Publications by authors named "Baldo C"

81 Publications

Targeting Soluble Epoxide Hydrolase and Cyclooxygenases Enhance Joint Pain Control, Stimulate Collagen Synthesis, and Protect Chondrocytes From Cytokine-Induced Apoptosis.

Front Vet Sci 2021 5;8:685824. Epub 2021 Aug 5.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States.

To determine the symptomatic and disease-modifying capabilities of sEH and COX inhibitors during joint inflammation. Using a blinded, randomized, crossover experimental design, 6 adult healthy horses were injected with lipopolysaccharide (LPS; 3 μg) from in a radiocarpal joint and concurrently received the non-selective cyclooxygenase (COX) inhibitor phenylbutazone (2 mg/kg), the sEH inhibitor -TUCB (1 mg/kg) or both (2 mg/kg phenylbutazone and 0.1, 0.3, and 1 mg/kg -TUCB) intravenously. There were at least 30 days washout between treatments. Joint pain (assessed inertial sensors and peak vertical forces), synovial fluid concentrations of prostanoids (PGE, TxB), cytokines (IL-1β, IL-6, TNF-α) and biomarkers of collagen synthesis (CPII) and degradation (C2C) were measured at pre-determined intervals over a 48-h period. The anti-apoptotic effect of COX and sEH inhibitors was determined ELISA technique in primary equine chondrocytes incubated with TNF-α (10 ng/ml) for 24 h. Apoptosis was also determined in chondrocytes incubated with sEH-generated metabolites. Combined COX and sEH inhibition produced significantly better control of joint pain, prostanoid responses, and collagen synthesis-degradation balance compared to each compound separately. When administered separately, pain control was superior with COX . sEH inhibition. Cytokine responses were not different during COX and/or sEH inhibition. In cultured chondrocytes, sEH inhibition alone or combined with COX inhibition, but not COX inhibition alone had significant anti-apoptotic effects. However, sEH-generated metabolites caused concentration-dependent apoptosis. Combined COX and sEH inhibition optimize pain control, attenuate loss of articular cartilage matrix during joint inflammation and cytokine-induced chondrocyte apoptosis.
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http://dx.doi.org/10.3389/fvets.2021.685824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375305PMC
August 2021

Clinical Manifestations in a Girl with NAA10-Related Syndrome and Genotype-Phenotype Correlation in Females.

Genes (Basel) 2021 06 10;12(6). Epub 2021 Jun 10.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

Since 2011, eight males with an X-linked recessive disorder (Ogden syndrome, MIM #300855) associated with the same missense variant p.(Ser37Pro) in the gene have been described. After the advent of whole exome sequencing, many variants have been reported as causative of syndromic or non-syndromic intellectual disability in both males and females. The gene lies in the Xq28 region and encodes the catalytic subunit of the major N-terminal acetyltransferase complex NatA, which acetylates almost half the human proteome. Here, we present a young female carrying a de novo [NM_003491:c.247C > T, p.(Arg83Cys)] variant. The 18-year-old girl has severely delayed motor and language development, autistic traits, postnatal growth failure, facial dysmorphisms, interventricular septal defect, neuroimaging anomalies and epilepsy. Our attempt is to expand and compare genotype-phenotype correlation in females with -related syndrome. A detailed clinical description could have relevant consequences for the clinical management of known and newly identified individuals.
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http://dx.doi.org/10.3390/genes12060900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230408PMC
June 2021

Coronary arterial compression testing by simultaneous balloon valvuloplasty and coronary angiography in an English bulldog with pulmonary valve stenosis.

J Vet Cardiol 2021 Jun 2;35:124-129. Epub 2021 Apr 2.

University of Chicago, Pediatric Cardiology, Chicago, IL, USA.

A 4-year-old male neutered English bulldog presented for heart murmur evaluation. Echocardiography identified severe pulmonic stenosis (an echocardiography-derived transpulmonary pressure gradient of 100 mmHg), and computed tomography confirmed the presence of an anomalous coronary artery with a prepulmonic course of the left coronary artery arising from the right coronary ostium. Before artificial pulmonic valve implantation, a coronary compression test was performed. A simultaneous aortic root angiogram and pulmonic balloon valvuloplasty revealed complete occlusion of the circumflex branch. Artificial valve implantation was aborted with concern for fatal coronary compression after implantation. Coronary compression testing is a critical component of the evaluation before catheter-based implantation of conduits across the pulmonic valve.
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http://dx.doi.org/10.1016/j.jvc.2021.03.009DOI Listing
June 2021

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature.

Genes (Basel) 2021 04 27;12(5). Epub 2021 Apr 27.

