalence of self-reported LUT symptoms was 60.8% (n = 31), whereas LUT symptoms was reported in 86.3%(n = 44) using the USP. Both storage and voiding symptoms were reported, urinary frequency and urgency being the most frequent (n = 34, 68%). Although LUT symptoms were most often classed as mild (n = 27, 61.4%), they impacted QoL in 38 patients (77.6%). Of these, 21 (55.3%) were not on pharmacological treatment for urinary dysfunction. Most common abnormalities in UDS (n = 14) were detrusor overactivity (storage phase) and detrusor underactivity (voiding phase). Bowel symptoms were less common (31.4%, n = 16) and of mild severity. Conclusion: LUT symptoms are prevalent in SCA patients and impact QoL, whereas bowel symptoms tend to be mild. These symptoms are overlooked by patients and physicians due to the complexity of neurological involvement in SCA, and therefore a multidisciplinary management approach should be adopted.

Objective Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. Methods We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. Results One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. Interpretation In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.

Background The development of new therapies may rely on the conduct of human experimentation as well as later clinical trials of therapeutic interventions. Ethical considerations seek to protect the patient from risk but few have sought to ascertain the attitude to such risk of patients with progressive debilitating or terminal conditions, for which no mitigating or curative therapies exist. Such understanding is also important if recruitment is to be maximized. We therefore sought to define the motivations for and barriers to trial participation amongst patients with progressive ataxias, as well as their condition-specific trial preferences. Methods We conducted an online survey consisting of 29 questions covering four key domains (demographics, personal motivation, drug therapy and study design) relating to the design of clinical trials. Two major ataxia charities, Ataxia UK and the Friedreich’s Ataxia Research Alliance (FARA) sent the survey to their members. Responses were analysed by disease and by ambulatory status. Results Of 342 respondents, 204 reported a diagnosis of Friedreich’s ataxia (FRDA), 55 inherited cerebellar ataxia (CA) and 70 idiopathic CA. The most important symptoms to be addressed by a trial were considered to be balance problems and ambulation, although these were superseded by speech problems in wheelchair users. Common motivations for participation were potential benefits to self and others. Reasons for non-participation included concerns about side effects, and the burden and cost of travel. Financial reimbursement for expenses was reported to be likely to increase trial engagement, Phase two trials were the most popular to participate in, and the use of a placebo arm was seen as a disincentive. Across all disease subgroups, drug repurposing trials proved popular and just under 70% of participants would be prepared to undergo intrathecal drug administration. Conclusions Knowledge of motivations for and barriers to trial participation as well as the acceptability of investigations, time commitments and routes of drug administration should inform better, more patient focused trial design. This in turn may improve recruitment and retention of participants to future trials.

Movement disorders 37(2), 405-410 (2022). doi:10.1002/mds.28844, Published by Wiley, New York, NY

Reliable diagnostic and prognostic markers of sepsis are lacking, but essential in veterinary medicine. We aimed to assess the accuracy of C-Reactive Protein (CRP), protein carbonyls (PCO) and paraoxonase-1 (PON1) in differentiating dogs with sepsis from those with sterile inflammation and healthy ones, and predict the outcome in septic dogs. These analytes were retrospectively evaluated at admission in 92 dogs classified into healthy, septic and polytraumatized. Groups were compared using the Kruskal–Wallis test, followed by a Mann–Whitney U test to assess differences between survivors and non-survivors. Correlation between analytes was assessed using the Spearman’s test, and their discriminating power was assessed through a Receiver Operating Characteristic (ROC) curve. PON1 and CRP were, respectively, significantly lower and higher in dogs with sepsis compared with polytraumatized and clinically healthy dogs (p < 0.001 for both the analytes), and also in dogs with trauma compared with healthy dogs (p = 0.011 and p = 0.017, respectively). PCO were significantly increased in septic (p < 0.001) and polytraumatized (p < 0.005) as compared with healthy dogs. PON1 and CRP were, respectively, significantly lower and higher in dogs that died compared with survivors (p < 0.001 for both analytes). Ultimately, evaluation of CRP and PON1 at admission seems a reliable support to diagnose sepsis and predict outcomes.

