Implementation of a hybrid healthcare model in rheumatic musculoskeletal diseases: 6-months results of the multicenter Digireuma study.

OBJECTIVES: Rheumatic and musculoskeletal diseases (RMDs) require a tailored follow-up that can be enhanced by the implementation of innovative tools. The Digireuma study aimed to test the feasibility of a hybrid follow-up utilizing an electronic patient reported outcomes (ePROs)-based monitoring strategy in patients with RMDs. METHODS: Adult patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) were recruited for a 6-month bicentric prospective follow-up consisting of face-to-face and digital assessments. Patients were asked to report disease-specific ePROs on a pre-established basis, and could also report flares, medication changes, and recent infections at any time. Four rheumatologists monitored these outcomes and contacted patients for interventions when deemed necessary. Results from face-to-face and digital assessments were described. RESULTS: Of 56 recruited patients, 47 (84%) submitted any ePROs to the digital platform. Most patients with RA were female (74%, median age of 47 years), while 48% of patients with SpA were female (median age 40.4 years). A total of 3,800 platform visits were completed, with a median of 57 and 29 visits in patients with RA and SpA, respectively. Among 52 reported alerts, 47 (90%) needed contact, of which 36 (77%) were managed remotely. Adherence rates declined throughout the study, with around half of patients dropping out during the 6 months follow-up. CONCLUSION: The implementation of a hybrid follow-up in clinical practice is feasible. Digital health solutions can provide granular knowledge of disease evolution and enable more informed clinical decision making, leading to improved patient outcomes. Further research is needed to identify target patient populations and engagement strategies.

A dense ring of the trans-Neptunian object Quaoar outside its Roche limit.

Planetary rings are observed not only around giant planets1, but also around small bodies such as the Centaur Chariklo2 and the dwarf planet Haumea3. Up to now, all known dense rings were located close enough to their parent bodies, being inside the Roche limit, where tidal forces prevent material with reasonable densities from aggregating into a satellite. Here we report observations of an inhomogeneous ring around the trans-Neptunian body (50000) Quaoar. This trans-Neptunian object has an estimated radius4 of 555 km and possesses a roughly 80-km satellite5 (Weywot) that orbits at 24 Quaoar radii6,7. The detected ring orbits at 7.4 radii from the central body, which is well outside Quaoar's classical Roche limit, thus indicating that this limit does not always determine where ring material can survive. Our local collisional simulations show that elastic collisions, based on laboratory experiments8, can maintain a ring far away from the body. Moreover, Quaoar's ring orbits close to the 1/3 spin-orbit resonance9 with Quaoar, a property shared by Chariklo's2,10,11 and Haumea's3 rings, suggesting that this resonance plays a key role in ring confinement for small bodies.

P-Rex1 is a novel substrate of the E3 ubiquitin ligase Malin associated with Lafora disease.

Laforin and Malin are two proteins that are encoded by the genes EPM2A and EPM2B, respectively. Laforin is a glucan phosphatase and Malin is an E3-ubiquitin ligase, and these two proteins function as a complex. Mutations occurring at the level of one of the two genes lead to the accumulation of an aberrant form of glycogen meant to cluster in polyglucosans that go under the name of Lafora bodies. Individuals affected by the appearance of these polyglucosans, especially at the cerebral level, experience progressive neurodegeneration and several episodes of epilepsy leading to the manifestation of a fatal form of a rare disease called Lafora disease (LD), for which, to date, no treatment is available. Despite the different dysfunctions described for this disease, many molecular aspects still demand elucidation. An effective way to unknot some of the nodes that prevent the achievement of better knowledge of LD is to focus on the substrates that are ubiquitinated by the E3-ubiquitin ligase Malin. Some substrates have already been provided by previous studies based on protein-protein interaction techniques and have been associated with some alterations that mark the disease. In this work, we have used an unbiased alternative approach based on the activity of Malin as an E3-ubiquitin ligase. We report the discovery of novel bonafide substrates of Malin and have characterized one of them more deeply, namely PIP3-dependent Rac exchanger 1 (P-Rex1). The analysis conducted upon this substrate sets the genesis of the delineation of a molecular pathway that leads to altered glucose uptake, which could be one of the origin of the accumulation of the polyglucosans present in the disease.

Ewing-like sarcoma bladder primary tumour: A case report and literature review.