Istituto Auxologico Italiano, IRCCS, Laboratory of Medical Cytogenetics and Molecular Genetics, 20145 Milan, Italy.

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which , , , and are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only , and genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of and better define how the two contiguous genes, and , might contribute to the clinical phenotype.
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http://dx.doi.org/10.3390/genes12050652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146486PMC
April 2021

Novel Pathway of Adenosine Generation in the Lungs from NAD: Relevance to Allergic Airway Disease.

Molecules 2020 Oct 27;25(21). Epub 2020 Oct 27.

Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.

Adenosine and uric acid (UA) play a pivotal role in lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). In the present experiments, we measured adenosine synthesis from nicotinamide adenine dinucleotide (NAD) in membranes prepared from wild type (WT) and CD38 knockout (CD38KO) mouse lungs, from cultured airway smooth muscle and epithelial cells, and in bronchoalveolar lavage fluid after airway challenge with epidemiologically relevant allergens. Adenosine was determined using an enzymatically coupled assay that produces ATP and is detected by luminescence. Uric acid was determined by ELISA. Exposure of cultured airway epithelial cells to extract caused significant nucleotide (NAD and ATP) release in the culture media. The addition of NAD to membranes prepared from WT mice resulted in faster generation of adenosine compared to membranes from CD38KO mice. Formation of adenosine from NAD affected UA and ATP concentrations, its main downstream molecules. Furthermore, NAD and adenosine concentrations in the bronchoalveolar lavage fluid decreased significantly following airway challenge with house-dust mite extract in WT but not in CD38KO mice. Thus, NAD is a significant source of adenosine and UA in the airways in mouse models of allergic airway disease, and the capacity for their generation from NAD is augmented by CD38, a major NADase with high affinity for NAD. This novel non-canonical NAD-adenosine-UA pathway that is triggered by allergens has not been previously described in the airways.
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http://dx.doi.org/10.3390/molecules25214966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663290PMC
October 2020

Owner evaluation of quality of life and mobility in osteoarthritic cats treated with amantadine or placebo.

J Feline Med Surg 2021 06 28;23(6):568-574. Epub 2020 Oct 28.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA.

Objectives: The aim of the study was to determine if amantadine improves owner-identified mobility impairment and quality of life associated with osteoarthritis in cats.

Methods: Using a blinded, placebo-controlled, randomized, crossover design, 13 healthy client-owned cats with clinical and radiographic evidence of osteoarthritis and owner-identified mobility impairment were studied. Cats received 5 mg/kg amantadine or placebo q24h PO for 3 weeks each with no washout period in between. Locomotor activity was continuously assessed with a collar-mounted activity monitor system, and owners chose and rated two mobility-impaired activities using a client-specific outcome measures (CSOM) questionnaire on a weekly basis. Locomotor activity on the third treatment week was analyzed with two-tailed paired -tests. The CSOM scores were analyzed using a mixed-effect model and the Bonferroni post-hoc test. Owner-perceived changes in quality of life were compared between treatments using the χ test. Statistical significance was set at 0.05.

Results: Mean ± SD activity counts during the third week of each treatment were significantly lower with amantadine (240,537 ± 53,880) compared with placebo (326,032 ± 91,759). CSOM scores assigned by the owners were significantly better with amantadine on the second (3 ± 1) and third (3 ± 1) weeks compared with placebo (5 ± 2 and 5 ± 1, respectively). A significantly greater proportion of owners reported improvement in quality of life with amantadine compared with placebo.

Conclusions And Relevance: Amantadine significantly decreased activity, but improved owner-identified impaired mobility and owner-perceived quality of life in cats with osteoarthritis. Amantadine appears to be an option for the symptomatic treatment of osteoarthritis in cats.
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http://dx.doi.org/10.1177/1098612X20967639DOI Listing
June 2021

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Am J Med Genet A 2020 12 11;182(12):2877-2886. Epub 2020 Oct 11.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients.
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http://dx.doi.org/10.1002/ajmg.a.61859DOI Listing
December 2020

Anesthetic risk during subsequent anesthetic events in brachycephalic dogs that have undergone corrective airway surgery: 45 cases (2007-2019).

J Am Vet Med Assoc 2020 Oct;257(7):744-749

Objective: To determine whether previous corrective upper airway surgery in brachycephalic dogs would decrease perianesthetic complications in subsequent anesthetic events.

Animals: 45 client-owned dogs.

