Long-term treatment persistence and maintained reduction of LDL-cholesterol levels with evolocumab over 30 months: Results from the Spanish cohort of the European prospective HEYMANS study / Persistencia al tratamiento a largo plazo y reducción mantenida de los niveles de colesterol LDL con evolocumab durante 30 meses: resultados de la cohorte española del estudio prospectivo europeo HEYMANS

Aims: Limited data exist on low-density lipoprotein-cholesterol (LDL-C) level variability or long-term persistence with the monoclonal antibody evolocumab in routine clinical practice. HEYMANS (NCT02770131) is the first multi-country, multicenter, observational study of European patients initiating evolocumab as part of their routine clinical management, based on local reimbursement criteria (overall data recently published). The aim of this analysis is to describe clinical characteristics, baseline and changes in LDL-C levels, treatment patterns and persistence to evolocumab over 30 months in the Spanish cohort using data from the HEYMANS Registry. Methods: HEYMANS was a prospective study of adult patients (≥18 years) who received at least one dose of evolocumab. A total of 1951 patients were enrolled from 12 countries and were followed up for 30 months after evolocumab initiation. Data were collected for 6 months before evolocumab initiation and up to 30 months thereafter. The Spanish cohort included patients who started evolocumab in routine clinical practice from March 2016 to September 2019. Demographic and clinical characteristics, lipid-lowering therapies (LLT), and lipid levels were collected. (AU)

Objetivos: Existen datos limitados sobre la variabilidad del nivel de colesterol de lipoproteínas de baja densidad (cLDL) o la persistencia a largo plazo con el anticuerpo monoclonal evolocumab en la práctica clínica habitual. HEYMANS (NCT02770131) es el primer estudio observacional multicéntrico y multinacional de pacientes europeos que iniciaron tratamiento con evolocumab en la práctica clínica habitual, basado en criterios de reembolso locales. El objetivo fue evaluar las características clínicas, los cambios en los niveles de cLDL, los patrones de tratamiento y la persistencia a este con evolocumab en la cohorte española con un seguimiento de 30 meses, utilizando datos del registro HEYMANS. Métodos: HEYMANS fue un estudio prospectivo de pacientes adultos (≥18 años) que recibieron al menos una dosis de evolocumab prescrita. Se incluyeron 1.951 sujetos de 12 países. Los datos fueron recopilados desde los seis meses previos al inicio del tratamiento hasta los 30 meses posteriores. La cohorte española incluyó pacientes que comenzaron evolocumab en la práctica clínica habitual desde marzo del 2016 hasta septiembre del 2019. Se recogieron las características demográficas y clínicas, los tratamientos hipolipemiantes (LLT) y el perfil lipídico. (AU)

Long-term treatment persistence and maintained reduction of LDL-cholesterol levels with evolocumab over 30 months: Results from the Spanish cohort of the European prospective HEYMANS study.

