Frasier syndrome: A case report / El síndrome de Frasier, caso clínico

Introduction: Frasier syndrome is a genetic disorder produced by a mutation in intron 9 of the WT1 gene, responsible for renal and genital dysfunctions. Clinical findings: It is characterized by discrepancy between the individual karyotype and the individual phenotype and corticosteroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis. Patients usually have a female phenotype with a 46 XY karyotype, which increases the risk of gonadoblastoma in 50% of cases. Kidney disease requires kidney transplantation in adulthood. Cardiovascular and bone-derived comorbidities such as hyperlipidaemia and osteopenia/osteoporosis, respectively, are also common. Main diagnoses: Mutations of the WT1 gene can lead to different clinical entities, most notably Denysh-Drash syndrome, Frasier syndrome, or isolated focal segmental glomerulosclerosis. We present a clinical case of a woman who debuted in childhood with difficult-to-control nephrotic syndrome, the lack of pubertal development, primary amenorrhoea and the absence of ovaries on imaging tests in adolescence, alerted to an underlying genetic problem that, after cytogenetic studies, allowed a diagnosis of Frasier syndrome. Therapeutic interventions: It is recommended to remove the gonads due to increased risk of developing gonadoblastoma. Treatment of associated dyslipidaemia and osteopenia is also necessary. Conclusion: Frasier syndrome is an unusual cause of infertility due to gonadal dysgenesis and is associated with kidney problems.(AU)

Introducción: El síndrome de Frasier es un trastorno genético producido por una mutación en el intrón 9 del gen WT1, responsable de disfunciones a nivel renal y genital. Principales síntomas: Se caracteriza por disgenesia gonadal con discrepancia entre cariotipo-fenotipo y síndrome nefrótico resistente a corticoides debido a glomeruloesclerosis focal y segmentaria. Las pacientes presentan habitualmente fenotipo femenino con cariotipo 46 XY, lo que aumenta el riesgo de gonadoblastoma en un 50% de los casos. La enfermedad renal obliga a trasplante renal en la edad adulta. Son habituales también las comorbilidades derivadas a nivel cardiovascular y óseo como hiperlipidemia y osteopenia/osteoporosis, respectivamente. Diagnósticos principales: Las mutaciones del gen WT1 pueden conducir en distintas entidades clínicas entre las que destaca el síndrome de Denys-Drash, el síndrome de Frasier o la glomeruloesclerosis focal y segmentaria aislada. Se presenta un caso clínico de una mujer que debutó en la infancia con síndrome nefrótico de difícil control y que, durante la adolescencia, ante la falta de desarrollo puberal, la amenorrea primaria y la ausencia de ovarios en las pruebas de imagen alertaron de un problema genético subyacente que, tras estudios citogenéticos, permitió el diagnóstico de síndrome de Frasier. Intervenciones terapéuticas: Se recomienda la exéresis de las gónadas debido al riesgo incrementado de gonadoblastoma. El tratamiento de la dislipemia y la osteopenia asociadas también es necesario. Conclusión: El síndrome de Frasier es una causa inusual de infertilidad debido a una disgenesia gonadal y se asocia con problemas a nivel renal.(AU)

Relationship between infrared skin radiation and functional tests in patients affected by Emery-Dreifuss muscular dystrophy: Part 2.

HYPOTHESIS: This study represents a second part of a recently published study about a new form of evaluation and development of rare genetic neurodegenerative diseases. The objective is to provide a more global vision of thermography with respect to the Emery-Dreifuss pathology, through the analysis of the data collection carried out for one year. The basic hypothesis is that thermography could become a valid tool for the diagnosis and follow-up of this pathology because is a very specific tool for registering temperature changes produced by a constant degenerative evolution of this muscular dystrophy.

Relationship between infrared skin radiation and muscular strength tests in patients affected by Emery-Dreifuss muscular dystrophy.

Considering that infrared thermography is presented as a diagnostic technique for non-invasive, non-ionizing, fast and easy to use imaging and Emery-Dreifuss muscular dystrophy is a clinical condition that seems to be related to changes in the emission of infrared radiation at the skin level due to its neurodegenerative character, we have conducted an investigation by infrared thermography and the use of functional strength tests in the lower limbs in a family of 4 affected members of Emery-Dreifuss muscular dystrophy to try to establish a relationship between the evolution of the disease and the emission of infrared radiation in this pathology at the lower limb level and provide a more general view of this disease for a better evaluation and monitoring of the disease.

Occupational rhinoconjunctivitis induced by unusual allergens of carrot

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Is infrared thermography (IRT) a possible tool for the evaluation and follow up of Emery-Dreifuss muscular dystrophy? A preliminary study.