Procedures: Brachycephalic dogs undergoing any combination of staphylectomy, nasal alaplasty, or laryngeal sacculectomy that were anesthetized at a later date for additional surgical procedures or imaging from August 2, 2007, to February 8, 2019, had their medical records reviewed during both anesthetic events for signalment, American Society of Anesthesiologists status, perianesthetic drug administration, anesthetic duration, presence and total time of positive-pressure ventilation, procedure invasiveness, and perianesthetic complications such as bradycardia, hypothermia, hypotension, cardiac arrhythmias, hypertension, vomiting or regurgitation, dysphoria, respiratory distress, hypoxemia, reintubation, and prolonged periods of recovery.

Results: The odds of having complications during the postanesthetic period following subsequent anesthetic events were decreased by 79% in dogs having previous surgical intervention to correct clinical signs of brachycephalic airway syndrome. Intra-anesthetic bradycardia increased the odds of developing a postanesthetic complication by 4.56 times. Every 15-minute increase in anesthetic duration increased the odds of having a postanesthetic complication by 12% and having an intra-anesthetic complication by 11%.

Conclusions And Clinical Relevance: Previous corrective upper airway surgery decreased odds of postanesthetic complications in brachycephalic dogs that underwent subsequent anesthetic events. Findings in this study indicated that corrective upper airway surgery for brachycephalic dogs may reduce postanesthetic complications following subsequent anesthetic events, which may reduce perianesthetic morbidity in patients undergoing multiple surgical or diagnostic imaging procedures.
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http://dx.doi.org/10.2460/javma.257.7.744DOI Listing
October 2020

Source apportionment of fine organic carbon (OC) using receptor modelling at a rural site of Beijing: Insight into seasonal and diurnal variation of source contributions.

Environ Pollut 2020 Nov 26;266(Pt 1):115078. Epub 2020 Jun 26.

Division of Environmental Health and Risk Management, School of Geography, Earth and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom. Electronic address:

This study was designed to investigate the seasonal characteristics and apportion the sources of organic carbon during non-haze days (<75 μg m) and haze (≥75 μg m) events at Pinggu, a rural Beijing site. Time-resolved concentrations of carbonaceous aerosols and organic molecular tracers were measured during the winter of 2016 and summer 2017, and a Chemical Mass Balance (CMB) model was applied to estimate the average source contributions. The concentration of OC in winter is comparable with previous studies, but relatively low during the summer. The CMB model apportioned seven separate primary sources, which explained on average 73.8% on haze days and 81.2% on non-haze days of the organic carbon in winter, including vegetative detritus, biomass burning, gasoline vehicles, diesel vehicles, industrial coal combustion, residential coal combustion and cooking. A slightly lower percentage of OC was apportioned in the summer campaign with 64.5% and 78.7% accounted for. The other unapportioned OC is considered to consist of secondary organic carbon (SOC). During haze episodes in winter, coal combustion and SOC were the dominant sources of organic carbon with 23.3% and 26.2%, respectively, followed by biomass burning emissions (20%), whereas in summer, industrial coal combustion and SOC were important contributors. Diurnal contribution cycles for coal combustion and biomass burning OC showed a peak at 6-9 pm, suggesting domestic heating and cooking were the main sources of organic aerosols in this rural area. Backward trajectory analysis showed that high OC concentrations were measured when the air mass was from the south, suggesting that the organic aerosols in Pinggu were affected by both local emissions and regional transport from central Beijing and Hebei province during haze episodes. The source apportionment by CMB is compared with the results of a Positive Matrix Factorization (PMF) analysis of ACSM data for non-refractory PM, showing generally good agreement.
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http://dx.doi.org/10.1016/j.envpol.2020.115078DOI Listing
November 2020

Pharmacokinetics and clinical effects of xylazine and dexmedetomidine in horses recovering from isoflurane anesthesia.

J Vet Pharmacol Ther 2020 Jul 12;43(4):369-376. Epub 2020 Mar 12.

Veterinary Clinical Sciences Department, College of Veterinary Medicine, University of Minnesota, Minneapolis, MN, USA.