Summary Background The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia. Methods EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov , NCT02069509 . Findings Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 [0·07]) than non-ambulatory (0·50 [0·07]). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 [0·07]) and non-ambulatory (0·91 [0·08]). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included. Interpretation Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia. Funding European Commission, Voyager Therapeutics, and EuroAtaxia.

Objective: To compare the impact of an IV bolus of hydroxyethyl starch 130/0.4 (HES) or hypertonic saline 7.5% (HS) on hemostasis in dogs resuscitated for gastric-dilation-volvulus (GDV). Design: Open-label, parallel-group randomized clinical trial. Animals: Twenty-three client-owned dogs. Interventions: Dogs affected by GDV and shock were randomly assigned to receive HES at 10mL/kg or HS at 4mL/kg every 15 minutes. Blood samples were collected for blood gas analysis, PCV, total plasma protein, albumin, standard coagulation profile, and thromboelastometry (ROTEM) at baseline (T0) and at the end of bolus (T1). To assess the differences between the 2 groups at T1, Student's t-test or Wilcoxon rank-sum test was used. To evaluate the differences between T0 and T1, ANOVA for paired data or Wilcoxon matched-pairs signed-ranks test was used. P&nbsp

A 4-year-old Dachshund was referred for management of a mandibular fracture. The dog underwent cardiopulmonary arrest after sedation for skull radiography. Cardiopulmonary resuscitation was started immediately, and return of spontaneous circulation was rapidly obtained. However, after resuscitation, the dog was hemodynamically unstable. Additionally, global left ventricular systolic dysfunction and a focal hyperechoic myocardial lesion were found echocardiographically, and serum cardiac troponin I was severely elevated (82.80 ng/mL, upper hospital limit

Our purpose was to investigate the incidence of gliomas and neuronal-glial tumors, their outcome, and H3.3K27M, BRAFV600E, and IDH status in children within 1 year of age affected by CNS tumor. We collected 28 consecutive gliomas and mixed tumors. Immunohistochemistry and/or molecular analyses were performed on formalin-fixed/paraffin-embedded specimens. 24 (86%) tumors were supratentorial. 15 (54%) tumors were astrocytomas (5 glioblastomas, 1 anaplastic astrocytoma, 1 pilocytic astrocytoma, 3 pilomixoid astrocytomas, 2 subependymal giant cell astrocytomas, 3 astrocytomas not otherwise specified (NOS)), 4 (14%) were anaplastic ependymomas, and 9 (32%) were mixed tumors (5 gangliogliomas, 2 gangliocytomas, 2 desmoplastic infantile gangliogliomas (DIGs)). Alive patients were: 4 (67%) affected by high-grade astrocytoma (mean follow-up 64 months), 4 (67%) affected by low-grade astrocytoma (mean follow-up 83 months), 2 (67%) affected by astrocytoma NOS (mean follow-up 60 months), 1 (25%) affected by anaplastic ependymoma (follow-up 12 months), and 9 (100%) affected by mixed tumors (mean follow-up 74 months). H3.3K27M and IDH were not-mutated in any tumor (100%). BRAFV600E mutation was documented in 6 (21%) tumors (4 gangliogliomas, 1 gangliocytoma, and 1 astrocytoma NOS resulted as anaplastic pleomorphic xanthoastrocytoma 8 years later). Gliomas and mixed tumors diagnosed within 1 year of age are morphologically heterogeneous. Moreover, analogously to those affecting older children, they are IDH1-2 and H3.3K27M (when located outside midline) not-mutated while BRAFV600E mutation is typical of gangliogliomas/gangliocytomas and pleomorphic xanthoastrocytomas. High-grade astrocytomas have a more favorable prognosis compared with the same lesions occurring later in life while ependymomas have a poorer outcome.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the SACS gene, encoding the 520 kDa modular protein sacsin, which comprises multiple functional sequence domains that suggest a role either as a scaffold in protein folding or in proteostasis. Cells from patients with ARSACS display a distinct phenotype including altered organisation of the intermediate filament cytoskeleton and a hyperfused mitochondrial network where mitochondrial respiration is compromised. Here, we used vimentin bundling as a biomarker of sacsin function to test the therapeutic potential of Hsp90 inhibition with the C-terminal-domain-targeted compound KU-32, which has demonstrated mitochondrial activity. This study shows that ARSACS patient cells have significantly increased vimentin bundling compared to control, and this was also present in ARSACS carriers despite them being asymptomatic. We found that KU-32 treatment significantly reduced vimentin bundling in carrier and patient cells. We also found that cells from patients with ARSACS were unable to maintain mitochondrial membrane potential upon challenge with mitotoxins, and that the electron transport chain function was restored upon KU-32 treatment. Our preliminary findings presented here suggest that targeting the heat-shock response by Hsp90 inhibition alleviates vimentin bundling and may represent a promising area for the development of therapeutics for ARSACS.

