Assessment of focused ultrasound stimulation to induce peripheral nerve activity and potential damage in vivo.

Introduction: Peripheral neuroprostheses are aimed to restore loss of sensory and motor functions by interfacing axons in the peripheral nerves. Most common interfaces in neuroprostheses are electrodes that establish electrical connection with peripheral axons. However, some challenges arise related to long-term functionality, durability, and body response. Recently, focused ultrasound stimulation (FUS) has emerged as a non-invasive approach to modulate the nervous system. However, it is controversial whether FUS can induce axon depolarization. Methods: We have assessed FUS applied in vivo to the rat peripheral nerve, with two objectives: first, to test whether FUS activates peripheral nerves under different stimulation conditions, and second, to evaluate if FUS inflicts damage to the nerve. FUS was delivered with three ultrasound transducers (Sonic Concept H115, H107, and H102) covering the largest set of parameters examined for FUS of peripheral nerves so far. Results: We did not obtain reliable evoked action potentials in either nerves or muscles, under any FUS condition applied, neither over the skin nor directly to the nerve exposed. Additional experiments ex vivo and in vivo on mice, confirmed this conclusion. When FUS stimulation was applied directly to the exposed sciatic nerve, neuromuscular function decreased significantly, and recovered one week later, except for FUS at 0.25 MHz. Histologically, degenerating nerve fibers were observed, with a tendency to be higher with the lower FUS frequency. Discussion: Past reports on the ability of ultrasound to stimulate the peripheral nerve are controversial. After testing a wide range of FUS conditions, we conclude that it is not a reliable and safe method for stimulating the peripheral nerve. Special consideration should be taken, especially when low-frequency FUS is applied, as it may lead to nerve damage.

A comprehensive coding and microRNA transcriptome of vertebral bone in postlarvae and juveniles of Senegalese sole (Solea senegalensis).

Understanding vertebral bone development is essential to prevent skeletal malformations in farmed fish related to genetic and environmental factors. This is an important issue in Solea senegalensis, with special impact of spinal anomalies in postlarval and juvenile stages. Vertebral bone transcriptomics in farmed fish mainly comes from coding genes, and barely on miRNA expression. Here, we used RNA-seq of spinal samples to obtain the first comprehensive coding and miRNA transcriptomic repertoire for postlarval and juvenile vertebral bone, covering different vertebral phenotypes and egg-incubation temperatures related to skeleton health in S. senegalensis. Coding genes, miRNA and pathways regulating bone development and growth were identified. Differential transcriptomic profiles and suggestive mRNA-miRNA interactions were found between postlarvae and juveniles. Bone-related genes and functions were associated with the extracellular matrix, development and regulatory processes, calcium binding, retinol and lipid metabolism or response to stimulus, including those revealed by the miRNA targets related to signaling, cellular and metabolic processes, growth, cell proliferation and biological adhesion. Pathway enrichment associated with fish skeleton were identified when comparing postlarvae and juveniles: growth and bone development functions in postlarvae, while actin cytoskeleton, focal adhesion and proteasome related to bone remodeling in juveniles. The transcriptome data disclosed candidate coding and miRNA gene markers related to bone cell processes, references for functional studies of the anosteocytic bone of S. senegalensis. This study establishes a broad transcriptomic foundation to study healthy and anomalous spines under early thermal conditions across life-stages in S. senegalensis, and for comparative analysis of skeleton homeostasis and pathology in fish and vertebrates.

ADAMTS13 recovery in acute thrombotic thrombocytopenic purpura after caplacizumab therapy.