Bladder primitive neuroectodermal tumors are extremely rare but are most frequent in older adult. 59-year-old man that complained of hematuria for the previous 24 h, urethral syndrome, and pain in the right renal fossa over the previous two weeks. No definitive management or treatment guidelines have been established. Hematuria is the most frequent symptom. Advanced age, metastasis, and incomplete tumor resection are determinants of a poor prognosis. Ewing-like bladder primary tumor is a rare entity with a poor prognosis, hence an aggressive treatment combining surgery and chemotherapy must be considered from the beginning.

Reliability and agreement analysis among 5 subjective methods of ocular torsion measurement.

OBJECTIVE: To evaluate the reliability in the measurement of ocular torsion and the agreement of the following subjective methods: double Maddox test, synoptophore, Gracis torsionometer, Harms screen and Awaya cyclodeviation test. METHOD: Patients with vertical strabismus acquired in adulthood were recruited and ocular torsion was measured with the 5 methods described on three occasions. As a gold standard test does not exist, the one that obtained the best repeatability data was chosen as the reference test. RESULTS: 25 patients were included in the study. The repeatability of each test was studied: double Maddox test (ICC = 0.783, CV = 29.33%), synoptophore (ICC = 0.976, CV = 6.71%), Gracis torsionometer (ICC = 0.937, CV = 20.10%), Harms screen (ICC = 0.962, CV = 11.86%) and Awaya test (ICC = 0.987, CV = 52.58%). The reference test to compare the agreement was the synoptophore. Statistically significant differences were found when comparing the ocular torsion ranges between the synoptophore and the Gracis torsionometer (p = 0.008) and between the synoptophore and the Awaya test (p = 0.02). CONCLUSIONS: The double Maddox test, the synoptophore, the Gracis torsionometer, and the Harms screen are reliable methods with good reproducibility indices. Among them, the synoptophore is the most consistent method. The Awaya test did not show good reliability. The bilateral Maddox test, the Gracis torsionometer, and the Harms screen were methods with good agreement with the synoptophore, which was determined as the reference test. The Awaya test did not show good agreement with the synoptophore.

High-flow priapism in pediatric population: Case series and review of the literature.

INTRODUCTION: Priapism is a prolonged erection that lasts longer than four hours. It is a rare pathology in the pediatric population, with an estimation of 0.3-1.5 per 100,000 children per year. The diagnostic sequence includes clinical history, physical examination and penile Doppler ultrasound (PDUS). Puncture of corpora cavernosa is not always necessary to establish the differential diagnosis between high-flow and low-flow priapism. The treatment of choice in pediatric age is not well defined. PATIENTS AND METHODS: Multicentric, retrospective and descriptive study including patients under 14 years with high-flow priapism between 2010 and 2020. RESULTS: A total of seven patients were diagnosed with high-flow priapism. None of them required puncture of the corpora cavernosa. Patients were treated with a conservative management, two patients required superselective arterial embolization due to persistent symptoms. CONCLUSIONS: High-flow priapism is a very rare entity in pediatric age; therefore, knowing the proper diagnosis and management is crucial. Currently, penile doppler ultrasound is enough for diagnosis in most cases and allows obviating the use of blood gas analysis. Children should be initially treated with a conservative management, reserving embolization for refractory cases.

High-flow Priapism in Pediatric Population: Case Series and Review of the Literature. / Priapismo de alto flujo en población pediátrica: serie de casos y revisión de la literatura.

INTRODUCTION: Priapism is a prolonged erection that lasts longer than four hours. It is a rare pathology in the pediatric population, with an estimation of 0.3-1.5 per 100,000 children per year. The diagnostic sequence includes clinical history, physical examination and penile Doppler ultrasound (PDUS). Puncture of corpora cavernosa is not always necessary to establish the differential diagnosis between high-flow and low-flow priapism. The treatment of choice in pediatric age is not well defined. PATIENTS AND METHODS: Multicentric, retrospective and descriptive study including patients under 14 years with high-flow priapism between 2010 and 2020. RESULTS: A total of seven patients were diagnosed with high-flow priapism. None of them required puncture of the corpora cavernosa. Patients were treated with a conservative management, two patients required superselective arterial embolization due to persistent symptoms. CONCLUSIONS: High-flow priapism is a very rare entity in pediatric age; therefore, knowing the proper diagnosis and management is crucial. Currently, penile doppler ultrasound is enough for diagnosis in most cases and allows obviating the use of blood gas analysis. Children should be initially treated with a conservative management, reserving embolization for refractory cases.

Craniofacial morphology/phenotypes influence on mandibular range of movement in the design of a mandibular advancement device.