AIMS: Limited data exist on low-density lipoprotein-cholesterol (LDL-C) level variability or long-term persistence with the monoclonal antibody evolocumab in routine clinical practice. HEYMANS (NCT02770131) is the first multi-country, multicenter, observational study of European patients initiating evolocumab as part of their routine clinical management, based on local reimbursement criteria (overall data recently published). The aim of this analysis is to describe clinical characteristics, baseline and changes in LDL-C levels, treatment patterns and persistence to evolocumab over 30 months in the Spanish cohort using data from the HEYMANS Registry. METHODS: HEYMANS was a prospective study of adult patients (≥18 years) who received at least one dose of evolocumab. A total of 1951 patients were enrolled from 12 countries and were followed up for 30 months after evolocumab initiation. Data were collected for 6 months before evolocumab initiation and up to 30 months thereafter. The Spanish cohort included patients who started evolocumab in routine clinical practice from March 2016 to September 2019. Demographic and clinical characteristics, lipid-lowering therapies (LLT), and lipid levels were collected. RESULTS: In total, 201 patients were included in the Spanish cohort. Median follow-up (Q1-Q3) was 30.0 (12-30) months. A total of 61.7% of patients were men and the mean (standard deviation) age was 59.5 (10.8) years. Most patients (68.7%) had experienced a prior cardiovascular event, 45.3% had coronary artery disease or stable angina, and 60.2% had a diagnosis of familial hypercholesterolemia. Overall, 57.7% of patients were receiving treatment with statins, most of them with high-intensity statins (85.3%); 45.8% of patients were intolerant to statins, and 26.4% of patients did not receive any LLT. At baseline, median (Q1-Q3) LDL-C levels were 151 (123-197) mg/dL. After 3 months of treatment, baseline LDL-C decreased by 66% to a median of 50 (30-83) mg/dL and these levels were maintained over time, with a median LDL-C of 55 (40-99) mg/dL at 30 months. At months 10-12 of treatment, LDL-C levels<55mg/dL were achieved by 56.3% of patients. LDL-C levels<70mg/dL were achieved by 70.1% of patients, and a lowering of LDL-C levels ≥50% was achieved by 76.8% of patients. The percentage of patients on evolocumab treatment was 95% at 12 months and 93% at 30 months. CONCLUSIONS: In the Spanish cohort in routine clinical practice, evolocumab therapy provided a reduction in LDL-C levels consistent with that reported in previous clinical trials, which was sustained during 30 months of follow-up. Treatment with evolocumab was started at LDL-C levels 50% higher than those recommended by The Spanish Society of Arteriosclerosis and the Therapeutic Positioning Report. The probability of achieving the 2019 ESC/EAS LDL-C goals would improve with combination therapy and also with a lower LDL-C threshold when starting evolocumab. Persistence to evolocumab remained high during follow-up, with a very low percentage of discontinuation (5% at 12 months; 7% at 30 months).

Parenteral supplementation of Cu, Zn and Mn enhances boars' sperm quality.

INTRODUCTION: The trace elements concentrations of blood might play a key role in the trace element concentration of seminal plasma, as well as in the improvement of semen volume and sperm morphology in boars. OBJECTIVE: To assess the effect of supplementation of Cu, Zn and Mn on their concentrations in blood serum and seminal plasma and sperm quality in boars. METHODS: Eighteen boars of the Duroc Jersey breed were selected and their blood and semen (54 ejaculates before supplementation) were extracted. Coinciding with the third sampling and after of blood taken, the boars were supplemented subcutaneously with 37.5 mg of Cu, 75 mg of Zn and 37.5 mg of Mn; 40 days after the supplementation the fourth sampling was taken. Cu and Zn concentrations in blood serum and seminal plasma were determined by atomic absorption spectrophotometry, while the sperm pathologies were determined by microscopy and the concentrations of Cu and Zn in blood serum and seminal plasma, and semen pathologies were compared using the t-Student test for paired samples. A simple linear correlation was made between the minerals concentration in seminal plasma with the percentage of spermatozoa with abnormal forms. RESULTS: Although the concentrations of Zn in blood serum did not show differences between sampling periods (P < 0.05), they were significantly higher (P < 0.01) in the seminal plasma after supplementation as compared to its levels before supplementation. In addition, the concentrations of Cu and Zn in seminal plasma were increased (P < 0.01), and the total spermatic pathologies were reduced; especially those of the head, neck and intermediate part of the tail (P < 0.001). Besides, macrocephaly, double head and broken acrosome were the most common pathologies (P < 0.05). Moreover, parenteral supplementation of Cu, Zn and Mn was a protective factor to the presentation of ejaculates with abnormal sperm percentages higher than 10% (χ2 = 6.1544; P = 0.0131). The prevalence of abnormal shapes of boars' sperm before supplementation was 0.40; after supplementation the answer was 0.05 and the prevalence ratio was 0.13 with a confidence interval of 95% from 0.01 to 0.94. Moreover, Zn concentrations in blood serum were not correlated with those of the seminal plasma (P > 0.05, r = - 0.0353); however, the concentrations of Cu in both fluids were correlated (P < 0.05, r = 0.2254). In addition, the Zn values in the seminal plasma and the percentage of abnormal spermatozoa had a negative and highly significant correlation (P < 0.0001, r = - 0.5628). However, the Cu concentrations in the semen were not significantly correlated with the abnormal sperm forms (P > 0.05, r = 0.0200). CONCLUSION: From the present study it can be concluded that in boars fed with diets that meeting their requirements in trace minerals according to NRC (2012) [1], parenteral supplementation of 37.5 mg of Cu, 75 mg of Zn and 37.5 mg of Mn increased the Zn concentrations in the seminal plasma and reduced the sperm pathologies, which resulted in an increase of the boars' sperm quality.