This study determined the pharmacokinetics and compared the clinical effects of xylazine and dexmedetomidine in horses recovering from isoflurane anesthesia. Six healthy horses aged 8.5 ± 3 years and weighing 462 ± 50 kg were anesthetized with isoflurane for 2 hr under standard conditions on two occasions one-week apart. In recovery, horses received 200 μg/kg xylazine or 0.875 μg/kg dexmedetomidine intravenously and were allowed to recover without assistance. These doses were selected because they have been used for postanesthetic sedation in clinical and research studies. Serial venous blood samples were collected for quantification of xylazine and dexmedetomidine, and the pharmacokinetic parameters were calculated. Two individuals blinded to treatment identity evaluated recovery quality with a visual analog scale. Times to stand were recorded. Results (mean ± SD) were compared using paired t tests or Wilcoxon signed-ranked test with p < .05 considered significant. Elimination half-lives (62.7 ± 21.8 and 30.1 ± 8 min for xylazine and dexmedetomidine, respectively) and steady-state volumes of distribution (215 ± 123 and 744 ± 403 ml/kg) were significantly different between xylazine and dexmedetomidine, whereas clearances (21.1 ± 17.3 and 48.6 ± 28.1 ml/minute/kg), times to stand (47 ± 24 and 53 ± 12 min) and recovery quality (51 ± 24 and 61 ± 22 mm VAS) were not significantly different. When used for postanesthetic sedation following isoflurane anesthesia in healthy horses, dexmedetomidine displays faster plasma kinetics but is not associated with faster recoveries compared to xylazine.
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http://dx.doi.org/10.1111/jvp.12855DOI Listing
July 2020

Fetal posterior fossa malformations: review of the current knowledge.

Radiol Bras 2019 Nov-Dec;52(6):380-386

Department of Obstetrics, Escola Paulista de Medicina da Universidade Federal de São Paulo (EPM-Unifesp), São Paulo, SP, Brazil.

Ultrasound diagnosis of posterior fossa malformations in the prenatal period is a challenge, having major implications for the counseling and follow-up of pregnant women. The purpose of this study was to review aspects of the ultrasound evaluation of the fetal posterior fossa, as well as to describe the most relevant ultrasound findings of the main posterior fossa malformations that can affect the fetus in the prenatal period.
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http://dx.doi.org/10.1590/0100-3984.2018.0141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007051PMC
February 2020

Production of fructooligosaccharides by Bacillus subtilis natto CCT7712 and their antiproliferative potential.

J Appl Microbiol 2020 May 28;128(5):1414-1426. Epub 2020 Jan 28.

Department of Biochemistry and Biotechnology, State University of Londrina - UEL, Londrina, Brazil.

Aims: Fructooligosaccharides (FOSs) known for their health properties and β-(2→6)-levan-type FOSs have shown prebiotic and immunomodulatory activities that overcome those of commercial β-(2→1)-FOSs, but costs do not favour their use. Moreover, FOSs can reach the bloodstream through the diet, and little is known about their direct effect on cells. The aim of this work was to produce high-content FOSs by Bacillus subtilis natto CCT7712 in a bioreactor using commercial sucrose and to evaluate their antiproliferative effects in OVCAR-3 cells.

Methods And Results: FOS production reached 173·60 g l , 0·2 vvm aeration and uncontrolled pH. Levan-type FOSs, composed of β-(2 → 6) links and mainly GF (6-nystose), were identified using RMN spectroscopy, FT-IR and ESI-MS. FOSs decreased the viability and proliferation of OVCAR-3 cells, and the effects were associated with an increased pro-inflammatory response by the induction of IL-8 and TNF-α, and the repression of ER-β genes. The metabolic profiles showed disruption of cellular homeostasis that can be associated with a decrease in proliferation.

Conclusions: The high production of levan-type FOSs from B. subtilis natto CCT7712 in a bioreactor was achieved, and they showed antiproliferative potential in OVCAR-3 cells.

Significance And Impact Of The Study: FOS could be a good target for future therapeutic studies and commercial use.
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http://dx.doi.org/10.1111/jam.14569DOI Listing
May 2020

Rabbit supraglottic airway device (V-GEL) for successful airway control in a hedgehog (Atelerix albiventris).

Vet Anaesth Analg 2020 01 29;47(1):141-143. Epub 2019 Aug 29.

Veterinary Medical Center, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.

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http://dx.doi.org/10.1016/j.vaa.2019.07.003DOI Listing
January 2020

Leukocyte recruitment induced by snake venom metalloproteinases: Role of the catalytic domain.

Biochem Biophys Res Commun 2020 01 25;521(2):402-407. Epub 2019 Oct 25.

