Long-term performance of show-jumping horses and relationship with severity of ataxia and complications associated with myeloencephalopathy caused by equine herpes virus-1.

BACKGROUND: Equine herpesvirus myeloencephalopathy (EHM) has severe impact on the sport horse population. OBJECTIVE: Study the influence of EHM on the likelihood of affected horses to return to their previous performance and investigate the association of clinical variables with prognosis. ANIMALS: Twenty-six horses positive for equine herpesvirus type 1 (EHV-1) were admitted to a veterinary teaching hospital (VTH) during a natural EHM outbreak at an international jumping event. METHODS: Data collected from the VTH, the International Equestrian Federation, and surveys completed by the riders and horse owners were retrospectively analyzed. RESULTS: Horses affected by EHM had 68% chance of returning to exercise, and 52.9% were able to achieve their preoutbreak performance level. Horses with an ataxia grade at admission ≥4/5 had an increased fatality rate (P < .05) and 10% chance of reaching their preoutbreak performance level. None of the horses with both vascular and urinary complications returned to their previous performance level. Finally, horses vaccinated against EHV-1 and those with urinary complications had a 71.4% and 43.7% fatality rate, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Horses affected by EHM were able to return to their previous performance levels, but certain clinical variables were negatively associated with postoutbreak performance. Ataxia grade upon admission and the development of systemic signs of vasculitis and urinary complications were potential poor prognostic indicators in sport horses. Variables linked to fatality included prior vaccination against EHV-1, ataxia grade upon admission, and the development of urinary complications.

Transcutaneous Auricular Vagal Nerve Stimulation in Healthy Non-Sedated Horses: A Feasibility Study.

This study aimed to evaluate the feasibility of transcutaneous auricular vagal nerve stimulation (tAVNS) in healthy horses and its effect on heart rate variability (HRV). The study comprised three phases: the selection of mares, their acclimatization to the tAVNS, and the stimulation phase. Stimulation was performed with two electrodes positioned on the right pinna. The settings were 0.5 mA, 250 µs, and 25 Hz for pulse amplitude, pulse width, and pulse frequency, respectively. HRV was analysed before (B1), during (T), and after (B2) the tAVNS. From the 44 mares initially included, only 7 completed the three phases. In these mares, the heart rate (HR) was significantly lower, and frequency domain parameters showed an increased parasympathetic tone in B2 compared with B1. However, in 3/7 mares, the HR was significantly higher during T compared with B1 and B2, compatible with a decreased parasympathetic tone, while in 4/7 mares, the HR was significantly lower and the parasympathetic nervous system index was significantly higher during T and B2 compared with B1. The tAVNS is an economical and easy procedure to perform and has the potential to stimulate vagal activity; however, it was poorly tolerated in the mares included in this study.

Detection of equine herpesvirus-1 (EHV-1) in urine samples during outbreaks of equine herpesvirus myeloencephalopathy.

BACKGROUND: Real-time PCR is the diagnostic technique of choice for the diagnosis and control of equine herpesvirus-1 (EHV-1) in an outbreak setting. The presence of EHV-1 in nasal swabs (NS), whole blood, brain and spinal cord samples has been extensively described; however, there are no reports on the excretion of EHV-1 in urine, its DNA detection patterns, and the role of urine in viral spread during an outbreak. OBJECTIVES: To determine the presence of EHV-1 DNA in urine during natural infection and to compare the DNA detection patterns of EHV-1 in urine, buffy coat (BC) and NS. STUDY DESIGN: Descriptive study of natural infection. METHODS: Urine and whole blood/NS samples were collected at different time points during the hospitalisation of 21 horses involved in two EHV-1 myeloencephalopathy outbreaks in 2021 and 2023 in Spain. Quantitative real-time PCR was performed to compare the viral DNA load between BC-urine samples in 2021 and NS-urine samples in 2023. Sex, age, breed, presence of neurological signs, EHV-1 vaccination status and treatment data were recorded for all horses. RESULTS: A total of 18 hospitalised horses during the 2021 and 2023 outbreaks were positive for EHV-1, and viral DNA was detected in urine samples from a total of 11 horses in both outbreaks. Compared with BC samples, DNA presence was detected in urine samples for longer duration and with slightly higher concentration; however, compared with NS, detection of EHV-1 in urine was similar in duration with lower DNA concentrations. MAIN LIMITATIONS: Limited sample size, different sampling times and protocols (BC vs. NS) in two natural infection outbreak settings. CONCLUSIONS: EHV-1 was detected in the urine from naturally infected horses. Urine should be considered as complimentary to blood and NS in diagnosis of EHV-1 infection.

