In-label, off-label prescription, efficacy and tolerability of dalbavancin: report from a National Registry.

PURPOSE: Although dalbavancin is currently approved for the treatment of ABSSIs, several studies suggest its efficacy and tolerance as long-term therapy for other off-label indications requiring prolonged intravenous antibiotic administration. METHODS: We conducted a prospective nationwide study of dalbavancin use in real-life settings for both approved and off-label indications analysing for each case the clinical and microbiological characteristics of infection the efficacy and safety of treatments. RESULTS: During the study period (from December 2018 to July 2021), the ID specialists from 14 different centres enrolled 223 patients treated with dalbavancin [141 males (63%) and 82 females (37%); male/female ratio 1.72; mean age 59 (SD 17.2) years, (range 15-96). Most patients in the study population (136/223; 61.0%) came from community rather than health care facilities and most of them were visited in Infectious Diseases wards (93/223; 41.7%) and clinics (55/223; 24.7%) even though some patients were cured in other settings, such as surgery wards (18/223; 8.1%), orthopaedic wards (11/223; 4.9%), Emergency Rooms (7/223; 3.1%) and non-surgical other than ID wards (6/223; 2.7%). The most common ID diagnoses were osteomyelitis (44 cases/223; 19.7%; of which 29 acute and 15 chronic osteomyelitis), cellulitis (28/223; 12.5%), cutaneous abscess (23/223; 10.3%), orthopaedic prosthesis-associated infection (22/223; 9.9%), surgical site infection (20/223; 9.0%) and septic arthritis (15/223; 6.7%). CONCLUSION: In conclusion, by virtue of its PK/PD properties, dalbavancin represents a valuable option to daily in-hospital intravenous or outpatient antimicrobial regimens also for off-label indications requiring a long-term treatment of Gram-positive infections.

Effects of animal position on M-mode, two-dimensional, and Doppler echocardiographic measurements in healthy French bulldogs.

Echocardiography is the most widely accepted diagnostic tool for assessment of cardiac function and morphology in dogs and is usually performed in lateral recumbency. However, in some situations or in stressed patients, it is necessary to perform it in a standing position. Only one study evaluated the effects of animal position on selected two-dimensional and M-mode echocardiographic variables in four healthy dogs of different breeds, but not in brachycephalic breeds. In these breeds echocardiographic evaluation is sometimes needed in standing position due to the severity of brachycephalic obstructive airway syndrome and the impossibility of managing them in lateral recumbency without causing stress and choking danger. The objectives of this prospective, observational study were to (a) evaluate the effects of lateral recumbency versus standing positions on echocardiographic M-mode, two-dimensional, Doppler flow measurements, and Tissue Doppler imaging in healthy French bulldogs (FBs); (b) assess the intra- and interoperator variability of the standing echocardiographic examination; and (c) compare the obtained results with the available data from the literature. Forty healthy FBs (20 females/20 males) were sampled. The median age and weight were 2.45 years (IQR25-75 , 1.18-4.16) and 12.7 kg (IQR25-75 , 10.88-13.46). There were no differences between lateral recumbency and standing position measurements (P > 0.05). Intraoperator coefficients of variation (CVs) ranged from 0.5% to 10.1%, whereas interoperator CVs ranged from 1% to 14.2%. Only E wave peak velocity, aortic, and pulmonary flows were consistent with the previously published reference ranges in lateral recumbency. In conclusion, echocardiography in a standing position could be a useful tool in FBs.

Breed-specific vertebral heart score, vertebral left atrial size, and radiographic left atrial dimension in Cavalier King Charles Spaniels: Reference interval study.