HYPOTHESIS: The hypothesis of this work is that infrared thermography could become a valid tool for the diagnosis and follow-up of the Emery-Dreifuss disease due to putative temperature changes produced by a constant degenerative evolution of this muscular dystrophy. TESTING THE HYPOTHESIS: To justify this hypothesis we proposed a pilot study with 2 brothers affected of Emery-Dreifuss who present a very different age, with the principal objective to evidence a possible evolution of this pathology. Acquisition and comparison of images of computerized axial tomography (CT) and thermography (IRT) of the distal limbs in 2 affected brothers. DATA AND DISCUSSION: Important image correlations in the region of the thighs and the posterior region of the legs have been highlighted. The comparison between the CT and the thermography showed how the first results are encouraged and promising and open a possible new line of research on the evaluation and follow-up of this disease. Despite this, a larger number of studies are needed to validate the thermography as a diagnostic technique and follow-up of this pathology.

Theoretical basis for a new approach of studying Emery-Dreifuss muscular dystrophy by means of thermography.

INTRODUCTION: Emery-Dreifuss muscular dystrophy (EDMD) is a clinical condition characterized by neuro-skeletal and cardiac impairments. By means of thermography, an image acquisition technique that allows the recording of the heat emitted by objects or bodies, news insight can be obtained insights about the evaluation and follow-up of this disease. Actually, musculoskeletal disorders are a major cause of counseling and access to rehabilitation services and are some of the most important problems that affect the quality of life of many people. There are urgent both clinical and research needs for the assessment and follow-up of patients with Emery-Dreifuss muscular dystrophy and the thermography is a rapid, non-invasive, easy to use and objective technique that analyzes the temperature of the examined tissue. HYPOTHESIS: The main aim is to offer a new possible hypothesis of validating the thermography techniques that support the evaluation and clinical follow-up of the Emery-Dreifuss dystrophy. To carry out this work we rely on the evidence of the existing bibliography. To perform this work and to evaluate the current situation on this topic, a systematic review was carried and after the application of an automatic and manual filter, inclusion and exclusion criteria, a total of 0 articles was obtained. Unfortunately, there is a lack of articles that relate the use of thermography in the Emery-Dreifuss muscular dystrophy. Due to the absence of information, we have expanded the search to articles concerning the use of thermography in relation to alterations of the musculoskeletal system compatible with those of Emery-Dreifuss, genetic diseases related to the X chromosome and more generally muscular atrophy. Based on other studies and results carried out in diseases that show signs and symptoms similar to Emery-Dreifuss Muscular Dystrophy, we believe that a new line of translational research could be opened with novel findings and we think that thermography could be an optimal tool for the clinical monitoring of this pathology. We believe that it would be of a great importance to carry out an observational study, to lay the foundations for future works, that relate thermography to the Emery-Dreifuss muscular dystrophies.

Evaluation of silver nanospheres on viability and innate cellular parameters of gilthead seabream (Sparus aurata L.) head-kidney leucocytes.

The increasing use of nanomaterials, e.g. nanosilver, has lead to concerns about environmental contamination and possible toxic effects on aquatic organisms. Here, we present evidence for the impact of silver nanospheres (AgNSs) on fish innate immune cells after in vitro exposure. AgNSs of 20, 50 or 100 nm in diameter were tested with the smallest ones (20 nm) clearly having the most deleterious effects, after an exposure period of 30 min, followed by the medium-sized ones; the NSs of 100 nm had no impact. The effective concentration was determined at 10 µg ml-1 while lower concentrations (1, 2.5 or 5 µg ml-1) were ineffective. Head-kidney mixed leucocyte population showed significant viability reduction which was attributable to diminished viability of macrophages/monocytes and lymphocytes only whereas granulocytes' viability was not affected at the above exposure regime. Furthermore, cellular respiratory burst activity, phagocytic capacity and phagocytic ability were all reduced, with the first two parameters exhibiting the sharper reductions. Finally, transmission electron microscopy revealed that the AgNSs' internalization was brought about via phagocytosis, pinocytosis, receptor-mediated endocytosis and macropinocytosis; also, that cell death could be effected in either an apoptotic or a necrotic manner. It is concluded that AgNSs are potentially very noxious for the teleost fish immune system as they can adversely affect the function and viability of the head-kidney leucocytes.

Characterization of the gilthead seabream (Sparus aurata L.) immune response under a natural lymphocystis disease virus outbreak.