HISTORIAL: PCR en tiempo real es la técnica diagnostica de preferencia para el diagnóstico y control del herpes virus equino­1 (EHV­1) en una situación de brote. La presencia de EHV­1 en torulas nasales (TN), muestras de sangre entera, cerebro, y medula espinal ha sido descrita en forma extensa; sin embargo, no hay informes de excreción de EHV­1 en orina, la detección del patrón de ADN, y el rol de la orina en la propagación vírica durante un brote. OBJETIVOS: Determinar la presencia de ADN de EHV­1 en muestras de orina durante un brote infeccioso natural y comparar los patrones de detección de ADN de EHV­1 en orina, capa leucocitaria (CL) y TN. DISEÑO DEL ESTUDIO: Estudio prospectivo en una infección natural en caballos hospitalizados. MÉTODOS: Muestras de orina y sangre entera/TN fueron recolectadas a distintos tiempos durante la hospitalización de veintiún caballos involucrados en dos brotes de mielo encefalopatía por EHV­1 en 2021 y 2023 en España. PCR a tiempo real cuantitativo fue llevado a cabo para comparar la carga de ADN viral entre muestras de CL­orina en 2021 y muestras TN­orina en 2023. Sexo, edad, raza, presencia de síntomas neurológicos, estatus de vacunación y datos de tratamiento fueron anotados para todos los caballos. RESULTADOS: Un total de diez y ocho caballos hospitalizados durante los brotes de 2021 y 2023 resultaron positivos a EHV­1, y ADN viral fue detectado en muestras de orina en un total de 11 caballos de ambos brotes. En comparación a muestras de CL, la presencia de AND fue detectado por mas largo tiempo y con una concentración ligeramente mas alta; sin embargo, en comparación a TN, la detección de EHV­1 en orina fue similar en tiempo pero demostró menor concentración de ADN. LIMITACIONES PRINCIPALES: Tamaño de muestra limitado, tiempos de muestreo diferentes, y de protocolos (CL vs. TN) en dos situaciones de brotes naturales. CONCLUSIONES: Se detecto EHV­1 en orina de caballos infectados naturalmente. La recolección, no invasive, de orina debería considerarse como un complemento a las muestras de sangre y TN en el control de caballos infectados en situaciones de brote.

Thyroid axis dysfunction in patients with Prader-Willi syndrome during the first 2 years of life.

INTRODUCTION: Prader-Willi syndrome (PWS) is a genetic disorder caused by the loss of expression of paternally transcribed genes in a highly imprinted region of chromosome 15q11-13. The clinical phenotype has been well characterized, mostly related to hypothalamic dysfunction. Even though central hypothyroidism has been documented in 20-30% of patients with PWS, thyroid function during the first 2 years of life has not been clearly defined. OBJECTIVE: To evaluate hypothalamic-pituitary-thyroid function in infant PWS patients. STUDY DESIGN: Eighteen patients with PWS, aged 0.16-2 years, were included in a prospective study. PWS diagnosis was based on clinical features and molecular analysis. Serum total (T) T4, free (F) T4, T3 and thyroid-stimulating hormone (TSH) were evaluated in the patients with PWS included in the study. Serum hormone values were compared to those of a large reference population of the same age. RESULTS: In 13 of 18 patients with PWS (72.2%), serum TT4 and/or FT4 levels were below the 2.5th percentile of the reference population, while in only one PWS patient serum T3 was below this cut-off. CONCLUSION: The results of this study suggest that transient or definitive thyrotropin-releasing hormone (TRH)-TSH thyroid axis dysfunction may frequently be present in infant PWS patients. Paediatricians should be aware of this dysfunction in this critical period of thyroid hormone action on neurological development.