ABSTRACT: Caplacizumab prevents the interaction between von Willebrand factor and platelets and is used to treat immune thrombotic thrombocytopenic purpura (iTTP). Its administration has been associated with a delay in ADAMTS13 activity restoration after plasma exchange (PEX) suspension. We analyzed the outcomes of 113 iTTP episodes, 75 of which were treated with caplacizumab, in 108 patients from the Spanish Registry of Thrombotic Thrombocytopenic Purpura. Caplacizumab shortened the time to platelet count normalization and reduced PEX requirement, exacerbations, and relapses. There was no difference in the time to achieve ADAMTS13 activity ≥20% after PEX end between caplacizumab-treated and nontreated episodes (median [interquartile range], 14.5 [7.7-27.2] vs 13.0 [8.0-29.0] days, P = .653). However, considering the 36 episodes in which caplacizumab was started ≤3 days after iTTP diagnosis, the time for ADAMTS13 restoration from PEX end was higher than in those episodes in which caplacizumab was started >3 days after iTTP diagnosis (20.0 [12.0-43.0] vs 11.0 [3.5-20.0] days, P = .003) or than in non-caplacizumab-treated episodes (P = .033). This finding could be related to a significantly shorter duration of PEX in early caplacizumab-treated episodes than in late caplacizumab-treated episodes (5.5 [4.0-9.0] vs 15.0 [11.0-21.5] days, P < .001) or non-caplacizumab-treated episodes (11.0 [6.0-26.0] days, P < .001). There were no differences in time to ADAMTS-13 restoration from PEX start (28.0 [17.2-47.5], 27.0 [19.0-37.5] and 29.5 [15.2-45.0] days in early caplacizumab-treated, late caplacizumab-treated and non-caplacizumab-treated episodes). Early administered caplacizumab does not prevent the requirement for immunosuppression but has beneficial effects by shortening PEX requirement without major safety concerns.

The prohibitin-binding compound fluorizoline induces the pro-inflammatory cytokines interleukin-8 and interleukin-6 through the activation of JNK and p38 MAP kinases.

Fluorizoline is a prohibitin (PHB)-binding compound that induces apoptosis in several cancer cell lines as well as in primary cells from hematologic malignancies. In this study, we show that fluorizoline treatment triggers the activation of the stress-activated kinases c-Jun N-terminal kinase (JNK) and p38 prior to caspase activation in human cell lines. However, the blockage of p38 and JNK activity with chemical inhibitors or siRNA-mediated downregulation of MAPK14 (p38) does not prevent fluorizoline-induced apoptosis, suggesting that the activation of these kinases plays an alternative role in the cell response to fluorizoline treatment. Here, we describe that fluorizoline treatment leads to the secretion of pro-inflammatory cytokines interleukin-8 (IL-8) and interleukin-6 (IL-6). Importantly, we demonstrate that the activation of the stress-activated kinases JNK and p38 mediates the secretion of both IL-8 and IL-6. This study shows novel insights into the pro-inflammatory role exhibited by a compound that binds to PHB, thus supporting the potential of PHBs as anti-inflammatory proteins.

The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI.

Fluorizoline is a synthetic molecule that induces apoptosis, by selectively targeting prohibitins (PHBs), through induction of the BH3-only protein NOXA. This induction is transcriptionally regulated by the integrated stress response (ISR)-related transcription factors ATF3 and ATF4. Here, we evaluate the role of the four eIF2α kinases, to decipher which is responsible for the mechanism of ISR activation triggered by fluorizoline in HeLa and HAP1 cells. First, we demonstrated the involvement of the eIF2α kinases using ISR inhibitor (ISRIB) and by simultaneous downregulation of all four eIF2α kinases, as both approaches were able to increase cell resistance to fluorizoline-induced apoptosis. Furthermore, we confirmed that fluorizoline treatment results in endoplasmic reticulum (ER) stress, as evidenced by PERK activation. Despite PERK activation, this kinase was not directly involved in the ISR activation by fluorizoline. In this regard, we found that the eIF2α kinases are capable of compensating for each other's loss of function. Importantly, we demonstrated that the mitochondrial-stress-related eIF2α kinase HRI mediates ISR activation after fluorizoline treatment.