Understanding the ecosystem of patients with lysosomal storage diseases in Spain: a qualitative research with patients and health care professionals.

BACKGROUND: Lysosomal Storage Diseases (LSDs) are a group of Rare Diseases (RDs) caused by lysosomal enzyme deficiencies. Patients with LSDs suffer from a wide range of symptoms with a strong impact in their daily routines. In this study we aimed to explore the impact of the disease on the lives of patients with four LSDs, as well as how they experience Patient Journey from diagnosis to follow up. Unmet Needs (UNs) perceived by patients and clinicians were assessed to have a better understanding of which initiatives could improve LSDs management and especially those that could result in an improvement of patients' quality of life. METHODS: Qualitative research was the research methodology selected for the study. It provides plentiful and holistic insights into people's views and actions. The study was conducted through in-depth face-to-face semi-structured interviews. RESULTS: In total, 20 patients and 25 Health Care Professionals (HCPs) from different Spanish regions were interviewed. Patients perceived that the highest impact of the LSDs was on their daily routines, specifically on their emotional side, their work/school environment, their family and their social life. Regarding the Patient Journey experience, the worst perceived stage was the pre-diagnosis, where patients only reported negative perceptions, being the delay in diagnosis and misdiagnosis the most commented issues. On the contrary, the follow-up stage was the one with less negative perceptions. Overall, patients and HCPs agreed on the priority UNs, such as accelerating diagnosis, reducing bureaucracy for the treatment access and a more coordinated attention for the patients, not only among different physicians but also with other professionals such as genetic counselors or social workers. CONCLUSIONS: Our data shows that there are still UNs to be addressed from the perspective of patients and HCPs. The main UN is accelerating diagnosis, which could be achieved by medical awareness and education, according to clinicians. A more comprehensive disease management was another main point to be worked on to improve LSD-patient experience and quality of life.

Condición corporal y reinicio de la actividad ovárica posparto en vacas Holstein en Ecuador / Corporal condition and restart of the ovarian postpartum on Holstein cows in Ecuador

RESUMEN Objetivo. Determinar la influencia de la condición corporal al parto (CCP) en el reinicio de la actividad ovárica (RAO) posparto de la vaca Holstein en la región andina de Ecuador. Materiales y métodos. Se trabajaron 30 vacas. Se determinaron el momento de aparición del folículo dominante (FD), de ovulación y de actividad luteal; la duración del ciclo estral, el volumen del cuerpo lúteo (CL) y las concentraciones de progesterona (P4) en suero sanguíneo. Los estadígrafos descriptivos de las variables del RAO y sus indicadores se compararon según la CCP mediante una prueba de t-Student para muestras independientes. Se evaluó la asociación entre la CCP y el RAO posparto mediante un estudio caso control. Resultados. La duración del ciclo estral fue 23.10 días, el 46.67% de las vacas tuvo ciclos normales y el 53.33% ciclos anormales. El FD, la ovulación y la actividad luteal ocurrieron a los 16.63, 27.76 y 41.38 días posparto, respectivamente; antes (p<0.05) en vacas con CCP ≥ 3.5; en las que fueron mayores (p<0.05) el volumen del CL y las concentraciones de P4. La CCP se correlacionó (p<0.05) con los parámetros del RAO. Las vacas con CCP <3.5 puntos, tienen 10.50 veces más probabilidades de tener RAO tardío que las que tienen CCP ≥ de 3.5 puntos. Conclusiones. El RAO fue temprano, sobre el influyó la CCP, la que constituyó un factor de riesgo (p<0.05) para que las vacas tengan un RAO tardío.