Laboratory of Pathophysiology, Butantan Institute, São Paulo, 05503-900, Brazil. Electronic address:

Snake venom metalloproteinases (SVMPs) are key toxins involved in local inflammatory reactions after snakebites. This study aimed to investigate the effect of SVMP domains on the alterations in leukocyte-endothelium interactions in the microcirculation of mouse cremaster muscle. We studied three toxins: BnP1, a PI-toxin isolated from Bothrops neuwiedi venom, which only bears a catalytic domain; Jararhagin (Jar), a PIII-toxin isolated from Bothrops jararaca venom with a catalytic domain, as well as ECD-disintegrin and cysteine-rich domains; and Jar-C, which is produced from the autolysis of Jar and devoid of a catalytic domain. All these toxins induced an increase in the adhesion and migration of leukocytes. By inhibiting the catalytic activity of Jar and BnP1 with 1.10-phenanthroline (oPhe), leukocytes were no longer recruited. Circular dichroism analysis showed structural changes in oPhe-treated Jar, but these changes were not enough to prevent the binding of Jar to collagen, which occurred through the ECD-disintegrin domain. The results showed that the catalytic domain of SVMPs is the principal domain responsible for the induction of leukocyte recruitment and suggest that the other domains could also present inflammatory potential only when devoid of the catalytic domain, as with Jar-C.
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http://dx.doi.org/10.1016/j.bbrc.2019.10.144DOI Listing
January 2020

Alazami syndrome: the first case of papillary thyroid carcinoma.

J Hum Genet 2020 Jan 28;65(2):133-141. Epub 2019 Oct 28.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Alazami syndrome (MIM#615071) is a rare developmental disorder caused by biallelic variants in the LARP7 gene. Hallmark features include short stature, global developmental delay, and distinctive facial features. To date, 23 patients from 11 families have been reported in the literature. Here we describe a 19-year-old man who, in association with the typical features of Alazami syndrome, was diagnosed at the age of 14 years with papillary thyroid carcinoma, harboring the somatic BRAF V600E mutation. Whole exome sequencing revealed two novel LARP7 variants in compound heterozygosity, whereas only common variants were detected in genes associated with familial nonmedullary thyroid cancer (MIM#188550). LARP7 acts as a tumor suppressor in breast and gastric cancer, and possibly, according to recent studies, in thyroid tumors. Since thyroid cancer is rare among children and adolescents, we hypothesize that the LARP7 variants identified in our patient are responsible for both Alazami syndrome and tumor susceptibility. We also provide an overview of the clinical findings in all Alazami syndrome patients reported to date and discuss the possible pathogenetic mechanism that may underlie this condition, including the role of LARP7 in tumor susceptibility.
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http://dx.doi.org/10.1038/s10038-019-0682-5DOI Listing
January 2020

FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the Gene.

Front Genet 2018 2;9:442. Epub 2018 Nov 2.

Center for Human Genetics, KU Leuven, Leuven, Belgium.

Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5'UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full-mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes.
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http://dx.doi.org/10.3389/fgene.2018.00442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224343PMC
November 2018

Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype.

Hum Genet 2018 Dec 27;137(11-12):905-909. Epub 2018 Oct 27.

Divisions of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada.

Lowry-Wood syndrome (LWS) is a skeletal dysplasia characterized by multiple epiphyseal dysplasia associated with microcephaly, developmental delay and intellectual disability, and eye involvement. Pathogenic variants in RNU4ATAC, an RNA of the minor spliceosome important for the excision of U12-dependent introns, have been recently associated with LWS. This gene had previously also been associated with microcephalic osteodysplastic primordial dwarfism (MOPD) and Roifman syndrome (RS), two distinct conditions which share with LWS some skeletal and neurological anomalies. We performed exome sequencing in two individuals with Lowry-Wood syndrome. We report RNU4ATAC pathogenic variants in two further patients. Moreover, an analysis of all RNU4ATAC variants reported so far showed that FitCons scores for nucleotides mutated in the more severe MOPD are higher than RS or LWS and that they were more frequently located in the 5' Stem-Loop of the RNA critical for the formation of the U4/U6.U5 tri-snRNP complex, whereas the variants are more dispersed in the other conditions. We are thus confirming that RNU4ATAC is the gene responsible for LWS and provide a genotype-phenotype correlation analysis.
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http://dx.doi.org/10.1007/s00439-018-1950-8DOI Listing
December 2018

ECG of the Month.

J Am Vet Med Assoc 2018 Jul;253(1):46-48

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http://dx.doi.org/10.2460/javma.253.1.46DOI Listing
July 2018

A Novel CCND2 Mutation in a Previously Reported Case of Megalencephaly and Perisylvian Polymicrogyria with Postaxial Polydactyly and Hydrocephalus.

Neuropediatrics 2018 06 11;49(3):222-224. Epub 2018 Apr 11.

Clinical Genetics Unit, Department of Obstetrics and Pediatrics, Azienda Unità Sanitaria Locale, Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia, Italy.

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http://dx.doi.org/10.1055/s-0038-1641722DOI Listing
June 2018

Why Methylene Blue Have to Be Always Present in the Stocking of Emergency Antidotes.