Lymphocystis or lymphocystis disease virus (LCDV) is distributed worldwide and affects many fresh and marine water fish species. LCDV is commonly found in aquaria fish species but also in farmed fish species, among them the gilthead seabream (Sparus aurata L.). The immune status of gilthead seabream (S. aurata) specimens under a natural outbreak of LCDV was studied. The replication of the virus was demonstrated in infected fish, but not in control fish. The results showed decreased total serum IgM levels and increased innate cellular immune response (peroxidase and respiratory burst activities) of head kidney leucocytes in LCDV-infected fish, compared to the values obtained in uninfected specimens. In addition, transcription of antiviral genes (ifn and irf3) was down-regulated in the skin of LCDV-positive fish as well as genes involved in cellular immunity (csf1r, mhc2a, tcra and ighm) that were down-regulated in skin and head kidney of infected fish. By contrast, the transcription of nccrp1 was up-regulated in head kidney after LCDV infection. These present results show that head kidney leucocytes are activated to encounter the virus at the sites of replication.

Selective estrogen receptor modulators differentially alter the immune response of gilthead seabream juveniles.

17α-ethynylestradiol (EE2), a synthetic estrogen used in oral contraceptives and hormone replacement therapy, tamoxifen (Tmx), a selective estrogen-receptor modulator used in hormone replacement therapy, and G1, a G protein-coupled estrogen receptor (GPER) selective agonist, differentially increased the hepatic vitellogenin (vtg) gene expression and altered the immune response in adult gilthead seabream (Sparus aurata L.) males. However, no information exists on the effects of these compounds on the immune response of juveniles. This study aims, for the first time, to investigate the effects of the dietary intake of EE2, Tmx or G1 on the immune response of gilthead seabream juveniles and the capacity of the immune system of the specimens to recover its functionality after ceasing exposures (recovery period). The specimens were immunized with hemocyanin in the presence of aluminium adjuvant 1 (group A) or 120 (group B) days after the treatments ceased (dpt). The results indicate that EE2 and Tmx, but not G1, differentially promoted a transient alteration in hepatic vtg gene expression. Although all three compounds did not affect the production of reactive oxygen intermediates, they inhibited the induction of interleukin-1ß (il1b) gene expression after priming. Interestingly, although Tmx increased the percentage of IgM-positive cells in both head kidney and spleen during the recovery period, the antibody response of vaccinated fish varied depending on the compound used and when the immunization was administered. Taken together, our results suggest that these compounds differentially alter the capacity of fish to respond to infection during ontogeny and, more interestingly, that the adaptive immune response remained altered to an extent that depends on the compound.

Mercury Accumulation, Structural Damages, and Antioxidant and Immune Status Changes in the Gilthead Seabream (Sparus aurata L.) Exposed to Methylmercury.

In aquatic systems, mercury (Hg) is an environmental contaminant that causes acute and chronic damage to multiple organs. In fish, practically all of the organic Hg found is in the form of methylmercury (MeHg), which has been associated with animal and human health problems. This study evaluates the impact of waterborne-exposure to sublethal concentrations of MeHg (10 µg L(-1)) in gilthead seabream (Sparus aurata). Hg was seen to accumulate in liver and muscle, and histopathological damage to skin and liver was detected. Fish exposed to MeHg showed a decreased biological antioxidant potential and increased levels of the reactive oxygen molecules compared with the values found in control fish (nonexposed). Increased liver antioxidant enzyme activities (superoxide dismutase and catalase) were detected in 2 day-exposed fish with respect to the values of control fish. However, fish exposed to MeHg for 10 days showed liver antioxidant enzyme levels similar to those of the control fish but had increased hepato-somatic index and histopathological alterations in liver and skin. Serum complement levels were higher in fish exposed to MeHg for 30 days than in control fish. Moreover, head-kidney leukocyte activities increased, although only phagocytosis and peroxidase activities showed a significant increase after 10 and 30 days, respectively. The data show that 30 days of exposure to waterborne MeHg provokes more significant changes in fish than a short-term exposure of 2 or 10 days.

Tamoxifen persistently disrupts the humoral adaptive immune response of gilthead seabream (Sparus aurata L.).