Introduction: To evaluate the clinical utility of placental growth factor (PlGF) for the prediction of preeclampsia (PE). Materials and methods: This prospective cohort study included women divided into three groups: (1) pregnancies without preconceptional risk of developing PE; (2) pregnancies with a preconceptional and/or current risk of developing PE; (3) PE-complicated pregnancies (control group). Blood samples were collected every 4-5 weeks or during hospitalization from early second trimester until delivery in the group 1 and 2, at the diagnosis of PE in the group 3. Plasma levels of PlGF were measured using The Triage PlGF test (Alere) and considered pathological under the 5th centile for gestational age. Sensitivity (Sn), specificity (Sp), positive and negative predictive value (PPV, NPV) were calculated. Results: In group 1, 30% of women (3/10) had pathological test but none of them developed PE (Sp 70%, NPV 100%). In group 2 (n = 75), none of the patients with normal test developed PE (0/24), while 39% of women with PlGF < 5th centile (20/51) developed PE (Sn 100%, Sp 44%, PPV 39%, NPV 100%). In group 3 (n = 11) all women except one had a pathological PlGF test (Sn 90%, PPV 100%). Conclusions: Our data support recent studies which identify PlGF as a biochemical marker not only of PE, but also of placental dysfunction. In fact, it is useful for ruling out PE in women at risk because of the high Sn and high NPV: a normal PlGF is related with a positive pregnancy outcome. Therefore, the measurement of this biomarker would simplify PE clinical management and would reduce costs.

Background: Sepsis is a life-threatening condition associated with an exacerbated production of both pro- and anti-inflammatory cytokines that can promote a hyperactive response to infection or induce immunoparalysis. Data regarding the immune response to sepsis in cats are scarce. Establishing the profiles of cytokines and chemokines in feline sepsis to characterize the nature of the immune responses to sepsis might enable individualized treatments to be developed and targeted. Objective: To evaluate the cytokine and chemokine network in cats with sepsis and septic shock, and to investigate the associations of these analytes with disease severity and outcome. Methods: Blood samples prospectively collected at presentation of cats with sepsis and septic shock to two veterinary teaching hospitals were analyzed. Forty healthy cats were included as controls. A 19-plex feline cytokine/chemokine magnetic bead assay system was used to measure analytes in citrated plasma samples. Cytokine concentrations were compared between groups using the Kruskal-Wallis test with Dunn's post-hoc correction for multiple comparisons. Cytokine concentrations were compared between survivors and non-survivors with the Mann-Whitney U test. Odds ratios were calculated using logistic regression. A multivariable logistic regression model for prediction of septic shock was constructed. Results: The study enrolled 35 septic cats. Many cytokines were undetectable in both sick and healthy control cats and were excluded from subsequent analyses. Comparisons of cytokine concentrations among healthy controls, cats with sepsis (n = 12) and cats with septic shock (n = 23) revealed that sick cats (sepsis or septic shock) had significantly higher plasma concentrations of IL-6, IL-8, KC-like, and RANTES compared to healthy controls. The combination of MCP-1, Flt-3L, and IL-12 was predictive of septic shock. None of the cytokines analyzed was predictive of outcome in this study population. Conclusion: Plasma concentrations of IL-6, IL-8, KC-like, and RANTES are increased in cats with sepsis and may play important roles in pathogenesis. Multivariable modeling suggested that analysis of cytokines might aid differentiation of septic shock from sepsis. None of the cytokines analyzed was predictive of outcome. Measurement of these cytokines might enable future studies to better diagnose and characterize feline sepsis and septic shock.