Cavalier King Charles Spaniels (CKCS) are predisposed to developing myxomatous mitral valve disease (MMVD), with radiographs frequently used to screen for evidence of left-sided cardiomegaly secondary to MMVD. Vertebral heart size (VHS), vertebral left atrial size (VLAS), modified VLAS (M-VLAS), and radiographic left atrial dimension (RLAD) are reported as objective measurements of global heart size and left atrial size. Normal VHS in CKCS (10.6 ± 0.5) is reportedly higher than the non-breed-specific value (9.7±0.5). Breed-specific VLAS, M-VLAS, and RLAD cut-offs have not been reported in CKCS. The aim of this prospective reference interval study was to describe the VHS, VLAS, M-VLAS, and RLAD values for 30 clinically healthy adult CKCS. Inclusion criteria were unremarkable physical examination, normal echocardiography, and thoracic radiographs without malposition/abnormalities. There were 22 female and eight male dogs. Ages ranged from 1 to 6 years. The VHS mean value in our sample was 10.08 ± 0.56 (95% range, 9.87-10.29). This was significantly greater than a previously published general canine reference value of 9.7 ± 0.5 and significantly less than a previously published CKCS breed-specific value of 10.6 ± 0.5 (P < 0.01). Mean VLAS, M-VLAS, and the RLAD values in our study were 1.79 ± 0.3 (95% range, 1.68-1.9), 2.23 ± 0.44 (95% range, 2.06-2.39), and 1.2 ± 0.34 (95% range, 1.07-1.33), respectively. These were significantly less than previously published reference interval values (P < 0.001). The VHS, M-VLAS, and the RLAD were not affected by sex, body weight, or BCS; whereas the VLAS was moderately affected by body weight. Findings from this study can be used as background for future thoracic radiographic assessments in CKCS.

High rates of sustained virological response despite premature discontinuation of directly acting antivirals in HCV-infected patients treated in a real-life setting.

In routine clinical practice, hepatitis C virus-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the predefined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years, and 53 (14.5%) patients were HIV-co-infected. Liver cirrhosis was observed in 251 (68.8%) subjects, and the most represented genotypes were 1b (n = 168, 46%) and 3 (n = 59, 16.2%). DAA was discontinued a median of 1 (IQR 1-4) weeks before the predefined EOT, with 164 (44.9%) patients stopping DAAs at least 2 weeks before the planned schedule. In patients with F0-F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n = 2/4) vs. 99.1% (n = 109/110) for ≥4 weeks, p = 0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3% (n = 25/30) vs. 94.6% (n = 209/221) for ≥8 weeks, p = 0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0-F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials.

Factors affecting the urinary aldosterone-to-creatinine ratio in healthy dogs and dogs with naturally occurring myxomatous mitral valve disease.

BACKGROUND: Chronic renin-angiotensin-aldosterone system (RAAS) activation in course of heart diseases contributes to cardiac remodeling and heart failure. Myxomatous mitral valve disease (MMVD) is characterized by different stages of severity and trend of RAAS activity during the course of the disease is still uncertain. The urinary aldosterone-to-creatinine ratio (UAldo:C) has been proven to reflect RAAS activation in dogs and might be a useful marker in monitoring therapy and disease progression, but data about this parameter need to be expanded. The objective of this study was to evaluate the UAldo:C in healthy dogs and dogs with naturally occurring MMVD, and to investigate the relationships between this parameter and clinical, echocardiographic and laboratory variables. RESULTS: The study population consisted of 149 dogs: 49 healthy and 100 MMVD dogs (45 stage B1, 13 stage B2 and 42 stage C). Urinary aldosterone-to-creatinine ratio was not significantly different among healthy and MMVD dogs of any stages. Breed, sex and age showed a significant impact on UAldo:C. In particular, Chihuahua and Cavalier King Charles spaniel showed significantly higher UAldo:C than other breeds, as well as intact females than other genders. In stage C dogs, UAldo:C appeared to be increased by spironolactone and was positively associated with furosemide dose (P = 0.024). Aldosterone breakthrough (ABT) appeared to occur in 36% (8/22) of stage C dogs not receiving spironolactone. A significant positive association between UAldo:C and left atrium-to-aortic root ratio (LA/Ao) was found. CONCLUSIONS: Individual factors such as breed, sex and age appeared to influence UAldo:C, and therapy seemed to add further variability. In the light of these results, comparing the UAldo:C of a single patient with a population-based reference value might lead to wrong interpretations and an individual monitoring should be considered. The prevalence of ABT in the present study (36%) was in line with those previously reported. However, due to the high individual variability of UAldo:C found in the study, even this result should be re-evaluated in the setting of an individual longitudinal approach. The positive association between UAldo:C and LA/Ao supports the mutual relationship between RAAS and cardiac remodeling.