There is increasing concern about the possible effect of pharmaceutical compounds may have on the fish immune system. Bath exposition of 17α-ethynylestradiol (EE2), a synthetic estrogen used in oral contraceptives, altered the immune response of the gilthead seabream (Sparus aurata L.), a marine hermaphrodite teleost. Tamoxifen (Tmx) is a selective estrogen-receptor modulator used in hormone replacement therapy, the effects of which are unknown in fish immunity. This study aims to investigate the effects of dietary administration of EE2 (5 µg/g food) and Tmx (100 µg/g food) on the immune response of gilthead seabream, and the capacity of the immune system to recover its functionality after a recovery period. The results show for the first time the reversibility of the effect of EE2 and Tmx on the fish immune response. Tmx promoted a transient alteration in hepatic vitellogenin gene expression of a different magnitude to that produced by EE2. Both, EE2 and Tmx inhibited the induction of interleukin-1ß gene expression while reversed the inhibition of ROI production in leukocytes following vaccination. However, none of these effects were observed after ceasing EE2 and Tmx exposure. EE2 and Tmx stimulated the antibody response of vaccinated fish although Tmx, but not EE2, altered the antibody response and modulated the percentage of IgM(+) B lymphocytes of vaccinated fish during the recovery phase. Taken together, our results suggest that EE2 and Tmx might alter the capacity of fish to appropriately respond to infection and show that Tmx has a long-lasting effect on humoral adaptive immunity.

Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.

BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB). OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA). SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles. SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB. MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75). AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

Static and dynamic experimental analysis of the galloping stability of porous H-section beams.

The phenomenon of self-induced vibrations of prismatic beams in a cross-flow has been studied for decades, but it is still of great interest due to their important effects in many different industrial applications. This paper presents the experimental study developed on a prismatic beam with H-section. The aim of this analysis is to add some additional insight into the behaviour of the flow around this type of bodies, in order to reduce galloping and even to avoid it. The influence of some relevant geometrical parameters that define the H-section on the translational galloping behaviour of these beams has been analysed. Wind loads coefficients have been measured through static wind tunnel tests and the Den Hartog criterion applied to elucidate the influence of geometrical parameters on the galloping properties of the bodies under consideration. These results have been completed with surface pressure distribution measurements and, besides, dynamic tests have been also performed to verify the static criterion. Finally, the morphology of the flow past the tested bodies has been visualised by using smoke visualization techniques. Since the rectangular section beam is a limiting case of the H-section configuration, the results here obtained are compared with the ones published in the literature concerning rectangular configurations; the agreement is satisfactory.

Modulatory effects of deltamethrin-exposure on the immune status, metabolism and oxidative stress in gilthead seabream (Sparus aurata L.).

Deltamethrin, a sintetic pyrethroid, is the insecticide that has been replacing recently to others like organochlorines, organophosphates and carbamates which are less toxic for birds and mammals, although, unfortunately, all of them are highly toxic to various non-targeted aquatic organisms including fish. In the present study, the consequences of the exposition of gilthead seabream (Sparus aurata L.) specimens to sublethal bath dose of deltamethrin (0.1 ppb) on organo-somatic indexes, immunity, seric metabolic parameters, oxidative stress and liver histology were determined after 1, 3, 7 and 14 days of exposure. Deltamethrin alters gilthead seabream immune status, the hepato-somatic index and various seric metabolic parameters since the first exposure day while important progressive deleterious morphological changes in liver were also observed. However, no statistically significant deviation was detected in the expression of oxidative stress-related genes whilst the expression of cytochrome P450 gene was up-regulated in head-kidney and liver of exposed fish. Overall, the present results indicate severe immunotoxicological and metabolic effects of deltamethrin in gilthead seabream, the species with the highest rate of production in Mediterranean aquaculture. In general, the values obtained for the tested parameters during the trial seem to indicate that specimens try to adapt to this adverse situation although the continuous presence of the toxic impede the hypothetic recovery of homoeostasis. The use of deltamethrin in the proximities of seabream farms should be carefully considered.

Accumulation, histopathology and immunotoxicological effects of waterborne cadmium on gilthead seabream (Sparus aurata).

Studies in fish have demonstrated that Cd-exposure produce skeletal deformities and alterations in tissue morphology, enzyme activities, stress response, ion regulation and immune response. In the present work, gilthead seabream (Sparus aurata) specimens were exposed to waterborne Cd (5 µM CdCl2 or 1 mg L(-1)) for 2, 10 or 30 days. Organo-somatic changes, Cd accumulation, liver histology and humoral and cellular immune responses were determined. Results showed that exposure of seabream specimens to Cd induced no alterations on spleen and liver organo-somatic indexes whilst produced progressive deleterious morphological alterations in liver and exocrine pancreas that correlated with the hepatic Cd-accumulation. Regarding the immunotoxicological potential, strikingly, Cd-exposure produced a reduction in the serum complement activity and leucocyte respiratory burst to a significant extent after 10 and 30 days whilst the serum peroxidase activity and leucocyte phagocytosis were increased at different sampling times. On the other hand, serum IgM levels and leucocyte peroxidase activity resulted unaltered. The present results seem to indicate that seabream exposed to Cd in the present conditions suffer toxicity.