ABSTRACT Objective. To determine the influence of corporal composition at delivery (CCD) on the ovarian postpartum restart (OPR) of the Holstein cow in the Andes Region in Ecuador. Materials and methods. 30 cows were produced. All of the following moments were determined: the appearing of the dominant follicle (DF), the ovulation and luteal activity; the duration of the estrous cycle, the volume of the luteum body (LC) and the progesterone concentrations (P4) on blood serum. Descriptive statisticians of the OPR variables and its indicators were compared according to the BC, by means of a t-Student test for independent samples. The relationship between the BC and the postpartum OPR through a case-control case was assessed. Results. The duration of the oestrous cycle was 23.10 days, 46.67% of the cows had regular cycles and 53.33% were abnormal cycles. The DF, the ovulation and the luteal activity were seen at 16.63, 27.76 and 41.38 after postpartum, respectively; before (p<0.05) on cows with BC ≥ 3.5; in which both the (p<0.05) and the volume of the LC and P4 concentrations were higher. The BC was correlated with (p<0.05) with the OPR parameters. The cows with <3.5 BC points, are 10.50 times more prompt to have a late OPR than those with a ≥ de 3.5 points BC. Conclusions. The OPR was early, BC had an influence on it, which constituted a major (p<0.05) risk factor on cows having a late OPR.

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

Nuevos tratamientos en la hipertrigliceridemia y en la hiperquilomicronemia / Novel therapeutics in hypertriglyceridaemia and chylomicronaemia

Existen evidencias del papel de la hipertrigliceridemia como factor de riesgo independiente de ateromatosis. Cuando es severa, la hiperquilomicronemia puede asociarse a pancreatitis aguda grave y recurrente. En la mayoría de las hipertrigliceridemias se combina una base predisponente poligénica con diversos factores ambientales u otras patologías precipitantes. Algunas hiperquilomicronemias son formas familiares monogénicas autosómicas recesivas. Una característica de los triglicéridos plasmáticos es la marcada variabilidad y su descenso con ajustes en la dieta y el estilo de vida. Los fármacos disponibles contribuyen también a su control, pero es más controvertida la disminución del riesgo vascular o de pancreatitis. Los avances en el conocimiento del metabolismo lipídico a nivel molecular y en la tecnología farmacológica posibilitan el desarrollo de nuevas estrategias terapéuticas que pueden facilitar el tratamiento de pacientes en los que las medidas convencionales no son efectivas. En algunos casos, el elevado coste podría limitar su acceso y su sostenibilidad

Currently there is evidence on hypertriglyceridaemia as an independent risk factor of atherosclerosis. Chylomicronaemia associated with very high concentration of triglycerides may cause severe and recurrent acute pancreatitis. The cause of most cases is a combination of a polygenetic basis with some lifestyles and pathological conditions. Some rare and familial chylomicronaemias are mendelian diseases with an autosomal recessive pattern. On the other hand, plasma triglycerides have considerable biological variability and usually descend with non-pharmacological interventions alone. In some cases, drugs are also required for their control, but their impact on vascular risk reduction or pancreatitis prevention is more controversial. The recent advances in knowledge of molecular lipid metabolism and pharmacological technologies are resulting in the development of new therapeutic strategies, which can be applied to patients with refractory hypertrigliceridaemia. The challenge may be how the health systems can cover its high costs

Novel therapeutics in hypertriglyceridaemia and chylomicronaemia. / Nuevos tratamientos en la hipertrigliceridemia y en la hiperquilomicronemia.