BACKGROUND: The mandibular opening path movements have different directions according to the craniofacial morphology of the patient but always downward and backward, therefore increasing the collapse of the upper airway. The aim of this work is to determine if there is a relationship between the craniofacial morphology and the mandibular movement to help understand the impact on the mandibular position. METHODS: 52 students with full permanent dentition aged 19 to 23 years (mean 21.3 SD 1.7; 29 females and 23 males), participated in the study. Each subject had a lateral cephalometric radiograph taken. The opening angle was determined for two levels of vertical openings at 5 and 10 mm. RESULTS: The opening angle showed a greater variability between subjects ranging from 63.15 to 77.08 for 5 mm angle and from for 61.65 to 75.72 for the 10 mm angle. Differences of facial phenotypes was evident when comparing the individual dissoccluding angle of the low angle horizontal pattern and high angle vertical pattern. CONCLUSIONS: The opening angle is related to craniofacial morphology with higher vertical anterior and shorter anteroposterior faces having a more horizontal path of mandibular movement than shorter vertical anterior and longer anteroposterior subjects who have a more vertical path.

Efficacy and complications of transposition surgery in Duane esotropia syndrome. / Eficacia y complicaciones de las transposiciones musculares en el síndrome de Duane con esotropía.

OBJECTIVE: To study the long-term efficacy and the complications of several transposition techniques for the treatment of Duane syndrome. These included, full vertical rectus transposition, partial vertical rectus transposition, transposition without muscle disinsertion, and superior rectus transposition. MATERIAL AND METHODS: A retrospective study of the patients diagnosed with Duane syndrome, and who underwent any of the different transposition techniques associated or not to the medial rectus recession with a follow-up longer than 12 months. A good result was considered a final deviation≤10 prism dioptres (pd) in primary position, anomalous head posture<10°, and an improvement of the abduction without diplopia. RESULTS: Seven cases were included (6 women, 6 unilateral), and a mean age of 37.71 years. Pre-operative central gaze esotropia of 28±11.68pd decreased to 6±4.62pd at the final visit (P=.009). The anomalous head posture decreased in 6 patients, and the abduction improved one degree from -3.14 to -2.14 (mean). An induced vertical deviation≤8pd was observed in 4 cases. None experienced diplopia at the final visit. The percentage of reoperations was 71.42%. Only 28.57% had a favourable outcome with a single surgery, which increased to 71.42% with further surgeries at the final follow-up. Mean evolution time was 52±31.65 months. CONCLUSIONS: Vertical rectus transpositions in Duane syndrome with moderate or severe clinical signs have only been effective in a small percentage of the cases. Most of them required further surgeries to resolve the complications or the under-corrections.

Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans.

Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together with salicylate, can synergistically reduce the number of aggregates produced after polyQ expression in Caenorhabditis elegans. Moreover, we demonstrate that incubation polyQ-stressed worms with low doses of both chemicals restores neuronal functionality. Both substances are pleitotropic and may activate a range of different targets. However, we demonstrate in this report that the beneficial effect induced by the combination of these drugs depends entirely on the catalytic action of AMPK, since loss of function mutants of aak-2/AMPKα2 do not respond to the treatment. To further investigate the mechanism of the synergetic activity of metformin/salicylate, we used CRISPR to generate mutant alleles of the scaffolding subunit of AMPK, aakb-1/AMPKß1. In addition, we used an RNAi strategy to silence the expression of the second AMPKß subunit in worms, namely aakb-2/AMPKß2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPKß2 is required for the synergistic action of metformin/salicylate to reduce polyQ aggregation. Finally, we showed that autophagy acts downstream of metformin/salicylate-related AMPK activation to promote healthy protein homeostasis in worms.

An optimized histological proceeding to study the female gametophyte development in grapevine.

BACKGROUND: Reproductive success in seed plants depends on a healthy fruit and seed set. Normal seed development in the angiosperms requires the production of functional female gametophytes. This is particularly evident in seedless cultivars where defects during megagametophyte's developmental processes have been observed through cytohistological analysis. Several protocols for embryo sac histological analyses in grapevine are reported in literature, mainly based on resin- or paraffin-embedding approaches. However their description is not always fully exhaustive and sometimes they consist of long and laborious steps. The use of different stains is also documented, some of them, such as hematoxylin, requiring long oxidation periods of the dye-solution before using it (from 2 to 6 months) and/or with a differentiation step not easy to handle. Paraffin-embedding associated to examination with light microscope is the simplest methodology, and with less requirements in terms of expertise and costs, achieving a satisfactory resolution for basic histological observations. Safranin O and fast green FCF is an easy staining combination that has been applied in embryological studies of several plant species. RESULTS: Here we describe in detail a paraffin-embedding method for the examination of grapevine ovules at different phenological stages. The histological sample preparation process takes 1 day and a half. Sections of 5 µm thickness can be obtained and good contrast is achieved with the safranin O and fast green FCF staining combination. The method allows the observation of megasporogenesis and megagametogenesis events in the different phenological stages examined. CONCLUSIONS: The histological sample preparation process proposed here can be used as a routine procedure to obtain embedded ovaries or microscope slides that would require further steps for examination. We suggest the tested staining combination as a simple and viable technique for basic screenings about the presence in grapevine of a normally and fully developed ovule with embryo sac cells, which is therefore potentially functional.