Analisis del impacto de la pandemia por covid-19 en recursos de rehabilitacion psicosocial / Analysis of the impact of the covid-19 pandemic on psychosocial rehabilitation resources

Como se ha podido comprobar, la irrupción de una pandemia como la generada por el COVID-19, así como, las consiguientes restricciones, afectan en mayor medida a los grupos más vulnerables como, entre otros, son las personas con Trastorno Mental Grave (TMG). Los objetivos fundamentales de este estudio pasan por analizar y comparar con la población general a la que pertenecen, el porcentaje de infecciones, hospitalizaciones y fallecimientos relacionados con el COVID-19 en el caso de recursos destinados a la atención a personas con TMG, como son los gestionados por la Línea de Rehabilitación Psicosocial (LRHP) de la organización Hermanas Hospitalarias. A su vez, también se analizan y comparan con periodos previos otras variables que han podido verse afectadas en esta crisis sanitaria tales como ingresos psiquiátricos, abandono de los recursos, intentos autolíticos o suicidios consumados. A diferencia de lo encontrado en la literatura previa, los resultados indican que no existen diferencias estadísticamente significativas entre los porcentajes de infecciones, hospitalizaciones o fallecimientos por COVID-19 entre la LRHP y los registrados en la población general. En cuanto a variables relacionadas con la Salud Mental, se encuentran diferencias estadísticamente significativas entre el año 2020 y el anterior, en el porcentaje de ingresos psiquiátricos y abandono en los recursos ambulatorios, siendo estos menores en 2020. Sin embargo, en el caso de los recursos residenciales, se registra un porcentaje significativamente mayor en el porcentaje de abandonos en 2020. Dichos resultados han de ser tomados con cautela, puesto que existen múltiples limitaciones que pudieran estar afectando a los mismos y pueden ser interpretados teniendo en cuenta los cambios contextuales relacionados con la pandemia respecto al funcionamiento de los recursos hospitalarios o a las restricciones a nivel de movilidad (AU)

As has been seen, the outbreak of a pandemic such as that generated by COVID-19, as well as the consequent restrictions, affect to a greater extent the most vulnerable groups such as, among others, people with Severe Mental Disorder (SMD). The fundamental objectives of this study are to analyze and compare with the general population to which they belong, the percentage of infections, hospitalizations and deaths related to COVID-19 in the case of resources destined to the care of people with TMG, such as those managed by the Linea de Rehabilitacion Psicosocial (LRHP) of the Sisters Hospitallers organization. At the same time, other variables that have been affected in this health crisis such as psychiatric admissions, abandonment of resources, autolytic attempts or completed suicides are also analyzed and compared with previous periods. Unlike what was found in the previous literature, the results indicate that there are no statistically significant differences between the percentages of infections, hospitalizations or deaths from COVID-19 between the LRHP and those registered in the general population. As for variables related to Mental Health, there are statistically significant differences between 2020 and the previous year, in the percentage of psychiatric admissions and abandonment in outpatient resources, these being lower in 2020. However, in the case of residential resources, there is a significantly higher percentage of abandonments in 2020. These results must be taken with caution, since there are multiple limitations that could be affecting them and can be interpreted taking into account the contextual changes related to the pandemic regarding the functioning of hospital resources or restrictions at the level of mobility (AU)

Applicability of the Thrombin Generation Test to Evaluate the Hemostatic Status of Hemophilia A Patients in Daily Clinical Practice.

Hemophilia A (HA) is a rare bleeding disorder caused by factor VIII (FVIII) deficiency due to various genetic mutations in the F8 gene. The disease severity inversely correlates with the plasma levels of functional FVIII. The treatment of HA patients is based on FVIII replacement therapy, either following a prophylactic or on-demand regime, depending on the severity of the disease at diagnosis and the patient's clinical manifestations. The hemorrhagic manifestations are widely variable amongst HA patients, who may require monitoring and treatment re-adjustment to minimize bleeding symptoms. Notably, laboratory monitoring of the FVIII activity is difficult due to a lack of sensitivity to various FVIII-related molecules, including non-factor replacement therapies. Hence, patient management is determined mainly based on clinical manifestations and patient-clinician history. Our goal was to validate the ST Genesia® automated thrombin generation analyzer to quantify the relative hemostatic status in HA patients. We recruited a cohort of HA patients from the Principality of Asturias (Spain), following treatment and at a stable non-bleeding phase. The entire cohort (57 patients) had been comprehensively studied at diagnosis, including FVIII and VWF activity assays and F8 genetic screening, and then clinically monitored until the Thrombin Generation Test (TGT) was performed. All patients were recruited prior to treatment administration, at the maximum time-window following the previous dose. Interestingly, the severe/moderate patients had a similar TGT compared to the mild patients, reflecting the non-bleeding phase of our patient cohort, regardless of the initial diagnosis (i.e., the severity of the disease), treatment regime, and FVIII activity measured at the time of the TGT. Thus, TGT parameters, especially the peak height (Peak), may reflect the actual hemostatic status of a patient more accurately compared to FVIII activity assays, which may be compromised by non-factor replacement therapies. Furthermore, our data supports the utilization of combined TGT variables, together with the severity of patient symptoms, along with the F8 mutation type to augment the prognostic capacity of TGT. The results from this observational study suggest that TGT parameters measured with ST Genesia® may represent a suitable tool to monitor the hemostatic status of patients requiring a closer follow-up and a tailored therapeutic adjustment, including other hemophilia subtypes or bleeding disorders.