Currently there is evidence on hypertriglyceridaemia as an independent risk factor of atherosclerosis. Chylomicronaemia associated with very high concentration of triglycerides may cause severe and recurrent acute pancreatitis. The cause of most cases is a combination of a polygenetic basis with some lifestyles and pathological conditions. Some rare and familial chylomicronaemias are mendelian diseases with an autosomal recessive pattern. On the other hand, plasma triglycerides have considerable biological variability and usually descend with non-pharmacological interventions alone. In some cases, drugs are also required for their control, but their impact on vascular risk reduction or pancreatitis prevention is more controversial. The recent advances in knowledge of molecular lipid metabolism and pharmacological technologies are resulting in the development of new therapeutic strategies, which can be applied to patients with refractory hypertrigliceridaemia. The challenge may be how the health systems can cover its high costs.

Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease. In this study, we performed in vitro characterization of new LDLR variants found in our patients. Genetic analysis was performed by Next Generation Sequencing using a customized panel of 198 genes in DNA samples of 516 subjects with a clinical diagnosis of probable or definitive FH. All new LDLR variants found in our patients were functionally validated in CHO-ldlA7 cells. The LDLR activity was measured by flow cytometry and LDLR expression was detected by immunofluorescence. Seven new variants at LDLR were tested: c.518 G>C;p.(Cys173Ser), c.[684 G>T;694 G>T];p.[Glu228Asp;Ala232Ser], c.926C>A;p.(Pro309His), c.1261A>G;p.(Ser421Gly), c.1594T>A;p.(Tyr532Asn), and c.2138delC;p.(Thr713Lysfs*17). We classified all variants as pathogenic except p.(Ser421Gly) and p.(Ala232Ser). The functional in vitro characterization of rare variants at the LDLR is a useful tool to classify the new variants. This approach allows us to confirm the genetic diagnosis of FH, avoiding the classification as "uncertain significant variants", and therefore, carry out cascade family screening.

Primary constitutional MLH1 epimutations: a focal epigenetic event.

BACKGROUND: Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. METHODS: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern. RESULTS: No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter-generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. CONCLUSION: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.

Uterine Involution in Hosltein cows in the province of Carchi, Ecuador / Involución uterina en vacas Holstein en la provincia El Carchi, Ecuador

Abstract Objective. To evaluate the uterine involution in Holstein cow, under the conditions of production of the bovine dairy cattle in the province El Carchi, Ecuador. Materials and Methods. Sixty cows were selected and the time for uterine involution was determined by the recto-vaginal examination, ultrasonography and the clinical score of the regression of the uterus. The statistical parameters for each variable were determined. The effect of parity and body condition (CC) on complete uterine involution was evaluated by multifactorial ANOVA and the LSD test to compare means. Results. The clinical involution of the uterus, without taking into account the clinical score occurred at 29.86±7.71 days but considering this notation was at 42 ± 0.39 days. The uterine involution took place earlier (p<0.05) in cows with BCS ≥ 3.5 at birth than in those with BCS <3.5. In second calving cows it was at 25.17±1.32 days and it was extended (p<0.05) for the third and fourth calving. The occurrence of the dominant follicle and ovulation occur at 16.63 ± 3.83 and 27.76±7.71 days, respectively. Conclusions. The clinical involution of the uterus occurred in less time when the recto-vaginal examination was considered, compared when it was evaluated taking into account the clinical score. The uterine involution process is influenced by parity and body condition at calving.