Current trends of strabismus surgery in a tertiary hospital. / Tendencias actuales de la cirugía de estrabismo en un hospital terciario.

OBJECTIVE: To analyze the strabismus surgeries and the outcomes during a year and a half in a tertiary hospital. MATERIAL AND METHODS: A retrospective study of patients who underwent strabismus surgery. The mean age, sex, diagnosis, diplopia, surgery, anesthesia, adjustable sutures, results, reoperations and follow up time from surgery were analyzed. A good outcome was considered when the final horizontal deviation was less than 10prism diopters (pd) and the vertical deviation less than 5pd without diplopia. RESULTS: A total of 153 cases were operated on, mean age: 43.14 ±25.58years (61.4%: women). 74.5% of patients were ≥18years (33.33% ≥60). Diplopia was present in 51% of patients. The most frequent deviation was horizontal: 83.6%. The most frequent diagnosis was cranial nerve palsies: 32% (VI nerve: 12.4%), restrictive strabismus: 7.2%, and the aged related distance esotropia: 6.5%. Adjustable sutures were used in 19.7% of cases and topical anesthesia in 65.4%. Good outcomes was present in 79.2% of cases at the end of follow-up. Reoperations were needed in 25.5%. Follow-up evolution time was 11.87 months ±6.5. The sex female (P=.012) and the oblique superior surgery (P=.017) were associated with bad outcome. CONCLUSION: The adult strabismus surgery was three times more frequent than the children strabismus surgery. The third of the adults that were operated on were ≥60 years. The cranial nerve palsies were the most frequent diagnosis. Adjustable sutures were rarely used. Good outcomes were obtained in most of the patients at the end of follow-up.

In vivo glutamate clearance defects in a mouse model of Lafora disease.

Lafora disease (LD) is a fatal rare neurodegenerative disorder characterized by epilepsy, neurodegeneration and insoluble polyglucosan accumulation in brain and other peripheral tissues. Although in the last two decades we have increased our knowledge on the molecular basis underlying the pathophysiology of LD, only a small part of the research in LD has paid attention to the mechanisms triggering one of the most lethal features of the disease: epilepsy. Recent studies in our laboratory suggested that a dysfunction in the activity of the mouse astrocytic glutamate transporter 1 (GLT-1) could contribute to epilepsy in LD. In this work, we present new in vivo evidence of a GLT-1 dysfunction, contributing to increased levels of extracellular glutamate in the hippocampus of a mouse model of Lafora disease (Epm2b-/-, lacking the E3-ubiquitin ligase malin). According to our results, Epm2b-/- mice showed an increased neuronal activity, as assessed by c-fos expression, in the hippocampus, an area directly correlated to epileptogenesis. This brain area presented lesser ability to remove synaptic glutamate after local GLT-1 blockade with dihydrokainate (DHK), in comparison to Epm2b+/+ animals, suggesting that these animals have a compromised glutamate clearance when a challenging condition was presented. These results correlate with a hippocampal upregulation of the minor isoform of the Glt-1 gene, named Glt-1b, which has been associated with compensatory mechanisms activated in response to neuronal stress. In conclusion, the hippocampus of Epm2b-/- mice presents an in vivo impairment in glutamate uptake which could contribute to epileptogenesis.

Organochlorine pesticides air monitoring near a historical lindane production site in Spain.