The prohibitin-binding compound fluorizoline inhibits mitophagy in cancer cells.

Fluorizoline is a prohibitin-binding compound that triggers apoptosis in several cell lines from murine and human origin, as well as in primary cells from hematologic malignancies by inducing the integrated stress response and ER stress. Recently, it was described that PHB (Prohibitin) 1 and 2 are crucial mitophagy receptors involved in mediating the autophagic degradation of mitochondria. We measured mitophagy in HeLa cells expressing Parkin and in A549, a lung cancer cell line that can undergo mitophagy in a Parkin-independent manner, and we demonstrated that both fluorizoline and rocaglamide A, another PHB-binding molecule, inhibit CCCP- and OA-induced mitophagy. Moreover, we demonstrated that PHBs are mediating Parkin-dependent mitophagy. In conclusion, besides being a potent pro-apoptotic compound, we present fluorizoline as a promising new mitophagy modulator that could be used as anticancer agent.

Activation of the Integrated Stress Response and ER Stress Protect from Fluorizoline-Induced Apoptosis in HEK293T and U2OS Cell Lines.

The prohibitin (PHB)-binding compound fluorizoline as well as PHB-downregulation activate the integrated stress response (ISR) in HEK293T and U2OS human cell lines. This activation is denoted by phosphorylation of eIF2α and increases in ATF4, ATF3, and CHOP protein levels. The blockage of the activation of the ISR by overexpression of GRP78, as well as an increase in IRE1 activity, indicate the presence of ER stress after fluorizoline treatment. The inhibition of the ER stress response in HEK293T and U2OS led to increased sensitivity to fluorizoline-induced apoptosis, indicating a pro-survival role of this pathway after fluorizoline treatment in these cell lines. Fluorizoline induced an increase in calcium concentration in the cytosol and the mitochondria. Finally, two different calcium chelators reduced fluorizoline-induced apoptosis in U2OS cells. Thus, we have found that fluorizoline causes increased ER stress and activation of the integrated stress response, which in HEK293T and U2OS cells are protective against fluorizoline-induced apoptosis.

Fluorizoline-induced apoptosis requires prohibitins in nematodes and human cells.

We previously showed that fluorizoline, a fluorinated thiazoline compound, binds to both subunits of the mitochondrial prohibitin (PHB) complex, PHB1 and PHB2, being the expression of these proteins required for fluorizoline-induced apoptosis in mouse embryonic fibroblasts. To investigate the conservation of this apoptotic mechanism, we studied the effect of PHB downregulation on fluorizoline activity on two human cell lines, HEK293T and U2OS. Then, we asked whether PHBs mediate the effect of fluorizoline in a multicellular organism. Interestingly, reduced levels of PHBs in the human cells impaired the induction of apoptosis by fluorizoline. We observed that fluorizoline has a detrimental dose-dependent effect on the development and survival of the nematode model Caenorhabditis elegans. Besides, such effects of fluorizoline treatment in living nematodes were absent in PHB mutants. Finally, we further explored the apoptotic pathway triggered by fluorizoline in human cell lines. We found that the BH3-only proteins NOXA, BIM and PUMA participate in fluorizoline-induced apoptosis and that the induction of NOXA and PUMA is dependent on PHB expression.