Interobserver variability of radiographic methods for the evaluation of left atrial size in dogs.

The objectives of this retrospective, observer agreement study were to (a) test variability of radiographic left atrial dimension (RLAD) and vertebral left atrial size (VLAS) measurements among observers with different levels of expertise in thoracic radiology and cardiology, (b) assess whether one method is better than the other in detecting left atrial enlargement (LAE), and (c) assess the agreement among RLAD, VLAS, and American College of Veterinary Internal Medicine (ACVIM) classes. Seventy-four dogs (eight healthy and 66 with mitral valve disease) with thoracic radiographs and echocardiography performed on the same day were reviewed. Thirty showed echocardiographic LAE. Left atrial dimension was quantified using RLAD and VLAS by six different operators with three levels of clinical experience in veterinary cardiology/radiology. Vertebral heart score and fourth thoracic vertebra (T4) were also measured. Differences in T4, vertebral heart score (VHS), RLAD, and VLAS measurements were found among six operators and among the three levels of clinical expertise as well as between veterinary cardiology readers and veterinary radiology readers (P < .05). The area under the receiver operating characteristic (AUC) curve for VHS showed good performances for all observers and level and type of expertise; the AUC for RLAD and VLAS was suboptimal only for the radiology student. Our RLAD and VLAS cutoffs (1.9 and 2.43 v, respectively) were better related to qualitative radiographic than quantitative echocardiographic LAE evaluation. Radiographic LA dimension and VLAS showed an increase proportional to the worsening of the ACVIM class. In conclusion, these results allow us to affirm that RLAD and VLAS are reproducible measurements for detecting LAE. Better performances are associated with clinical expertise and background.

HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment.

Hypoxia-inducible transcription factors (HIFs) regulate a wide array of adaptive responses to hypoxia and are often activated in solid tumors and hematologic malignancies due to intratumoral hypoxia and emerging new layers of regulation. We found that in chronic lymphocytic leukemia (CLL), HIF-1α is a novel regulator of the interaction of CLL cells with protective leukemia microenvironments and, in turn, is regulated by this interaction in a positive feedback loop that promotes leukemia survival and propagation. Through unbiased microarray analysis, we found that in CLL cells, HIF-1α regulates the expression of important chemokine receptors and cell adhesion molecules that control the interaction of leukemic cells with bone marrow and spleen microenvironments. Inactivation of HIF-1α impairs chemotaxis and cell adhesion to stroma, reduces bone marrow and spleen colonization in xenograft and allograft CLL mouse models, and prolongs survival in mice. Of interest, we found that in CLL cells, HIF-1α is transcriptionally regulated after coculture with stromal cells. Furthermore, HIF-1α messenger RNA levels vary significantly within CLL patients and correlate with the expression of HIF-1α target genes, including CXCR4, thus further emphasizing the relevance of HIF-1α expression to CLL pathogenesis.

Serum proteomic profiles in CKCS with Mitral valve disease.