The landfilling and dumping of persistent organic pollutants (POPs) and other persistent hazardous chemicals, such as hexachlorocyclohexane (HCH) isomers can have significantly adverse environmental consequences and cause contamination in soil, water, and atmosphere systems. Approximately 115,000 t of HCH wastes were generated by INQUINOSA Factory located in Sabiñánigo (Aragón, Spain) from 1975 to 1992, and were mainly dumped at Bailín and Sardas landfills. Under the frame of the project plan approved by the Government of Aragón, remediation and containment measures were implemented at the derelict production facility and landfill sites. To protect and assess the local environment, the concentrations of HCH isomers, pentachlorobenzene (PeCB) and hexachlorobenzene (HCB) in air were periodically monitored in the Sardas landfills and surroundings by passive sampling devices. The influence of meteorological parameters was evaluated, showing positive correlations between temperature and HCH and HCB concentrations. The highest HCH levels were detected in Sardas landfill and INQUINOSA Factory sites. PeCB values were statistically higher in Sardas landfill than in Sabiñánigo urban core, nevertheless, HCB concentrations were similar in both sampling points. Statistically positive correlations were found among HCH isomers in all sampling points, showing a major common source. The chlorobenzenes also correlated positively with each other. The α-/γ-HCH ratios were calculated (1.46 ±â€¯1.25; mean ±â€¯S.D.), corroborating that concentrations detected were mainly originated from the historical production, storage and waste disposal of technical HCH.

Unilateral accommodation spasm: Case report and literature review. / Espasmo de acomodación unilateral: descripción de un caso y revisión de la literatura.

This case report describes a probable unilateral accommodation spasm in a 10 year-old girl with no significant medical history. The right eye showed decreased visual acuity, 0.2 to 0.6 for far distance and 0.125 for near distance. Refraction without cycloplegia showed myopization up to -6 and cycloplegic refraction of+0.50. The patient had normal ocular motility, orthophoria, normal pupil reflex, normal anterior and posterior segments, normal optical coherence tomography. Neurophysiological tests and brain magnetic resonance imaging were all normal. Treatment with atropine 1% drops for 15 days improved distance visual acuity to 0.8. Accommodation spasm is a rare condition and is usually bilateral. Imaging test are necessary because it may be associated with ocular or head trauma. Treatment consists of cycloplegic drugs (atropine, cyclopentolate); however, there is no defined guideline.

[Lafora disease: a review of the literature]. / Enfermedad de Lafora: revision de la bibliografia.

INTRODUCTION: Lafora disease is autosomal recessive progressive myoclonus epilepsy with late childhood-to teenage-onset caused by loss-of-function mutations in either EPM2A or EPM2B genes encoding laforin or malin, respectively. DEVELOPMENT: The main symptoms of Lafora disease, which worsen progressively, are: myoclonus, occipital seizures, generalized tonic-clonic seizures, cognitive decline, neuropsychiatric syptoms and ataxia with a fatal outcome. Pathologically, Lafora disease is characterized by the presence of polyglucosans deposits (named Lafora bodies), in the brain, liver, muscle and sweat glands. Diagnosis of Lafora disease is made through clinical, electrophysiological, histological and genetic findings. Currently, there is no treatment to cure or prevent the development of the disease. Traditionally, antiepileptic drugs are used for the management of myoclonus and seizures. However, patients become drug-resistant after the initial stage. CONCLUSIONS: Lafora disease is a rare pathology that has serious consequences for patients and their caregivers despite its low prevalence. Therefore, continuing research in order to clarify the underlying mechanisms and hopefully developing new palliative and curative treatments for the disease is necessary.

TITLE: Enfermedad de Lafora: revision de la bibliografia.Introduccion. La enfermedad de Lafora es una forma de epilepsia mioclonica progresiva de herencia autosomica recesiva, de inicio en la infancia tardia o en la adolescencia, y producida por mutaciones de perdida de funcion en los genes EPM2A o EPM2B, los cuales codifican para las proteinas laforina y malina, respectivamente. Desarrollo. Los principales sintomas de la enfermedad, que empeoran progresivamente, son mioclonias, crisis occipitales, crisis tonicoclonicas generalizadas, deterioro cognitivo, sintomas neuropsiquiatricos y ataxia. El curso es progresivo y fatal. Patologicamente, se caracteriza por la presencia de depositos de poliglucosanos (denominados cuerpos de Lafora) en el cerebro, el higado, el musculo y las glandulas sudoriparas. El diagnostico de enfermedad de Lafora se realiza mediante hallazgos clinicos, electrofisiologicos, histologicos y geneticos. En la actualidad no existe un tratamiento que erradique o prevenga su desarrollo. Tradicionalmente, se utilizan farmacos antiepilepticos para el tratamiento de las mioclonias y las convulsiones, aunque aparecen resistencias a estas. Conclusiones. La enfermedad de Lafora es una patologia rara que, pese a su baja prevalencia, supone graves consecuencias para los pacientes y sus cuidadores. Asi pues, resulta necesario continuar la investigacion para clarificar los mecanismos subyacentes y desarrollar nuevos tratamientos paliativos y curativos de la enfermedad.