Immunotoxicological effects of inorganic arsenic on gilthead seabream (Sparus aurata L.).

Arsenic (As) has been associated with multitude of animal and human health problems; however, its impact on host immune system has not been extensively investigated. In fish, there are very few works on the potential risks or problems associated to the presence of arsenic. In the present study we have evaluated the effects of exposure (30 days) to sub-lethal concentrations of arsenic (5 µM As2O3) in the teleost fish gilthead seabream (Sparus aurata), with special emphasis in the innate immune response. The arsenic concentration was determined using atomic fluorescence spectrometry (AFS) in liver and muscle of exposed fish showing As accumulation in the liver after 30 days of exposure. The hepatosomatic index was increased at significant extent after 10 days but returned to control values after 30 days of exposure. Histological alterations in the liver were observed including hypertrophy, vacuolization and cell-death processes. Focusing on the immunological response, the humoral immune parameters (seric IgM, complement and peroxidase activities) were no affected to a statistically significant extent. Regarding the cellular innate parameters, head-kidney leucocyte peroxidase, respiratory burst and phagocytic activities were significantly increased after 10 days of exposition compared to the control fish. Overall, As-exposure in the seabream affects the immune system. How this might interfere with fish biology, aquaculture management or human consumers warrants further investigations. This paper describes, for the first time, the immunotoxicological effects of arsenic exposure in the gilthead seabream, which is a species with the largest production in Mediterranean aquaculture.

Specific and non-overlapping functions of testosterone and 11-ketotestosterone in the regulation of professional phagocyte responses in the teleost fish gilthead seabream.

Sex hormones, both estrogens and androgens, have a strong impact on immunity in mammals. In fish, the role of androgens in immunity has received little attention and contradictory conclusions have been obtained. However, it is well known that sex steroids are involved in fish growth, osmoregulation and gonad remodelation. In this study, we examine the in vitro effects of testosterone and 11-ketotestosterone, the two main fish androgens, on the professional phagocytes of the teleost fish gilthead seabream (Sparus aurata L.). Although both testosterone and 11-ketotestosterone failed to modulate the respiratory burst of seabream phagocytes, testosterone but not 11-ketotestosterone was able to increase the phagocytic ability of non-activated phagocytes. Curiously, 11-ketotestosterone was more powerful than testosterone at inducing the expression of its own receptor, namely androgen receptor b (ARb), in acidophilic granulocytes (AGs), but none of them affected the basal ARb expression levels in macrophages (MØ). Furthermore, although physiological concentrations of testosterone exerted a pro-inflammatory effect on both AGs and MØs, 11-ketotestosterone showed an anti-inflammatory effect in AGs and a strong pro-inflammatory effect in MØs. Interestingly, both androgens modulated the expression of toll-like receptors in these two immune cell types, suggesting that androgens might regulate the sensitivity of phagocytes to pathogens and damage signals. Testosterone and 11-ketotestosterone have a competitive effect, at least, on the modulation of the expression of some genes. Therefore, our results show for the first time a non-overlapping role for testosterone and 11-ketotestosterone in the regulation of professional phagocyte functions in fish.

In situ forming microparticle implants for delivery of sex steroids in fish: Modulation of the immune response of gilthead seabream by testosterone.

Current knowledge on the sensitivity of marine fish to androgenic environmental chemicals is limited, despite the growing interest in the effects of endocrine disrupting chemicals. To study in vivo the effects of testosterone (T) on the fish immune response, we used a microencapsulation implant technique, the in situ forming microparticle system, containing 1 mg T/kg body weight (T-ISM), in adult specimens of gilthead seabream (Sparus aurata L.), a species of great economic interest. We demonstrated that implants themselves (without T) have no significant effect on most of the parameters measured. In T-ISM implanted fish, T serum levels reached supraphysiological concentrations accompanied by a slight increase in 11-ketotestosterone and 17ß-estradiol levels 21 days post-implantation (dpi). Liver and head-kidney samples were processed 7 and 21 dpi to assess T-ISM effect on (i) the mRNA expression of genes involved in the metabolism of steroid hormones and in the immune response, and (ii) phagocyte activities. The expression profile of cytokines, chemokines and immune receptors was altered in T-ISM implanted animals that showed an early pro-inflammatory tendency, and then, a mixed pro-/anti-inflammatory activation during longer exposure. Furthermore, the enhancement of phagocytic activity and the production of reactive oxygen species by leukocytes 21 dpi in T-ISM implanted specimens suggest fine modulation of the innate immune response by T. Taken together, these data demonstrate for the first time the feasibility of using ISM implants in an aquatic species, and provide new data on the role played by T on the immune response in fish.