Molecular characterization of a balanced rearrangement of chromosome 12 in two siblings with Noonan syndrome.

The etiology of Noonan syndrome (NS) has been greatly elucidated with the discovery of the disease causative genes PTPN11, KRAS, SOS1, and RAF1, all involved in the RAS/MAPK-signaling cascade. Given that overall mutations are identified in about 70% of patients, identification of other NS associated genes remains a high priority to fully understand the etiopathogenesis of the condition. We report two affected siblings with an apparently balanced rearrangement of chromosome 12 ins(12)(q12p11.2p12.3) which segregates with the Noonan phenotype. The rearrangement was inherited from the phenotypically normal mother who had mosaicism for the derivative chromosome 12. There were no mutations of PTPN11, KRAS, SOS1, or RAF1 genes detected in the probands. Using fluorescence in situ hybridization analysis we identified the three breakpoints involved at 12p12.3, 12p11.2, and 12q12. By microarray analysis, there were no gains or losses near the breakpoints. Neither, the PTPN11 or KRAS region on chromosome 12 was involved in the rearrangement. We hypothesize that other NS candidate gene(s) may be located in the breakpoint regions of chromosome 12 causing the Noonan phenotype in both of these children.

Heme oxygenase-1 arrests Leydig cells functions and impairs their regulation by histamine.

Testicular Leydig cells (LC) are modulated by several pathways, one of them being the histaminergic system. Heme oxygenase-1 (HO-1), whose upregulation comprises the primary response to oxidative noxae, has a central homeostatic role and might dysregulate LC functions when induced. In this report, we aimed to determine how hemin, an HO-1 inducer, affects LC proliferative capacity and whether HO-1 effects on LC functions are reversible. It was also evaluated if HO-1 interacts in any way with histamine, affecting its regulatory action over LC. MA-10 and R2C cell lines and immature rat LC were used as models. Firstly, we show that after a 24-h incubation with 25 µmol/L hemin, LC proliferation is reversibly impaired by cell cycle arrest in G2/M phase, with no evidence of apoptosis induction. Even though steroid production is abrogated after a 48-h exposure to 25 µmol/L hemin, steroidogenesis can be restored to control levels in a time-dependent manner if the inducer is removed from the medium. Regarding HO-1 and histamine interaction, it is shown that hemin abrogates histamine biphasic effect on steroidogenesis and proliferation. Working with histamine receptors agonists, we elucidated that HO-1 induction affects the regulation mediated by receptor types 1, 2 and 4. In summary, HO-1 induction arrests LC functions, inhibiting steroid production and cell cycle progression. Despite their reversibility, HO-1 actions might negatively influence critical phases of LC development and differentiation affecting their function as well as other androgen-dependent organs. What's more, we have described a hitherto unknown interaction between HO-1 induction and histamine effects.

Characterization of alterations in carbohydrate metabolism in children with Prader-Willi syndrome.

OBJECTIVE: To study carbohydrate metabolism and insulin sensitivity and secretion in children and adolescents with Prader-Willi syndrome (PWS) compared with multifactorial obesity (MO) controls. PATIENTS AND METHODS: Seventy-five patients with PWS and 395 controls with MO were studied by oral glucose tolerance test. Insulin resistance (IR) and beta-cell function were assessed by homeostasis model assessment (HOMA), insulin glucose index, fasting insulin and insulin sensitivity index. RESULTS: The incidence of diabetes mellitus was 0% in PWS and 1.5% in MO, while carbohydrate intolerance was 9.3% in the former group and 7.6% in the latter (NS); basal insulin level (12 +/- 8.2 vs 22.3 +/- 25 mU/ml) and HOMA-IR (2.47 +/- 1.6 vs 4.18 +/- 5.05) were lower in PWS (p = 0.004 and 0.04, respectively), whereas HOMA beta-cell index was lower in PWS than in MO (59 +/- 42 vs 102 +/- 119, p = 0.03). ISI Composite was higher in PWS compared to MO (6 +/- 5.7 vs 4.18 +/- 5.05, p = 0.04). CONCLUSION: Patients with PWS presented lower insulin resistance and a dissociation between beta-cell secretion and the degree of obesity.

Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy.

Lafora disease is the most severe teenage-onset progressive epilepsy, a unique form of glycogenosis with perikaryal accumulation of an abnormal form of glycogen, and a neurodegenerative disorder exhibiting an unusual generalized organellar disintegration. The disease is caused by mutations of the EPM2A gene, which encodes two isoforms of the laforin protein tyrosine phosphatase, having alternate carboxyl termini, one localized in the cytoplasm (endoplasmic reticulum) and the other in the nucleus. To date, all documented disease mutations, including the knockout mouse model deletion, have been in the segment of the protein common to both isoforms. It is therefore not known whether dysfunction of the cytoplasmic, nuclear, or both isoforms leads to the disease. In the present work, we identify six novel mutations, one of which, c.950insT (Q319fs), is the first mutation specific to the cytoplasmic laforin isoform, implicating this isoform in disease pathogenesis. To confirm this mutation's deleterious effect on laforin, we studied the resultant protein's subcellular localization and function and show a drastic reduction in its phosphatase activity, despite maintenance of its location at the endoplasmic reticulum.

Combined cytogenetic and molecular analyses for the diagnosis of Prader-Willi/Angelman syndromes.

Prader-Willi (PWS) and Angelman (AS) are syndromes of developmental impairment that result from the loss of expression of imprinted genes in the paternal (PWS) or maternal (AS) 15q11-q13 chromosome. Diagnosis on a clinical basis is difficult in newborns and young infants; thus, a suitable molecular test capable of revealing chromosomal abnormalities is required. We used a variety of cytogenetic and molecular approaches, such as, chromosome G banding, fluorescent in situ hybridization, a DNA methylation test, and a set of chromosome 15 DNA polymorphisms to characterize a cohort of 27 PWS patients and 24 suspected AS patients. Molecular analysis enabled the reliable diagnosis of 14 PWS and 7 AS patients, and their classification into four groups: (A) 6 of these 14 PWS subjects (44 %) had deletions of paternal 15q11-q13; (B) 4 of the 7 AS patients had deletions of maternal 15q11-q13; (C) one PWS patient (8 %) had a maternal uniparental disomy (UPD) of chromosome 15; (D) the remaining reliably diagnoses of 7 PWS and 3 AS cases showed abnormal methylation patterns of 15q11-q13 chromosome, but none of the alterations shown by the above groups, although they may have harbored deletions undetected by the markers used. This study highlights the importance of using a combination of cytogenetic and molecular tests for a reliable diagnosis of PWS or AS, and for the identification of genetic alterations.

Partial distal 5p trisomy resulting from paternal translocation (5;15)(p15.1;p13) in a boy with no mental retardation.

We report a boy with partial distal 5p15.1-->pter trisomy and normal development. We compared the clinical findings in our patient with those previously reported of the same 5p duplicated region. Several cases of autosomal duplications and normal development have been described. The present case is another example of a chromosomal anomaly with little, if any, phenotypic effect without mental retardation.

Synthesis and biological evaluation of a series of aminoalkyl-tetralones and tetralols as dual dopamine/serotonin ligands.