Curr Drug Targets 2018 ;19(13):1550-1559

Department of Surgery and Anatomy, Ribeirao Preto School of Medicine, University of Sao Paulo, SP, Brazil.

Evidence-based review of the existing literature ultimately recommends stocking of Methylene Blue (MB) as an emergency antidote in the United States. The same is reported around the world in Japan, Greece, Italy and Canada. The observation that MB is always present as the main antidote required in emergency and critical care units calls for a revisit on its effects on the NO/cGMP system to reemphasize its multisystem actions. Therefore, the present review aimed to display the role of MB in emergency units, concerning: 1) Polytrauma and circulatory shock; 2) Neuroprotection, 3) Anaphylaxis and, 4) Overdose and poisoning.
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http://dx.doi.org/10.2174/1389450119666180403100410DOI Listing
October 2019

Transversus abdominis plane block in ponies: a preliminary anatomical study.

Vet Anaesth Analg 2018 May 7;45(3):392-396. Epub 2018 Feb 7.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.

Objective: To describe a single-site transversus abdominis plane (TAP) block technique in horses.

Study Design: Prospective, descriptive, experimental anatomical study.

Animals: Four adult pony cadavers.

Methods: Freshly euthanized ponies were positioned in dorsal recumbency. A 6-13 MHz linear ultrasonic probe was used to scan the abdominal wall bilaterally midway between the last rib and iliac crest in search of the TAP location. By modifying the technique to accommodate the equine anatomy, the TAP was successfully visualized with the transducer positioned in a transverse plane with its side indicator over the intercept of two lines, one connecting the most cranial aspect of the iliac crest and the most caudal extent of the last rib and another originating just caudal to the umbilicus and extending laterally. Each hemiabdomen was injected with 0.5 mL kg of a 1:1 solution of 1% methylene blue and 0.5% bupivacaine via a 21 gauge 10 cm stimulating needle inserted ventral-dorsally and in plane with the ultrasound beam. Approximately 3 hours after injection, the abdomen was dissected and nerves stained over 1 cm in length were identified.

Results: Staining was evident from the fourteenth thoracic (T14) to the third lumbar (L3) nerves. The ventral branches of the fifteenth to the eighteenth thoracic nerves (T15-T18) and first and second lumbar nerves (L1 and L2) were stained in three, six, eight, eight, eight and seven of eight injections, respectively.

Conclusions And Clinical Relevance: Nerves T16-L2 had over 75% success rate in staining, suggesting that this technique would block transmission from T16 to L2, assuming that staining indicates potential nerve block. Dorsal spread occurred in three of eight hemiabdomens. Further studies developing techniques for the cranial abdomen and adjusting volume and concentration of injectate are warranted.
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http://dx.doi.org/10.1016/j.vaa.2018.01.009DOI Listing
May 2018

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care.

Genet Med 2018 09 4;20(9):965-975. Epub 2018 Jan 4.

Neuropsychiatric Department, Spedali Civili Brescia, Brescia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.

Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.

Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.

Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
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http://dx.doi.org/10.1038/gim.2017.221DOI Listing
September 2018

Co-production of Fructooligosaccharides and Levan by Levansucrase from Bacillus subtilis natto with Potential Application in the Food Industry.

Appl Biochem Biotechnol 2018 Mar 4;184(3):838-851. Epub 2017 Sep 4.

Department of Biochemistry and Biotechnology, Centre of Exact Science, Londrina State University, Highway Celso Garcia Cid-Pr 445 Km 380-University campus, Mailbox 10.011, Londrina, PR, 86057-970, Brazil.

Fructooligosaccharides and levan have a wide range of applications in the food industry due to their physiological and functional properties. The enzymatic synthesis of these molecules exhibits great advantages when compared with microbial fermentation. In this study, the production of levansucrase from Bacillus subtilis natto and its utilization in fructooligosaccharides and levan syntheses using different reaction conditions were described. The best condition for levansucrase production was 420.7 g L of sucrose at pH 7.0, which reached 23.9 U ml of transfructosylation activity. In a bioreactor, the highest production of fructooligosaccharides was 41.3 g L using a medium containing 350 g L sucrose at 35 °C for 36 h. The enzymatic synthesis of levan resulted in 86.9 g L when conditions similar to those used for fructooligosaccharides synthesis were applied. These results indicate that the levansucrase from B. subtilis natto could be applied for the co-production of fructooligosaccharides and levan, which are biomolecules that have health benefits and are used successfully in the food industry.
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http://dx.doi.org/10.1007/s12010-017-2587-0DOI Listing
March 2018

Guideline recommendations for diagnosis and clinical management of Ring14 syndrome-first report of an ad hoc task force.