Decreased serum apolipoprotein A1 (Apo-A1) concentration is associated with mortality in human sepsis. The diagnostic and prognostic role of serum Apo-A1 concentrations in canine sepsis was evaluated. Serum samples from septic dogs (n = 91) and healthy controls (n = 15) were retrospectively analyzed. According to the sepsis origin, four categories were identified: parvoviral enteritis (n = 26), pyometra (n = 20), septic peritonitis (n = 19), and miscellanea (n = 26). The canine acute patient physiologic and laboratory evaluation fast score (APPLEfast), serum C-reactive protein (CRP) and albumin concentrations were reviewed in all enrolled dogs. Increased CRP (252.6 ± 119.2 mg/L; Reference Interval: 0–8.5 mg/L) and significant lower serum albumin and Apo-A1 concentrations were documented in dogs with sepsis (22.8 ± 5.3 g/L and 1.17 ± 0.27 g/L, respectively) compared to healthy ones (33.1 ± 2.5 g/L and 1.32 ± 0.05 g/L, respectively) (P < 0.0001). According to the origin of sepsis, only the subgroup of dogs with septic peritonitis had significantly lower Apo-A1 (1.03 ± 0.26 g/L) concentrations compared to healthy dogs (P < 0.001). No significant differences were found in serum albumin and CRP concentrations, and in APPLEfast score values among the different subgroups of sepsis. Diagnosis of septic peritonitis was associated with a higher frequency of death (P = 0.006). In septic dogs, significant lower Apo-A1 concentrations were detected in non-survivors (1.02 ± 0.28 g/L; n = 27) compared to survivors (1.23 ± 0.24 g/L; n = 64; P = 0.0007). Moreover, significant higher values of the APPLEfast score were calculated in non-survivors (26 ± 4; n = 19) compared to survivors (23 ± 4; n = 51) (P = 0.0114). According to the area under the ROC curve analysis, Apo-A1

Large amount of nitric oxide (NO) can be released in patients with sepsis. Methemoglobin is formed from the interaction between NO and hemoglobin. Mild methemoglobinemia reflecting NO overproduction has been reported in septic people, and occasionally associated to septic shock and organ dysfunction. The aim of this retrospective study was to evaluate circulating methemoglobin fraction in dogs with sepsis and to assess its prognostic value. Methemoglobin reference interval (RI) was calculated in 41 healthy dogs and was set at 0–2.2%. A total of 131 dogs with sepsis were included in the study; 24/131 had a circulating methemoglobin ≥2.2%. The median methemoglobin fraction was significantly higher in dogs with sepsis compared to healthy ones (1.7%, 0.4–3.5% vs. 1.0, 0.3–2.2%, P = 0.0005). No significant difference was observed between dogs with uncomplicated sepsis (n = 98) vs. dogs with septic shock (n = 33) (1.8%, 0.4–2.8% vs. 1.5%, 0.4–3.5%, P = 0.74), between dogs with and without multi-organ dysfunction (n = 38 and n = 93, respectively) (1.7%, 0.4–3.5% vs. 1.7%, 0.5–2.8%, P = 0.27), and between survivors (n = 77) vs. non survivors (n = 54) (1.5%, 0.4–2.8% vs. 1.8%, 0.4–3.5%, P = 0.05). Dogs with methemoglobin fraction above or equal to the upper limit of the RI had a significantly higher frequency of death compared to dogs with methemoglobin levels