A series of novel α-tetralone and α-tetralol derivatives was synthesized, and their binding affinities for 5-HT(2A) and D2 receptors, the most important targets implicated in the anti-schizophrenia drug action, were evaluated to elucidate how substitutions in the aromatic ring of the pharmacophore affect to the affinity or selectivity for these receptors. The replacement of the H-7 in the tetrahydronaphthalene system by an amino group resulted in privileged 5-HT(2A) affinity of the 6-fluorobenzo[d]isoxazol derivative 36 and the alcohol 25 both showing a pK(i) value for 5-HT(2A) higher than 8.3 and good binding affinities for D2 receptor leading to a Meltzer's ratio characteristic of an atypical antipsychotic profile. Additionally, a small collection of 3-aminomethyltetralone derivatives was prepared and examined here for their affinities and selectivities as 5-HT(2A)/D2 dual ligands. Compound 11 shows the best profile with good pKi values for 5-HT(2A) and D2 receptors leading to a Meltzer's ratio characteristic of a typical antipsychotic behaviour. These three compounds behaved as competitive antagonists of both 5-HT(2A) and D2 receptors, and might be promising pharmacological tools for the investigation of the dual function of the 5HT(2A)-D2 ligands.

Terminal osseous dysplasia with pigmentary defects (TODPD) due to a recurrent filamin A (FLNA) mutation.

Terminal osseous dysplasia with pigmentary defects (TODPD) is an X-linked dominant syndrome with distal limb anomalies, pigmentary skin defects, digital fibromas, and generalized bone involvement due to a recurrent mutation in the filamin A (FLNA) gene. We here report the mutation c.5217G>A in FLNA in three families with TODPD and we found possible germline and somatic mosaicism in two out of the three families. The occurrence of somatic and germline mosaicism for TODPD indicates that caution should be taken in counseling recurrence risks for these conditions upon presentation of an isolated case.

[Etiologic evaluation of genetically-caused mental retardation. Diagnostic algorithm and new molecular techniques]. / Evaluación etiológica del retardo mental de origen genético. Algoritmo diagnóstico y nuevas técnicas moleculares.

Mental retardation affects 1-3% of the population. Its etiology is heterogeneous and approximately 47% of cases are caused by genetic factors. The aim of this paper is to report on etiologies of mental retardation, to present updates on new technologies of molecular diagnosis, and to analyze their limitations for the appropriate and rational use of them. Finally, an algorithm based on genetics is suggested for the study of mental retardation by reporting on the techniques available in Argentina and in developed countries. A well-defined etiology will lead to the proper management of children with mental retardation, and suitable family counseling.

Clinical-etiologic correlation in children with Prader-Willi syndrome (PWS): an interdisciplinary study.

Prader-Willi syndrome (PWS) is a multisystemic disorder caused by the loss of expression of paternally transcribed genes within chromosome 15q11-q13. Most cases are due to paternal deletion of this region; the remaining cases result from maternal uniparental disomy (UPD) and imprinting defects. To better understand the phenotypic variability of PWS, a genotype-phenotype correlation study was performed in 91 children with PWS. Patients were diagnosed by Southern Blot Methylation assay and genetic subtypes were established using FISH and microsatellite analyses. Fifty-nine subjects with deletion (31/28 males/females; mean age 3.86 years), 30 with UPD (14/16 males/females; mean age 3.89 years) and 2 girls with a presumed imprinting defect (mean age 0.43 yrs) were identified. For correlation purposes patients were grouped as "deleted" and "non-deleted." An increased maternal age was found in the UPD group. Four of Holm's criteria were more frequently present in the deleted group: need for special feeding techniques, sleep disturbance, hypopigmentation, and speech articulation defects. Concerning cognitive assessments, only 9.52% of subjects with deletion had Full-Scale IQ (FSIQ) > or =70, while 61.53% of subjects without deletion had FSIQ > or =70. Similar results were found in behavioral measures. Sleep disorders and carbohydrate metabolism were systematically assessed. Polysomnoghaphic studies revealed a higher frequency of central events with desaturations > or =10% in the deleted group (P = 0.020). In summary, the phenotype was significantly different between both groups in certain parameters related to the CNS. These results might be related to the differences in brain gene expression of the genetic subtypes.