BACKGROUND: Myxomatous mitral valve disease (MVD) is the most common acquired heart disease in dogs, and the Cavalier King Charles Spaniel (CKCS) is the most studied breed because of the high prevalence, early onset and hereditary component evidenced in the breed. MVD has different severity levels, and there are many practical limitations in identifying its asymptomatic stages. Proteomic techniques are valuable for studying the proteins and peptides involved in cardiovascular diseases, including the period prior to the clinical onset of the disease. The aim of this study was to identify the serum proteins that were differentially expressed in healthy CKCS and those affected by MVD in mild to severe stages. Proteomics analysis was performed using two-dimensional gel electrophoresis separation and a bioinformatics analysis for the detection of differentially expressed spots. In a comparative analysis, protein spots with a p < 0.05 (ANOVA) were considered statistically significant and were excised from the gels for analysis by MALDI-TOF-MS for protein identification. RESULTS: Eight proteins resulted differentially expressed among the groups and significantly related to the progression of the disease. In mild affected group versus healthy dogs complement factor H isoform 2, inhibitor of carbonic anhydrase, hemopexin, dystrobrevin beta isoform X7 and CD5 molecule-like resulted to be down-regulated, whereas fibronectin type-III domain-containing protein 3A isoform X4 was up-regulated. In severe affected dogs versus healthy group complement factor H isoform 2, calpain-3 isoform X2, dystrobrevin beta isoform X7, CD5 molecule-like and l-2-hydroxyglutarate dehydrogenase resulted to be down-regulated. Complement factor H isoform 2, calpain-3 isoform X2, dystrobrevin beta isoform X7, CD5 molecule-like and hydroxyglutarate dehydrogenase were found to be down-regulated in mild affected group versus healthy dogs. All of these proteins except complement factor H followed a decreasing trend according to the progression of the pathology. CONCLUSION: The differential expression of serum proteins demonstrates the possibility these might be valuable for the detection and monitoring of the disease. Further longitudinal studies are required to determine whether differential protein expression occurs sufficiently early in the progression of the disease and with sufficient predictive value to allow proteomics analysis to be used as an early detection and on-line diagnostic tool.

Angiostrongylus vasorum infection in dogs from a cardiopulmonary dirofilariosis endemic area of Northwestern Italy: a case study and a retrospective data analysis.

BACKGROUND: In Italy, Angiostrongylus vasorum, an emergent parasite, is being diagnosed in dogs from areas considered free of infection so far. As clinical signs are multiple and common to other diseases, its diagnosis can be challenging. In particular, in areas where angiostrongylosis and dirofilariosis overlap, a misleading diagnosis of cardiopulmonary dirofilariosis might occur even on the basis of possible misleading outcomes from diagnostic kits. CASE PRESENTATION: Two Cavalier King Charles spaniel dogs from an Italian breeding in the Northwest were referred to a private veterinary hospital with respiratory signs. A cardiopulmonary dirofilariosis was diagnosed and the dogs treated with ivermectin, but one of them died. At necropsy, pulmonary oedema, enlargement of tracheo-bronchial lymphnodes and of cardiac right side were detected. Within the right ventricle lumen, adults of A. vasorum were found. All dogs from the same kennel were subjected to faecal examination by FLOTAC and Baermann's techniques to detect A. vasorum first stage larvae; blood analysis by Knott's for Dirofilaria immitis microfilariae, and antigenic tests for both A. vasorum (Angio Detect™) and D.immitis (DiroCHEK® Heartworm, Witness®Dirofilaria). The surviving dog with respiratory signs resulted positive for A. vasorum both at serum antigens and larval detection. Its Witness® test was low positive similarly to other four dogs from the same kennel, but false positive results due to cross reactions with A. vasorum were also considered. No dogs were found infected by A. vasorum. Eventually, the investigation was deepened by browsing the pathological database of Veterinary Pathology Laboratories at Veterinary School of Milan University through 1998-2016, where 11 cases of angiostrongylosis were described. Two out of 11 dogs had a mixed infection with Crenosoma vulpis. CONCLUSION: The study demonstrates the need for accurate surveys to acquire proper epidemiological data on A. vasorum infection in Northwestern Italy and for appropriate diagnostic methods. Veterinary clinicians should be warned about the occurrence of this canine parasite and the connected risk of a misleading diagnosis, particularly in areas endemic for cardiopulmonary dirofilariosis.

A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity.

OBJECTIVE: A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalized approach. The aim of the present study is to identify biomarkers for further clinical development and to yield insights into the pathophysiology of disease activity. METHODS: We performed a genome-wide association study in interferon-ß (IFNß)-treated MS patients followed by validation in 3 independent cohorts. The role of the validated variant was examined in several RNA data sets, and the function of the presumed target gene was explored using an RNA interference approach in primary T cells in vitro. RESULTS: We found an association between rs9828519(G) and nonresponse to IFNß (pdiscovery = 4.43 × 10(-8)) and confirmed it in a meta-analysis across 3 replication data sets (preplication = 7.78 × 10(-4)). Only 1 gene is found in the linkage disequilibrium block containing rs9828519: SLC9A9. Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. Moreover, SLC9A9 knockdown in T cells in vitro leads an increase in expression of IFNγ, which is a proinflammatory molecule. INTERPRETATION: This study identifies and validates the role of rs9828519, an intronic variant in SLC9A9, in IFNß-treated subjects, demonstrating a successful pharmacogenetic screen in MS. Functional characterization suggests that SLC9A9, an Na(+) -H(+) exchanger found in endosomes, appears to influence the differentiation of T cells to a proinflammatory fate and may have a broader role in MS disease activity, outside of IFNß treatment.