Resumen Objetivo. Evaluar la involución uterina en vacas Holstein, en las condiciones de producción de la ganadería bovina lechera en la provincia El Carchi, Ecuador. Materiales y métodos. Se seleccionaron 60 vacas y se determinó el tiempo para la involución uterina mediante la exploración recto-vaginal, ultrasonografía y la puntuación clínica de la regresión del útero. Se determinaron los estadígrafos descriptivos de cada variable. Se evaluó el efecto de la paridad y la condición corporal (CC) sobre la completa involución uterina mediante un ANOVA multifactorial y la prueba LSD para comparar las medias. Resultados. La involución del útero, sin tomar en cuenta la puntuación clínica ocurrió a los 29.86 ± 7.71 días pero considerando esta notación fue a los 42±0.39 días. La involución uterina ocurrió más temprano (p<0.05) en las vacas con CC al parto ≥ que 3.5 que en las que la tenían < de 3.5. En las vacas de segundo parto fue a los 25.17 ± 1.32 días y se prolongó (p<0.05) en el tercero y cuarto parto. La aparición del folículo dominante y la ovulación ocurrieron a los 16.63±3.83 y 27.76±7.71 días, respectivamente. Conclusiones. La involución clínica del útero considerando el examen recto-vaginal ocurrió en menor tiempo que cuando se evaluó considerando la puntuación clínica. El proceso de involución uterina está iinfluenciado por la paridad y la CC al parto.

Fabry Nephropathy: An Evidence-Based Narrative Review.

Fabry disease (FD) is a rare, X-linked disorder caused by mutations in the GLA gene encoding the enzyme α-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, endothelial cells, epithelial cells, and tubular cells contribute to the renal symptoms of FD, which manifest as proteinuria and reduced glomerular filtration rate leading to renal insufficiency. A correct diagnosis of FD, although challenging, has considerable implications regarding treatment, management, and counseling. The diagnosis may be confirmed by demonstrating the enzyme deficiency in males and by identifying the specific GLA gene mutation in male and female patients. Treatment with enzyme replacement therapy, as part of the therapeutic strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline, particularly in the early stages of the disease. Emergent treatments for FD include the recently approved chaperone molecule migalastat for patients with amenable mutations. The objective of this report is to provide an updated overview on Fabry nephropathy, with a focus on the most relevant aspects of its epidemiology, diagnosis, pathophysiology, and treatment options.

Mutations causing acrodysostosis-2 facilitate activation of phosphodiesterase 4D3.

Type 2 acrodysostosis (ACRDYS2), a rare developmental skeletal dysplasia characterized by short stature, severe brachydactyly and facial dysostosis, is caused by mutations in the phosphodiesterase (PDE) 4D (PDE4D) gene. Several arguments suggest that the mutations should result in inappropriately increased PDE4D activity, however, no direct evidence supporting this hypothesis has been presented, and the functional consequences of the mutations remain unclear. We evaluated the impact of four different PDE4D mutations causing ACRDYS2 located in different functional domains on the activity of PDE4D3 expressed in Chinese hamster ovary cells. Three independent approaches were used: the direct measurement of PDE activity in cell lysates, the evaluation of intracellular cAMP levels using an EPAC-based (exchange factor directly activated by cAMP) bioluminescence resonance energy transfer sensor , and the assessment of PDE4D3 activation based on electrophoretic mobility. Our findings indicate that PDE4D3s carrying the ACRDYS2 mutations are more easily activated by protein kinase A-induced phosphorylation than WT PDE4D3. This occurs over a wide range of intracellular cAMP concentrations, including basal conditions, and result in increased hydrolytic activity. Our results provide new information concerning the mechanism whereby the mutations identified in the ACRDYS2 dysregulate PDE4D activity, and give insights into rare diseases involving the cAMP signaling pathway. These findings may offer new perspectives into the selection of specific PDE inhibitors and possible therapeutic intervention for these patients.

Effects of copper parenteral supplementation on the weight gain in fattening bulls / Efecto de la suplementación parenteral del cobre sobre la ganancia de peso de toros en ceba

ABSTRACT Objective. In order to evaluate the effect of copper parenteral supplementation on cupremia and weight gain in fattening bulls. Materials and methods. Fifty animals hybrids holstein and zebu were selected, with 18-20 months of age, 210 - 220 kg body weight, clinically healthy and in a system of intensive fattening. Two groups of 25 animals were divided, one control and another supplemented with 50 mg of intravenous Cu every 2 months to complete 3 applications; hemochemical indicators and weight gain were evaluated. The variables were compared using the t-Student test for independent samples and growth curves its parameters were determined. Results. Cu supplementation increased (p<0.001) the cupremia, hemoglobin and hematocrit, and (p<0.01) the average daily gain and the weight of the bulls, with increases in weight between .86 y 9.54 % for the treated group. Final Live weight (446 and 586 kg) and average daily gain (534 and 684 g/d) in control and treated group, respectively, were higher in the supplemented animals with Cu. Conclusions. The parenteral suplementation of 50 mg of Cu increased serum levels of Cu, hemoglobin, hematocrit and live weight gain in fattening bulls.