Evaluación etiológica del retardo mental de origen genético: algoritmo diagnóstico y nuevas técnicas moleculares / Etiologic evaluation of genetically caused mental retardation: diagnostic alrithm and new molecular techiques

El retardo mental afecta al 1-3 por ciento de la población. Su etiología es heterogénea, se deben a factores genéticos. El objetivo del artículo es informar sobre etiologías del retardo mental; actualizar sobre las nuevas tecnologías de diagnóstico molecular y entender sus limitaciones para un uso adecuado y racional. Finalmente, se sugiere un algoritmo orientado desde la genética para el estudio del retardo mental; se informa sobre las técnicas disponibles en el país y las que se realizan en países desarrollados. Determinar la etiología permitirá el manejo adecuado del niño y efectuar un correcto asesoramiento familiar.

Evaluación etiológica del retardo mental de origen genético: algoritmo diagnóstico y nuevas técnicas moleculares / Etiologic evaluation of genetically caused mental retardation: diagnostic alrithm and new molecular techiques

El retardo mental afecta al 1-3 por ciento de la población. Su etiología es heterogénea, se deben a factores genéticos. El objetivo del artículo es informar sobre etiologías del retardo mental; actualizar sobre las nuevas tecnologías de diagnóstico molecular y entender sus limitaciones para un uso adecuado y racional. Finalmente, se sugiere un algoritmo orientado desde la genética para el estudio del retardo mental; se informa sobre las técnicas disponibles en el país y las que se realizan en países desarrollados. Determinar la etiología permitirá el manejo adecuado del niño y efectuar un correcto asesoramiento familiar.(AU)

Chemoenzymatic synthesis and binding affinity of novel (R)- and (S)-3-aminomethyl-1-tetralones, potential atypical antipsychotics.

A series of (R)- and (S)-3-aminomethyl-1-tetralones, conformationally constrained analogues of haloperidol, have been obtained by enzymatic resolution of the corresponding racemic 3-hydroxymethyl-1-tetralones using Pseudomonas fluorescens lipase. Their binding affinities at dopamine D(2) and serotonin 5-HT(2A) and 5-HT(2C) receptors were determined showing in some cases an atypical antipsychotic profile with Meltzer's ratio higher than 1.30.

Correlación clínico-molecular en niñas con retardo mental y síndrome de sitio frágil del X / Clinical and molecular correlation in girls with MR and FRA-X syndrome

El síndrome de Fra-X es la causa más frecuente de retardo mental heredable,su incidencia en mujeres se estima en 1 cada 2.500.En los varones,el RM está asociado a un fenotipo clínico-conductual que permitió elaborar un sistema de puntaje de signos para facilitar su detección clínica.El objetivo del presente trabajo fue evaluar la utilidad de dicho sistema de puntaje en una población de niñas con retardo mental.Se realizó para ello un estudio comparativo entre los hallazgos clínicos y los resultados de los estudios moleculares.Material y Método: Durante un período de 6 años se seleccionaron 49 niñas con retardo mentalsin diagnóstico.Se aplicó a cada una de ellas un sistema de selección compuesto por 16 signos clínico-conductales,se realizaron estudios citogénicos y moleculates para diagnóstico de Fra-X y evaluación psicopedagógica

Correlación clínico-molecular en niñas con retardo mental y síndrome de sitio frágil del X / Clinical and molecular correlation in girls with MR and FRA-X syndrome

El síndrome de Fra-X es la causa más frecuente de retardo mental heredable,su incidencia en mujeres se estima en 1 cada 2.500.En los varones,el RM está asociado a un fenotipo clínico-conductual que permitió elaborar un sistema de puntaje de signos para facilitar su detección clínica.El objetivo del presente trabajo fue evaluar la utilidad de dicho sistema de puntaje en una población de niñas con retardo mental.Se realizó para ello un estudio comparativo entre los hallazgos clínicos y los resultados de los estudios moleculares.Material y Método: Durante un período de 6 años se seleccionaron 49 niñas con retardo mentalsin diagnóstico.Se aplicó a cada una de ellas un sistema de selección compuesto por 16 signos clínico-conductales,se realizaron estudios citogénicos y moleculates para diagnóstico de Fra-X y evaluación psicopedagógica