NOXA upregulation by the prohibitin-binding compound fluorizoline is transcriptionally regulated by integrated stress response-induced ATF3 and ATF4.

Fluorizoline is a new synthetic molecule that induces p53-independent apoptosis, in several tumor cell lines and in primary leukemia cells, by selectively targeting prohibitins (PHBs). In this study, we describe how fluorizoline induces BCL-2 homology 3-only protein NOXA, without modulating the protein levels of anti-apoptotic B-cell lymphoma-2 (BCL-2) family members prior to caspase activation, as well as how it synergizes with the BCL-2 and BCL-XL inhibitor ABT-737 to induce apoptosis. Interestingly, fluorizolinetreatment triggers the activation of the integrated stress response (ISR) in HeLa and HAP1 cells, with increased eukaryotic translation initiation factor 2α phosphorylation, and induction of ATF3, ATF4, and CHOP. Moreover, PHB downregulation induces similar ISR activation and apoptosis as with fluorizoline treatment. In addition, we studied the essential role of the pro-apoptotic protein NOXA in fluorizoline-induced apoptosis and we describe its mechanism of induction in HeLa and HAP1 cells. Moreover, we identified ATF3 and ATF4 as the transcription factors that bind to NOXA promoter upon fluorizoline treatment. Furthermore, using ATF3 and ATF4 CRISPR HeLa and HAP1 cells, we confirmed that both factors mediate the induction of NOXA and apoptosis by fluorizoline. In conclusion, fluorizoline treatment triggers the activation of the ISR that results in the induction of ATF3 and ATF4, important regulators of NOXA transcription in fluorizoline-induced apoptosis.

Skeletal Anomalies in Senegalese Sole (Solea senegalensis, Kaup) Fed with Different Commercial Enriched Artemia: A Study in Postlarvae and Juveniles.

The high incidence of skeletal anomalies in Senegalese sole (Solea senegalensis) still constitutes a bottleneck constraining its production. There are diverse commercially available products for the enrichment of live preys, but few reports of their influence on skeletogenesis in Senegalese sole. This study evaluated the presence of vertebral anomalies in postlarvae and juvenile Senegalese sole fed with Artemia spp. metanauplii enriched with four commercial products (EA, EB, EC, and ED) in a fish farm. The most frequent alterations consisted of deformations of the neural/haemal arches and spines and fusions and deformations of hypurals, epural, or parhypural. The correspondence analysis ordered fish from each age in separated semiaxis, indicating the presence of different anomaly patterns for the two sampled stages. The results showed only very light changes in the frequency of vertebral abnormalities among tested enrichment products, i.e., individuals from EC and EA lots displayed less vertebral body anomalies and/or vertebral column deviations at 31 and 105 days after hatching, respectively. The existence of a large shared malformation pattern in all the experimental groups leads to impute to the rearing conditions as the main driving factor of the onset of such group of anomalies, probably masking some dietary effect.

The BCL-2 family members NOXA and BIM mediate fluorizoline-induced apoptosis in multiple myeloma cells.

Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In this study, we have assessed the pro-apoptotic effect of fluorizoline in 3 different multiple myeloma cell lines and 12 primary samples obtained from treatment-naïve multiple myeloma patients. Fluorizoline induced apoptosis in both multiple myeloma cell lines and primary samples at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline. Moreover, fluorizoline increased the mRNA and protein levels of the pro-apoptotic BCL-2 family member NOXA both in cell lines and primary samples analyzed. Finally, NOXA-depletion by CRISPR/Cas9 in cells that do not express BIM conferred resistance to fluorizoline-induced apoptosis in multiple myeloma cells. These results suggest that targeting prohibitins could be a new therapeutic strategy for myeloma multiple.