Breast cancer circulating biomarkers: advantages, drawbacks, and new insights.

As of today, the level of individualization of cancer therapies has reached a level that 20 years ago would be considered visionary. However, most of the diagnostic, prognostic, and therapy-predictive procedures which aim to improve the overall level of personalization are based on the evaluation of tumor tissue samples, therefore requiring surgical operations with consequent low compliance for patients and high costs for the hospital. Hence, the research of a panel of circulating indicators which may serve as source of information about tumor characteristics and which may be obtainable by a simple withdrawal of peripheral blood today represents a growing field of interest. This review aims to objectively summarize the characteristics of the currently available breast cancer circulating biomarkers, also providing an overview about the multitude of novel potential soluble predictors which are still under evaluation. Specifically, the usefulness of a so-called "liquid biopsy" will be discussed in terms of improvements of diagnosis, prognosis, and therapy-prediction, but an overview will be given also on the potentiality of the molecular characterization arising from the isolation of circulating biomarkers and cells. Although this review will focus on the specific case of the breast, in the future liquid biopsies will hopefully be available for virtually any type of neoplasms.

Inverse correlation of genetic risk score with age at onset in bout-onset and progressive-onset multiple sclerosis.

We correlated the weighted genetic risk score measured using 107 established susceptibility variants for multiple sclerosis (MS) with the age at onset in bout-onset (BOMS, n=906) and progressive-onset MS Italian patients (PrMS) (n=544). We observed an opposite relationship in the two disease courses: a higher weighted genetic risk score was associated with an earlier age at onset in BOMS (rho= -0.1; p=5 × 10(-3)) and a later age at onset in PrMS cases (rho=0.07; p=0.15) (p of difference of regression=1.4 × 10(-2)). These findings suggest that established MS risk variants anticipate the onset of the inflammatory phase, while they have no impact on, or even delay, the onset of the progressive phase.

The burden of multiple sclerosis variants in continental Italians and Sardinians.

BACKGROUND: Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. OBJECTIVE: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. METHODS: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves. RESULTS: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles. CONCLUSIONS: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics.

Amino acid starvation induces reactivation of silenced transgenes and latent HIV-1 provirus via down-regulation of histone deacetylase 4 (HDAC4).

The epigenetic silencing of exogenous transcriptional units integrated into the genome represents a critical problem both for long-term gene therapy efficacy and for the eradication of latent viral infections. We report here that limitation of essential amino acids, such as methionine and cysteine, causes selective up-regulation of exogenous transgene expression in mammalian cells. Prolonged amino acid deprivation led to significant and reversible increase in the expression levels of stably integrated transgenes transcribed by means of viral or human promoters in HeLa cells. This phenomenon was mediated by epigenetic chromatin modifications, because histone deacetylase (HDAC) inhibitors reproduced starvation-induced transgene up-regulation, and transcriptome analysis, ChIP, and pharmacological and RNAi approaches revealed that a specific class II HDAC, namely HDAC4, plays a critical role in maintaining the silencing of exogenous transgenes. This mechanism was also operational in cells chronically infected with HIV-1, the etiological agent of AIDS, in a latency state. Indeed, both amino acid starvation and pharmacological inhibition of HDAC4 promoted reactivation of HIV-1 transcription and reverse transcriptase activity production in HDAC4(+) ACH-2 T-lymphocytic cells but not in HDAC4(-) U1 promonocytic cells. Thus, amino acid deprivation leads to transcriptional derepression of silenced transgenes, including integrated plasmids and retroviruses, by a process involving inactivation or down-regulation of HDAC4. These findings suggest that selective targeting of HDAC4 might represent a unique strategy for modulating the expression of therapeutic viral vectors, as well as that of integrated HIV-1 proviruses in latent reservoirs without significant cytotoxicity.