Orphanet J Rare Dis 2017 04 11;12(1):69. Epub 2017 Apr 11.

Ring14 International, Scientific office, Via Flavio Gioia, 5-42124, Reggio Emilia, Italy.

Background: Ring chromosome 14 syndrome is a rare chromosomal disorder characterized by early onset refractory epilepsy, intellectual disability, autism spectrum disorder and a number of diverse health issues.

Results: The aim of this work is to provide recommendations for the diagnosis and management of persons affected by ring chromosome 14 syndrome based on evidence from literature and experience of health professionals from different medical backgrounds who have followed for several years subjects affected by ring chromosome 14 syndrome. The literature search was performed in 2016. Original papers, meta-analyses, reviews, books and guidelines were reviewed and final recommendations were reached by consensus.

Conclusion: Conventional cytogenetics is the primary tool to identify a ring chromosome. Children with a terminal deletion of chromosome 14q ascertained by molecular karyotyping (CGH/SNP array) should be tested secondarily by conventional cytogenetics for the presence of a ring chromosome. Early diagnosis should be pursued in order to provide medical and social assistance by a multidisciplinary team. Clinical investigations, including neurophysiology for epilepsy, should be performed at the diagnosis and within the follow-up. Following the diagnosis, patients and relatives/caregivers should receive regular care for health and social issues. Epilepsy should be treated from the onset with anticonvulsive therapy. Likewise, feeding difficulties should be treated according to need. Nutritional assessment is recommended for all patients and nutritional support for malnourishment can include gastrostomy feeding in selected cases. Presence of autistic traits should be carefully evaluated. Many patients with ring chromosome 14 syndrome are nonverbal and thus maintaining their ability to communicate is always essential; every effort should be made to preserve their autonomy.
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http://dx.doi.org/10.1186/s13023-017-0606-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387247PMC
April 2017

Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.

Genet Med 2017 06 10;19(6):691-700. Epub 2016 Nov 10.

Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.

Methods: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations.

Results: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.

Conclusion: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.
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http://dx.doi.org/10.1038/gim.2016.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438871PMC
June 2017

The alliance between genetic biobanks and patient organisations: the experience of the telethon network of genetic biobanks.

Orphanet J Rare Dis 2016 10 24;11(1):142. Epub 2016 Oct 24.

U.O.S.D. Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto G. Gaslini, Via G. Gaslini 5, 16147, Genoa, Italy.

Background: Rare diseases (RDs) are often neglected because they affect a small percentage of the population (6-8 %), which makes research and development of new therapies challenging processes. Easy access to high-quality samples and associated clinical data is therefore a key prerequisite for biomedical research. In this context, Genetic Biobanks are critical to developing basic, translational and clinical research on RDs. The Telethon Network of Genetic Biobanks (TNGB) is aware of the importance of biobanking as a service for patients and has started a dialogue with RD-Patient Organisations via promotion of dedicated meetings and round-tables, as well as by including their representatives on the TNGB Advisory Board. This has enabled the active involvement of POs in drafting biobank policies and procedures, including those concerning ethical issues. Here, we report on our experience with RD-Patient Organisations who have requested the services of existing biobanks belonging to TNGB and describe how these relationships were established, formalised and maintained.

Results: The process of patient engagement has proven to be successful both for lay members, who increased their understanding of the complex processes of biobanking, and for professionals, who gained awareness of the needs and expectations of the people involved. This collaboration has resulted in a real interest on the part of Patient Organisations in the biobanking service, which has led to 13 written agreements designed to formalise this process. These agreements enabled the centralisation of rare genetic disease biospecimens and their related data, thus making them available to the scientific community.

Conclusions: The TNGB experience has proven to be an example of good practice with regard to patient engagement in biobanking and may serve as a model of collaboration between disease-oriented Biobanks and Patient Organisations. Such collaboration serves to enhance awareness and trust and to encourage the scientific community to address research on RDs.
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http://dx.doi.org/10.1186/s13023-016-0527-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078978PMC
October 2016

BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia.

Am J Hum Genet 2016 06 26;98(6):1243-1248. Epub 2016 May 26.