RESUMEN Objetivo. Evaluar el efecto de la suplementación del cobre por vía parenteral sobre la cupremia y ganancia de peso en toros en ceba. Materiales y métodos. Se seleccionaron 50 animales mestizos Holstein x Cebú con 18 a 20 meses de edad, 210-220 kg de peso vivo, clínicamente sanos y en un sistema de ceba intensiva. Se dividieron 2 grupos de 25 animales, uno control y otro suplementado con 50 mg de Cu por vía parenteral cada 2 meses hasta completar 3 aplicaciones; se evaluaron los indicadores hematoquímicos y la ganancia de peso. Las variables se compararon mediante la prueba de t-Student para muestras independientes y se determinaron las curvas de crecimiento y sus parámetos. Resultados. La suplementación con Cu incrementó (p<0.001) la cupremia, la hemoglobina y el hematocrito y (p<0.01) la ganancia media diaria y el peso vivo de los toros, con incrementos del mismo entre el 4.86 y 9.54 %,a favor del grupo tratado. El peso vivo final (446 y 586 kg) y la ganancia media diaria de peso (534 y 684 g/d) en los grupo control y tratado, respectivamente, son superiores en los animales suplementados con Cu. Conclusiones. La suplementación parenteral de 50 mg de Cu por vía parenteral incrementó los niveles séricos de Cu, la hemoglobina, el hematocrito y la ganancia de peso en toros en ceba.

Changes in Gastric Volume and Their Implications for Weight Loss after Laparoscopic Sleeve Gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a relatively new surgical technique for the treatment of morbid obesity. It is unclear whether the volume of the gastric remnant can expand after surgery as a result of intraluminal pressure maintained over time. If this were the case, the increased volume could affect weight loss and the improvement in comorbidities. This study aims to assess the evolution of residual gastric volume (RGV) during the first year after LSG and its relationship with weight loss. MATERIAL AND METHODS: We conducted a prospective study of 112 patients who underwent LSG from February 2009 to December 2013. In order to measure the RGV after surgery, all patients were evaluated radiologically by an esophagogastroduodenal (EGD) transit at 1 and 12 postoperative months. RESULTS: All patients showed a significant reduction in BMI compared with the preoperative measurement (33.48 ± 5.78 vs. 50.54 ± 6.69 kg/m2; p < 0.001). Increased RGV was observed when comparing the results obtained by EGD transit at 1 (68.39 ± 25.89 cm3) and 12 postoperative months (122.58 ± 38.76 cm3; p < 0.001). There was no association between increase in gastric volume and weight loss at 1-year follow-up (r = 0.01; p = 0.910). CONCLUSIONS: The volume of the gastric remnant increased significantly during the first year after LSG. However, this increase was not associated with weight loss. Further prospective research with longer follow-up periods is needed to confirm or contrast the present results.