DDIT4/REDD1/RTP801 is a novel negative regulator of Schwann cell myelination.

Signals that promote myelination must be tightly modulated to adjust myelin thickness to the axonal diameter. In the peripheral nervous system, axonal neuregulin 1 type III promotes myelination by activating erbB2/B3 receptors and the PI3K/AKT/mTOR pathway in Schwann cells. Conversely, PTEN (phosphatase and tensin homolog on chromosome 10) dephosphorylates PtdIns(3,4,5)P3 and negatively regulates the AKT pathway and myelination. Recently, the DLG1/SAP97 scaffolding protein was described to interact with PTEN to enhance PIP3 dephosphorylation. Here we now report that nerves from mice with conditional inactivation of Dlg1 in Schwann cells display only a transient increase in myelin thickness during development, suggesting that DLG1 is a transient negative regulator of myelination. Instead, we identified DDIT4/RTP801/REDD1 as a sustained negative modulator of myelination. We show that DDIT4 is expressed in Schwann cells and its maximum expression level precedes the peak of AKT activation and of DLG1 activity in peripheral nerves. Moreover, loss of DDIT4 expression both in vitro and in vivo in Ddit4-null mice provokes sustained hypermyelination and enhanced mTORC1 activation, thus suggesting that this molecule is a novel negative regulator of PNS myelination.

Genetic burden of common variants in progressive and bout-onset multiple sclerosis.

BACKGROUND: The contribution of genetic variants underlying the susceptibility to different clinical courses of multiple sclerosis (MS) is still unclear. OBJECTIVE: The aim of the study is to evaluate and compare the proportion of liability explained by common SNPs and the genetic burden of MS-associated SNPs in progressive onset (PrMS) and bout-onset (BOMS) cases. METHODS: We estimated the proportion of variance in disease liability explained by 296,391 autosomal SNPs in cohorts of Italian PrMS and BOMS patients using the genome-wide complex trait analysis (GCTA) tool, and we calculated a weighted genetic risk score (wGRS) based on the known MS-associated loci. RESULTS: Our results identified that common SNPs explain a greater proportion of phenotypic variance in BOMS (36.5%±10.1%) than PrMS (20.8%±6.0%) cases, and a trend of decrease was observed when testing primary progressive (PPMS) without brain MRI inflammatory activity (p = 7.9 × 10(-3)). Similarly, the wGRS and the variance explained by MS-associated SNPs were higher in BOMS than PPMS in males (wGRS: 6.63 vs 6.51, p = 0.04; explained variance: 4.8%±1.5% vs 1.7%±0.6%; p = 0.05). CONCLUSIONS: Our results suggest that the liability of disease is better captured by common genetic variants in BOMS than PrMS cases. The absence of inflammatory activity and male gender further raise the difference between clinical courses.

Study of correlations between serum taurine, thyroid hormones and echocardiographic parameters of systolic function in clinically healthy Golden retrievers fed with commercial diet.

Taurine deficiency predisposes to the development of nutritional dilated cardiomyopathy and is widespread in dogs fed with non-traditional diets. However, Golden retrievers show lower plasma taurine concentration and an impaired systolic function compared to breeds of the same size and morphotype. For these reasons, it can be difficult to classify a subject from a cardiological point of view, with the risk of considering as pathological characteristics that can be completely normal in this breed. This is a cross-sectional multicenter study. The aims were 1) to identify breed-specific range of serum taurine concentration, 2) to describe a correlation between serum taurine concentration and echocardiographic parameters of systolic function in clinically healthy Golden retrievers fed with traditional diet, 3) to identify a correlation between thyroid hormones, serum taurine concentration and echocardiographic indices. Sixty clinically healthy Golden retrievers (33% males, 67% females) were included. Fifty-three dogs were fed with traditional diets and their range of serum taurine concentration was 398.2 (31.8-430) nmol/ml. Serum taurine concentration was found to be negatively correlated to systolic internal diameter of the left ventricle and systolic and diastolic left ventricular indices and volumes obtained with different methods, whereas was positively correlated to the left ventricle ejection and shortening fractions but difference was not statistically significative. A weak but significant correlation between serum taurine and T4 was demonstrated. Serum taurine median values in dogs with normal systolic function were higher than in dogs with impaired systolic function. A cut-off of serum taurine concentration of 140.6 nmol/ml had a moderate sensitivity and specificity in the identification of an impaired left ventricular systolic function (AUC 0.6, Se 78%, Sp 44%). This study showed that the median serum taurine concentration was significantly lower in dogs with impaired systolic function. Therefore, echocardiographic monitoring is recommended in all dogs with serum taurine concentration lower than 140.6 nmol/ml.