Brote de hepatitis A asociado a un manipulador de alimentos en Bizkaia, 2017 / Hepatitis A outbreak associated with a food handler in Bizkaia, 2017

INTRODUCCIÓN: La notificación de un caso de hepatitis A en un manipulador de alimentos de una pastelería y de 5 casos en trabajadores de una empresa tras consumir productos de la misma dio lugar a una investigación de brote. MÉTODOS: Se definieron como casos las personas con infección por el virus de la hepatitis A (VHA) confirmada por el laboratorio, con comienzo de síntomas en junio y que, durante el periodo de incubación, trabajaron con el manipulador y/o tuvieron contacto estrecho con él y/o consumieron productos de la pastelería. Se realizó una encuesta epidemiológica y se tomaron muestras de sangre para analizar la presencia de anticuerpos anti-hepatitis A. Se realizó la caracterización molecular por PCR, secuenciación de la región VP1/2A y análisis filogenético con el método de máxima verosimilitud, bootstrap 1000 (software MEGA 7.0). RESULTADOS: Se identificaron 14 casos primarios: 11 relacionados con el consumo de productos de la pastelería, 2 compañeros de trabajo del manipulador y un contacto familiar. Los 12 virus secuenciados eran genotipo IA, coincidiendo con una de las cepas (RIVM-HAV16-090) responsable de los brotes producidos en ese momento en Europa y que afectaban fundamentalmente a hombres que tienen sexo con hombres. CONCLUSIONES: Se debería reforzar la vacunación frente al VHA de grupos de riesgo para prevenir brotes futuros. La implementación del uso del tipado molecular en casos de hepatitis A podría mejorar la investigación de brotes, que se puede esperar que aumenten en el futuro debido al descenso de inmunidad en la población

INTRODUCTION: The reporting of one case of hepatitis A in a food handler at a bakery and five cases in employees of a company after consuming products from the same bakery prompted an outbreak investigation. METHODS: Outbreak cases were defined as individuals with laboratory-confirmed hepatitis A (HAV) infection, with symptoms which started in June and who, during the incubation period, worked with the food handler and/or had close contact with him and/or consumed products from the bakery. Epidemiologic questionnaires were performed and blood samples were obtained to be tested for the presence of anti-hepatitis A antibodies. Molecular characterisation was carried out by PCR, sequencing of the VP1/2A region and phylogenetic analysis with the maximum likelihood estimation method, bootstrap 1000 (MEGA 7.0 software). RESULTS: A total of 14 primary hepatitis A cases were identified: eleven cases related to the consumption of products from the bakery, two cases among co-workers of the food handler, and one case was a household contact. All 12 sequenced viruses were genotype IA, matching one of the strains (RIVM-HAV16-090) responsible for the outbreaks occurring at that time in Europe, mostly affecting men who have sex with men. CONCLUSIONS: HAV vaccination of at-risk groups should be reinforced in order to prevent future outbreaks. Increasing the use of molecular typing in hepatitis A cases could improve the investigation of outbreaks, which can be expected to increase in the future because of decreasing immunity in the population

Hepatitis A outbreak associated with a food handler in Bizkaia, 2017. / Brote de hepatitis A asociado a un manipulador de alimentos en Bizkaia, 2017.

INTRODUCTION: The reporting of one case of hepatitis A in a food handler at a bakery and five cases in employees of a company after consuming products from the same bakery prompted an outbreak investigation. METHODS: Outbreak cases were defined as individuals with laboratory-confirmed hepatitis A (HAV) infection, with symptoms which started in June and who, during the incubation period, worked with the food handler and/or had close contact with him and/or consumed products from the bakery. Epidemiologic questionnaires were performed and blood samples were obtained to be tested for the presence of anti-hepatitis A antibodies. Molecular characterisation was carried out by PCR, sequencing of the VP1/2A region and phylogenetic analysis with the maximum likelihood estimation method, bootstrap 1000 (MEGA 7.0 software). RESULTS: A total of 14 primary hepatitis A cases were identified: eleven cases related to the consumption of products from the bakery, two cases among co-workers of the food handler, and one case was a household contact. All 12 sequenced viruses were genotype IA, matching one of the strains (RIVM-HAV16-090) responsible for the outbreaks occurring at that time in Europe, mostly affecting men who have sex with men. CONCLUSIONS: HAV vaccination of at-risk groups should be reinforced in order to prevent future outbreaks. Increasing the use of molecular typing in hepatitis A cases could improve the investigation of outbreaks, which can be expected to increase in the future because of decreasing immunity in the population.