This preliminary study was designed to contribute to the evaluation of reliability of plasma lactate concentration (PLC) and its clearance as predictive and prognostic factors of gastric necrosis and clinical outcome of dogs affected by gastric dilatation-volvulus (GDV). Main aims of the study were: 1) to evaluate the prognostic reliability of PLC at presentation (T0) in dogs with GDV, 2) to compare the obtained data and considerations with the veterinary literature, and 3) to introduce the possible validity of PLC values at 24 (T24) and 48 (T48) hours after surgery as a predictive factor. Dogs with GDV were retrospectively evaluated. PLC at T0, T24 and T48 were recorded and correlated to the presence or absence of macroscopic necrosis of the stomach and to outcome. Forty-five dogs met the inclusion criteria. Significant differences were not detected in the mean values between the initial PLC in dogs with and without necrosis of the gastric wall, as well as between surviving and non-surviving dogs; these values were not associated with higher risk of gastric necrosis or death. At T24 and T48 no significant differences were recorded between necrosis and non-necrosis, and surviving and non-surviving categories. A median plasma lactate concentration clearance from arrival to T24 ≥ 50% was identified in both groups (with and without necrosis), and this parameter failed in identifying dogs that survived to discharge. In conclusion, the results presented here failed to detect PLC at T0 and its clearance at T24 as prognostic factors in this population of dogs with GDV., Surgery; Veterinary Medicine; Health Sciences; Surgery; Abdominal Surgery; Emergency Medicine; Plasma lactate concentration; Prognostic factor; Gastric dilatation-volvulus; dog; Gastric necrosis

Background Procalcitonin (PCT) is a valuable prognostic biomarker in human sepsis that is predictive of organ dysfunction, septic shock and mortality. Data on PCT in dogs is limited. This study aimed to investigate the prognostic value of baseline and serial PCT measurements in dogs with sepsis and to determine the association between PCT and sepsis severity and the presence of organ dysfunction. PCT concentrations were measured in citrated plasma samples collected from 53 dogs with sepsis at the time of admission (T0, n = 53) and at 24 h (T1, n = 35) and 48 h (T2, n = 30) post-admission using a commercial ELISA. Dogs were classified by sepsis severity (sepsis without organ dysfunction; severe sepsis; septic shock) and outcome (survivors; non-survivors). Organ dysfunctions were recorded at T0 and during hospitalization, and the APPLEfast score calculated at T0. Healthy dogs (n = 12) were used as controls. Results There were 18 septic dogs without organ dysfunction, 24 dogs with severe sepsis and 11 with septic shock. Baseline PCT concentrations were significantly greater in dogs with sepsis compared to healthy controls (P

In the past decades, the improving knowledge of genes implicated in the pathogenesis of psychiatric disorders together with the advancements in genetic engineering has led to the creation of mice in which one or more genes are inactivated or 'knocked out'. Knockout mice are extensively used to better investigate the molecular and cellular mechanisms underlying these diseases as well as the biological role of specific genes. Moreover, they are also useful tools for developing new therapeutic strategies. The success of using knockout mice is possible due to availability of several models used to mimic some clinical manifestations reported in psychiatric patients. In the present review, we will give an update of the most used gene knockout models in the field of psychiatric disorders including depression, anxiety, and obsessive-compulsive disorder.

Objectives Friedreich's ataxia is the most common inherited ataxia, and pathogenesis is known to involve mitochondrial oxidative stress. Idebenone is a potent antioxidant which has already been evaluated in several clinical trials in FRDA, with reports of symptomatic benefit but inconclusive objective results. Following patient consultation on design, we have completed a treatment-withdrawal study to establish whether patients could correctly determine their treatment allocation to placebo or idebenone. Our aim was to capture subjective experiences of symptoms such as fatigue, which can be difficult to measure with questionnaires or semi-quantitative scales, particularly in chronic, slowly progressive conditions. Materials and methods Patients taking idebenone for at least 12 months as part of the open-label MICONOS Extension Study were randomized to receive either placebo or idebenone continuation for 2-month treatment cycles. The primary endpoint was patient assessment of treatment assignment. Results A total of 29 patients were randomized, forming the idebenone group (n = 16) and the placebo group (n = 13). No significant differences were detected between the idebenone and placebo groups on assessment of treatment assignment or early study withdrawal. A small but significant difference in ataxia rating scale scores was detected between treatment groups when considering ambulatory patients only. Conclusions This study provides no data to suggest that FRDA patients could correctly determine their treatment assignment over a 2-month period. We hope that this study design will help inform future trials so that patients' experiences of symptoms are more reliably measured.