Improved metabolic and cardiorespiratory fitness during a recreational training program in obese children.

Physical activity may protect from the adverse effects of obesity. In obese children, an increased adherence and a decreased drop-out rate during exercise could be achieved with adapted activities. We studied a recreational 12-week controlled training program for sedentary obese children, including interactive video games. We enrolled 22 obese subjects (13.23±1.76 years) in an exercise program, implemented twice a week for a 12-week period. The program consisted of a combination of circuit-based aerobics, strength and resistance exercises; specifically soccer, rugby, volleyball and basketball and interactive video game exercises. Outcome measurements included body composition, metabolic profile and cardiorespiratory fitness. During the 12-week training program there was a significant decrease in body mass index (BMI) (p=0.002), SDS-BMI (p=0.003), waist circumference (p=0.004), waist circumference/height ratio (p=0.001),% fat mass (p=0.001), blood glucose (p=0.001), homeostasis model assessment for insulin resistance (HOMA-IR) (p=0.04), triglycerides (p=0.03) and systolic pressure (p=0.04) before and after exercise. Improvement in estimated maximum oxygen consumption (VO2max) (p<0.001) correlated with a decrease in fat mass (p=0.01), triglycerides (p=0.04) and insulin resistance (p=0.02). Exercise improved metabolic and cardiorespiratory fitness in obese children. Exercise training does not necessarily need to be vigorous, recreational programs are also effective and may encourage children to participate in physical activity and limit initial drop-out.

Does the Cambridge classification alone predict the possibility to perform echocardiographic examination in lateral recumbency in dogs affected by brachycephalic obstructive airways syndrome?

OBJECTIVES: To evaluate if the functional grading system (Cambridge classification) of brachycephalic obstructive airways syndrome (BOAS) and the temperament score can be useful tools in predicting the feasibility of echocardiographic examination in lateral recumbency. The hypothesis is that the temperament of the dog, rather than the severity of BOAS alone, can exacerbate respiratory symptoms (dyspnea, stertor, stridor and/or cyanosis) during lateral containment. METHODS: Prospective cross-sectional study. Twenty-nine French Bulldogs were included and classified according to the Cambridge classification for the BOAS and to the Maddern score for the temperament. Receiver operating characteristic analysis was used to evaluate the sensitivity (Se) and specificity (Sp) of the Cambridge classification, of the temperament score and their sum to predict the feasibility of the echocardiography in lateral recumbency without dyspnea/cyanosis. RESULTS: 8 females (27.59%) and 21 (72.41%) males French Bulldogs of 3 years (IQR25-75 1-4), and 12.45 kg (IQR25-7511.5-13.25) were included. The Cambridge classification alone was not predictive for the possibility of performing the echocardiography in lateral recumbency, unlike temperament score and the sum of the two classification indices. The diagnostic accuracy of Cambridge classification (AUC 0.81, Se 50%, Sp 100%), temperament score (AUC 0.73, Se 75%, Sp 69%), and their sum (AUC 0.83, Se 75%, Sp 85%) cut-offs was moderate for each score. CLINICAL SIGNIFICANCE: The dog's temperament, and therefore its susceptibility to stress, rather than the severity of BOAS (Cambridge classification) alone, is a good predictor of the possibility of performing the echocardiographic examination in standing instead of lateral recumbency.