Empleo de plasma autólogo rico en plaquetas en el tratamiento de fístulas perianales complejas / Using autologous platelet-rich plasma for the treatment of complex fistulas

Objetivo: este estudio tiene como objetivo demostrar la efectividad y seguridad de un gel de fibrina autóloga rico en factores de crecimiento plaquetario para el tratamiento de las fístulas perianales complejas. Material y métodos: estudio epidemiológico prospectivo descriptivo. Se incluyen pacientes que presentan fístula perianal compleja o fístula perianal simple con alteración de la continencia. Se realiza identificación de ambos orificios y del trayecto, legrado del mismo e instilación del Vivostat PRF® en el trayecto hasta observar exceso de material por el OFE. Las variables a analizar son: edad, sexo, uso de setón previo, clínica prevalente, tipo de fístula, complicaciones postoperatorias, cierre de la fístula y alteraciones en la calidad de vida mediante el test sf-36(v2). Resultados: desde enero del 2011 hasta mayo del 2013 se ha intervenido a 23 pacientes, 12 hombres y 11 mujeres, con una media de edad de 49 años y un seguimiento mínimo de 12 meses. Dos abandonaron el estudio. 17 pacientes presentaban fístula transesfinteriana baja; 2, transesfinteriana alta, y 2, interesfinteriana con alteración de la continencia. El síntoma más frecuente es la supuración. Doce pacientes llevaban un setón laxo (62%), de los cuales curaron nueve. De todos los pacientes que hemos intervenido el porcentaje de éxitos es de un 62%. Ningún paciente desarrolló incontinencia después del tratamiento. Sólo dos refieren una peor calidad de vida después de la intervención. Conclusión: este estudio demuestra que hay un claro beneficio con el uso de Vivostat PRF® como tratamiento para las fístulas perianales complejas. Es una técnica altamente reproductible con resultados aceptables y que no produce alteraciones de la continencia (AU)

Objective: This study aims to demonstrate the effectiveness and safety of autologous fibrin gel rich in platelet growth factors for the treatment of complex perianal fistulas. Material and Methods: Prospective epidemiological study. Patients with complex perianal fistula or perianal fistula mere alteration of continence are included. identification of both holes and the journey, curettage of it and instillation of Vivostat PRF® in the way it is done to observe excess material by OFE. The variables analyzed were: age, sex, use of prior Seton clinic prevalent type of fistula, postoperative complications, fistula closure and impaired quality of life using the SF-36 test (v2). Results: From January 2011 to May 2013 have involved 23 patients, 12 men and 11 women, with an average age of 49 years and a minimum follow-up of 12 months. Two dropped out. 17 patients had low transsphincteric fistulas, 2 and 2 high transsphincteric intersphincteric with impaired continence. The most common symptom is the discharge. Twelve patients had a loose seton (62%), of which nine cured. Of all the patients we have operated the success rate is 62%. No patient developed incontinence after treatment. Only two reported a worse quality of life after surgery. Conclusion: This study demonstrates that there is a clear benefit to the use of Vivostat PRF® as a treatment for complex perianal fistulas. It is a highly reproducible technique with acceptable results and does not produce impairment of continence (AU)

Using autologous platelet-rich plasma for the treatment of complex fistulas.

OBJECTIVE: This study aims to demonstrate the effectiveness and safety of autologous fibrin gel rich in platelet growth factors for the treatment of complex perianal fistulas. MATERIAL AND METHODS: Prospective epidemiological study. Patients with complex perianal fistula or perianal fistula mere alteration of continence are included. identification of both holes and the journey, curettage of it and instillation of Vivostat PRF® in the way it is done to observe excess material by OFE. The variables analyzed were: age, sex, use of prior Seton clinic prevalent type of fistula, postoperative complications, fistula closure and impaired quality of life using the SF-36 test (v2). RESULTS: From January 2011 to May 2013 have involved 23 patients, 12 men and 11 women, with an average age of 49 years and a minimum follow-up of 12 months. Two dropped out. 17 patients had low transsphincteric fistulas, 2 and 2 high transsphincteric intersphincteric with impaired continence. The most common symptom is the discharge. Twelve patients had a loose seton (62%), of which nine cured. Of all the patients we have operated the success rate is 62%. No patient developed incontinence after treatment. Only two reported a worse quality of life after surgery. CONCLUSION: This study demonstrates that there is a clear benefit to the use of Vivostat PRF® as a treatment for complex perianal fistulas. It is a highly reproducible technique with acceptable results and does not produce impairment of continence.