Progressive ataxia in adults can be difficult to diagnose, owing to its heterogeneity and the rarity of individual causes. Many patients remain undiagnosed (‘idiopathic’ ataxia). This paper provides suggested diagnostic pathways for the general neurologist, based on Ataxia UK’s guidelines for professionals. MR brain scanning can provide diagnostic clues, as well as identify ‘structural’ causes such as tumours and multiple sclerosis. Advances in molecular genetics, including the wider and cheaper availability of ‘next-generation sequencing’, have enabled clinicians to identify many more cases with a genetic cause. Finally, autoimmunity is probably an under-recognised cause of progressive ataxia: as well as patients with antigliadin antibodies there are smaller numbers with various antibodies, including some associated with cancer. There are a few treatable ataxias, but also symptomatic treatments to help people with the spectrum of complications that might accompany progressive ataxias. Multidisciplinary team involvement and allied health professionals’ input are critical to excellent patient care, including in the palliative phase. We can no longer justify a nihilistic approach to the management of ataxia.

Xeroderma pigmentosum (XP) encompasses a group of rare diseases characterized in most cases by malfunction of nucleotide excision repair (NER), which results in an increased sensitivity to UV radiation in affected individuals. Approximately 25-30% of XP patients present with neurological symptoms, such as sensorineural deafness, mental deterioration and ataxia. Although it is known that dysfunctional DNA repair is the primary pathogenesis in XP, growing evidence suggests that mitochondrial pathophysiology may also occur. This appears to be secondary to dysfunctional NER but may contribute to the neurodegenerative process in these patients. The available pharmacological treatments in XP mostly target the dermal manifestations of the disease. In the present review, we outline how current understanding of the pathophysiology of XP could be used to develop novel therapies to counteract the neurological symptoms. Moreover, the coexistence of cancer and neurodegeneration present in XP led us to focus on possible new avenues targeting mitochondrial pathophysiology. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.

International audience; Government policies on abortion are a longstanding topic of heated political debates. The COVID-19 pandemic shook health systems to the core adding further to the complexity of this topic, as imposed national lockdowns and movement restrictions affected access to timely abortion for millions of women across the globe. In this paper, we examine how countries within the European Union and the United Kingdom responded to challenges brought by the COVID-19 crisis in terms of access to abortion. By combining information from various sources, we have explored different responses according to two dimensions: changes in policy and protocols, and reported difficulties in access. Our analysis shows significant differences across the observed regions and salient debates around abortion. While some countries made efforts to maintain and facilitate abortion care during the pandemic through the introduction or expansion of use of telemedicine and early medical abortion, others attempted to restrict it further. The situation was also diverse in the countries where governments did not change policies or protocols. Based on our data analysis, we provide a framework that can help policy makers improve abortion access.; Government policies on abortion are a longstanding topic of heated political debates. The COVID-19 pandemic shook health systems to the core adding further to the complexity of this topic, as imposed national lockdowns and movement restrictions affected access to timely abortion for millions of women across the globe. In this paper, we examine how countries within the European Union and the United Kingdom responded to challenges brought by the COVID-19 crisis in terms of access to abortion. By combining information from various sources, we have explored different responses according to two dimensions: changes in policy and protocols, and reported difficulties in access. Our analysis shows significant differences across the observed regions and salient debates around abortion. While some countries made efforts to maintain and facilitate abortion care during the pandemic through the introduction or expansion of use of telemedicine and early medical abortion, others attempted to restrict it further. The situation was also diverse in the countries where governments did not change policies or protocols. Based on our data analysis, we provide a framework that can help policy makers improve abortion access.