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea. Electronic address:

Spondyloepimetaphyseal dysplasias (SEMDs) comprise a heterogeneous group of autosomal-dominant and autosomal-recessive disorders. An apparent X-linked recessive (XLR) form of SEMD in a single Italian family was previously reported. We have been able to restudy this family together with a second family from Korea by segregating a severe SEMD in an X-linked pattern. Exome sequencing showed missense mutations in BGN c.439A>G (p.Lys147Glu) in the Korean family and c.776G>T (p.Gly259Val) in the Italian family; the c.439A>G (p.Lys147Glu) mutation was also identified in a further simplex SEMD case from India. Biglycan is an extracellular matrix proteoglycan that can bind transforming growth factor beta (TGF-β) and thus regulate its free concentration. In 3-dimensional simulation, both altered residues localized to the concave arc of leucine-rich repeat domains of biglycan that interact with TGF-β. The observation of recurrent BGN mutations in XLR SEMD individuals from different ethnic backgrounds allows us to define "XLR SEMD, BGN type" as a nosologic entity.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908150PMC
June 2016

Jararhagin disruption of endothelial cell anchorage is enhanced in collagen enriched matrices.

Toxicon 2015 Dec 31;108:240-8. Epub 2015 Oct 31.

Laboratório de Imunopatologia, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil. Electronic address:

Hemorrhage is one of the most striking effects of bites by viper snakes resulting in fast bleeding and ischemia in affected tissues. Snake venom metalloproteinases (SVMPs) are responsible for hemorrhagic activity, but the mechanisms involved in SVMP-induced hemorrhage are not entirely understood and the study of such mechanisms greatly depends on in vivo experiments. In vivo, hemorrhagic SVMPs accumulate on basement membrane (BM) of venules and capillary vessels allowing the hydrolysis of collagen IV with consequent weakness and rupture of capillary walls. These effects are not reproducible in vitro with conventional endothelial cell cultures. In this study we used two-dimension (2D) or three-dimension (3D) cultures of HUVECs on matrigel and observed the same characteristics as in ex vivo experiments: only the hemorrhagic toxin was able to localize on surfaces or internalize endothelial cells in 2D cultures or in the surface of tubules formed on 3D cultures. The contribution of matrigel, fibronectin and collagen matrices in jararhagin-induced endothelial cell damage was then analyzed. Collagen and matrigel substrates enhanced the endothelial cell damage induced by jararhagin allowing toxin binding to focal adhesions, disruption of stress fibers, detachment and apoptosis. The higher affinity of jararhagin to collagen than to fibronectin explains the localization of the toxin within BM. Moreover, once located in BM, interactions of jararhagin with α2β1 integrin would favor its localization on focal adhesions, as observed in our study. The accumulation of toxin in focal adhesions, observed only in cells grown in collagen matrices, would explain the enhancement of cell damage in these matrices and reflects the actual interaction among toxin, endothelial cells and BM components that occurs in vivo and results in the hemorrhagic lesions induced by viper venoms.
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http://dx.doi.org/10.1016/j.toxicon.2015.10.016DOI Listing
December 2015

Jararhagin-induced mechanical hyperalgesia depends on TNF-α, IL-1β and NFκB in mice.

Toxicon 2015 Sep 30;103:119-28. Epub 2015 Jun 30.

Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, CEP 86057-970, Cx Postal 10.011, Londrina, Paraná, Brazil. Electronic address:

Jararhagin is a hemorrhagic metalloprotease from Bothrops jararaca snake venom. The hyperalgesic mechanisms of jararhagin were investigated focusing on the role of proinflammatory cytokines (TNF-α and IL-1β) and the transcription factor NFκB. Intraplantar administration of jararhagin (1, 10, 100 and 1000 ng/paw) induced mechanical hyperalgesia, and increased TNF-α levels at 1, 3 and 5 h, and IL-1β levels at 0.5, 1 and 3 h after its injection in the paw tissue. Pre-treatment with morphine (2, 6, 12 μg/paw) inhibited jararhagin-induced mechanical hyperagesia. The systemic or local pre-treatment with etanercept (10 mg/kg and 100 μg/paw) and IL-1ra (30 mg/kg and 100 pg/paw) inhibited jararhagin-induced mechanical hyperalgesia. Co-administration of jararhagin (0.1 ng/paw) and TNF-α (0.1 pg/paw) or jararhagin (0.1 ng/paw) and IL-1β (1 pg/paw) enhanced the mechanical hyperalgesia. The systemic or local pre-treatment with PDTC (NFκB inhibitor; 100 mg/kg and 100 μg/paw) inhibited jararhagin-induced mechanical hyperalgesia as well as PDTC decreased the jararhagin-induced production of TNF-α and IL-1β. Thus, these data demonstrate the involvement of pro-inflammatory cytokines TNF-α and IL-1β and nuclear transcription factor NFκB in jararhagin-induced mechanical hyperalgesia indicating that targeting these mechanisms might contribute to reduce the pain induced by B. jararaca snake venom.
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http://dx.doi.org/10.1016/j.toxicon.2015.06.024DOI Listing
September 2015
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