Skeletal Anomalies in Senegalese Sole ( Solea senegalensis), an Anosteocytic Boned Flatfish Species.

Skeletal anomalies affect animal welfare and cause important economic problems in aquaculture. Despite the high frequency of skeletal problems in reared Solea senegalensis, there is lack of information regarding the histological features of normal and deformed vertebrae in this flatfish. The aim of this study was to describe the histopathological and radiographical appearance of vertebral body anomalies. Sixty-seven juvenile fish were radiographically examined 104 or 105 days after hatching. Through radiographic images, vertebral segments were selected and processed for histopathological examination from 7 normal and 7 affected fish. Alterations in bone shape and vertebral fusion were the most significant anomalies in the vertebral bodies. These alterations occurred most frequently between the last 3 abdominal vertebrae and the first 10 caudal centra. Radiographically, deformed vertebrae showed flattening of the endplates and narrowing of the intervertebral spaces. The radiographic findings concurred with the histological lesions where affected vertebrae exhibited irregular endplates and changes in trabecular bone. Radiolucent cartilaginous tissue was evident in the endplates of the deformed vertebra and, in some cases, the cartilaginous material extended from the growth zone into the intervertebral space. These changes were likely the primary alterations that led to vertebral fusion. Fused vertebrae were often reshaped and showed a reorganization of the trabeculae. The formation of metaplastic cartilage is frequent in a variety of anomalies affecting teleost species.

Giant choledochal cyst presenting during third trimester of pregnancy.

Biliary cystic disease is a rare entity. Twenty-five per cent of cases are diagnosed during adulthood and only a few reports have described this condition during pregnancy, where it represents a therapeutic challenge for both obstetricians and surgeons with regard to the risks it entails for the patient and the fetus.Definitive management is surgical resection, as cysts may progress to malignancy if untreated. During pregnancy, resection is generally deferred to after delivery, especially in the context of suspected cholangitis.A 19-year-old young woman with no previous prenatal control, presented to the emergency department on her 32nd week of gestation with abdominal pain and jaundice. A giant Todani I biliary cyst was observed on imaging along with dilation of the proximal biliary tree suggesting acute cholangitis. Fetal compromise prompted immediate delivery after which percutaneous biliary drainage was performed. Following recovery, the cyst was surgically resected.

Polymorphisms in genes implicated in base excision repair (BER) pathway are associated with susceptibility to Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic bone metabolic disorder. Currently, PDB is the second most frequent bone disorder. PDB is a focal disorder affecting the skeleton segmentally but the cause of which is unknown. It has been hypothesised that somatic mutations could be responsible for the mosaicism described in PDB patients. Therefore, our hypothesis is that defective response to DNA damage may lead to somatic mutations favouring an increased risk of PDB. So that we have analysed polymorphisms in DNA repair genes involved in the BER, NER and DSBR pathways in order to evaluate the role of these variants in modulating PDB risk. We found statistically significant differences in genotypic and allelic distribution for polymorphisms in genes implicated in the BER pathway. Our results showed that carrying the allele T of XRCC1 rs1799782 polymorphism and the allele G of APEX rs1130409 polymorphism increased the risk of developing PDB. These polymorphisms could cause a lower DNA repair efficiency and this might lead to local somatic mutations favouring bone metabolic alterations characteristic of PDB. This is the first report showing an association between polymorphism in genes implicated in the BER pathway with PDB.

The prohibitin-binding compound fluorizoline induces apoptosis in chronic lymphocytic leukemia cells through the upregulation of NOXA and synergizes with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax.

Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In the study herein, the pro-apoptotic effect of fluorizoline was assessed in 34 primary samples from patients with chronic lymphocytic leukemia. Fluorizoline induced apoptosis in chronic lymphocytic leukemia cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespective of patients' clinical or genetic features, whereas normal T lymphocytes were less sensitive. Fluorizoline increased the protein levels of the pro-apoptotic B-cell lymphoma 2 family member NOXA in chronic lymphocytic leukemia cells. Furthermore, fluorizoline synergized with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax to induce apoptosis. These results suggest that targeting prohibitins could be a new therapeutic strategy for chronic lymphocytic leukemia.