Cerebrospinal fluid administration of recombinant adeno-associated viral (rAAV) vectors has been demonstrated to be effective in delivering therapeutic genes to the central nervous system (CNS) in different disease animal models. However, a quantitative and qualitative analysis of transduction patterns of the most promising rAAV serotypes for brain targeting in large animal models is missing. Here, we characterize distribution, transduction efficiency, and cellular targeting of rAAV serotypes 1, 2, 5, 7, 9, rh.10, rh.39, and rh.43 delivered into the cisterna magna of wild-type pigs. rAAV9 showed the highest transduction efficiency and the widest distribution capability among the vectors tested. Moreover, rAAV9 robustly transduced both glia and neurons, including the motor neurons of the spinal cord. Relevant cell transduction specificity of the glia was observed after rAAV1 and rAAV7 delivery. rAAV7 also displayed a specific tropism to Purkinje cells. Evaluation of biochemical and hematological markers suggested that all rAAV serotypes tested were well tolerated. This study provides a comprehensive CNS transduction map in a useful preclinical large animal model enabling the selection of potentially clinically transferable rAAV serotypes based on disease specificity. Therefore, our data are instrumental for the clinical evaluation of these rAAV vectors in human neurodegenerative diseases.

Background Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) causes unique retinal abnormalities, which have not been systematically investigated. Objective To deeply phenotype the retina in ARSACS in order to better understand its pathogenesis and identify potential biomarkers. Methods We evaluated 29 patients with ARSACS, 66 with spinocerebellar ataxia (SCA), 38 with autosomal recessive cerebellar ataxia (ATX), 22 with hereditary spastic paraplegia (SPG), 21 cases of papilledema, and 20 healthy controls (total n = 196 subjects). Participants underwent visual acuity assessment, intraocular pressure measurement, fundoscopy, and macular and peripapillary optical coherence tomography (OCT). Macular layers thicknesses in ARSACS were compared with those of age-matched healthy controls. Ophthalmologists analyzed the scans for abnormal signs in the different patient groups. Linear regression analysis was conducted to look for associations between retinal changes and age, age at onset, disease duration, and Scale for the Assessment and Rating of Ataxia (SARA) scores in ARSACS. Results Only patients with ARSACS exhibited peripapillary retinal striations (82%) on fundoscopy, and their OCT scans revealed foveal hypoplasia (100%), sawtooth appearance (89%), papillomacular fold (86%), and macular microcysts (18%). Average peripapillary retinal nerve fiber layer (pRNFL) was thicker in ARSACS than in SCA, ATX, SPG, and controls; a cut-off of 121 μm was 100% accurate in diagnosing ARSACS. All macular layers were thicker in ARSACS when compared to healthy controls. RNFL thickness in the inferior sector of the macula positively correlated with SARA scores. Conclusions Retinal abnormalities are highly specific for ARSACS, and suggest retinal hyperplasia due to abnormal retinal development. OCT may provide potential biomarkers for future clinical trials. © 2021 International Parkinson and Movement Disorder Society.

The aim of the present study was to evaluate the size of the penis in flaccidity and in erection of Italian men. A total of 4,685 men living in Italy and who have been visited at the Italian urology operating units were involved in the study between January 2019 and January 2020. Each patient was given details on how to measure their penis (erect length and circumference) in flaccidity and in erection, from the lower base to the distal penile tip. Mean (standard deviation [SD]) flaccid penis length was 9.47 (2.69), mean (SD) flaccid penis circumference was 9.59 (3.08), mean (SD) erect penis length was 16.78 (2.55) and mean (SD) erect penis circumference was 12.03 (3.82). At the linear regression analysis, height was associated with flaccid penis length (β = 0.04; p‐value = .01), and erect penis length was (β = 0.05; p‐value