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Introduction: Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) infection is characterised by a viral phase and a severe pro-inflammatory phase. The inhibition of the JAK/STAT pathway limits the pro-inflammatory state in moderate to severe COVID-19. Methodology: We analysed the data obtained by an observational cohort of patients with SARS-CoV-2 pneumonia treated with ruxolitinib in 22 hospitals of Mexico. The applied dose was determined based on physician’s criteria. The benefit of ruxolitinib was evaluated using the 8-points ordinal scale developed by the NIH in the ACTT1 trial. Duration of hospital stay, changes in pro-inflammatory laboratory values, mortality, and toxicity were also measured. Results: A total of 287 patients were reported at 22 sites in Mexico from March to June 2020; 80.8% received ruxolitinib 5 mg BID and 19.16% received ruxolitinib 10 mg BID plus standard of care. At beginning of treatment, 223 patients were on oxygen support and 59 on invasive ventilation. The percentage of patients on invasive ventilation was 53% in the 10 mg and 13% in the 5 mg cohort. A statistically significant improvement measured as a reduction by 2 points on the 8-point ordinal scale was described (baseline 5.39 ± 0.93, final 3.67± 2.98, p = 0.0001). There were 74 deaths. Serious adverse events were presented in 6.9% of the patients. Conclusions: Ruxolitinib appears to be safe in COVID-19 patients, with clinical benefits observed in terms of decrease in the 8-point ordinal scale and pro-inflammatory state. Further studies must be done to ensure efficacy against mortality.

PURPOSE Several preoperation prognosis models used on the treatment of metastatic bone disease on appendicular skeleton have been devised. The purpose of this study was to compare the performance of different survival prognostic models on patients with metastatic bone disease in long bones in a Chilean population. METHODS This is a multicentric retrospective study. We retrospectively reviewed the medical records of 136 patients who were confirmed with metastatic bone disease of the appendicular skeleton and who were treated surgically from 2016 to 2019. The minimum follow-up time was 12 months. All patients were assessed using four appendicular metastatic bone disease scoring systems. A preoperative predicted survival time for all 136 patients was retrospectively calculated making use of the revised Katagiri, PathFx, Optimodel and IOR score model. RESULTS The PathFx model demonstrated an accuracy at predicting 3 (area under the curve [AUC] = 0.61) and 6-month (AUC = 0.65) survival time after surgical management. IOR score model demonstrated an accuracy at predicting 12-month survival time (AUC = 0.64). The survival rate reached the 44% in a year. The median survival time to death or last follow-up time was 14.9 months (SD ± 15). CONCLUSION PathFx score model demonstrated the highest accuracy at predicting a survival time of 3 and 6 months. IOR score model was the most accurate measure at predicting a survival time of 12-months. To our knowledge, this is the first study reporting a comparative analysis of metastatic bone disease with predicting models in a country located in Latin America. PathFx's and IOR score models are the ones to be used in the Chilean population as the predictive models in metastatic bone disease of the appendicular skeleton.

Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. PROTACs that target oncogene products are avidly being explored for cancer therapies, and several are currently in clinical trials. Drug resistance is a substantial challenge in clinical oncology, and resistance to PROTACs has been reported in several cancer cell models. Here, using proteomic analysis, we found intrinsic and acquired resistance mechanisms to PROTACs in cancer cell lines mediated by greater abundance or production of the drug efflux pump MDR1. PROTAC-resistant cells were resensitized to PROTACs by genetic ablation of ABCB1 (which encodes MDR1) or by coadministration of MDR1 inhibitors. In MDR1-overexpressing colorectal cancer cells, degraders targeting either the kinases MEK1/2 or the oncogenic mutant GTPase KRAS G12C synergized with the dual epidermal growth factor receptor (EGFR/ErbB)/MDR1 inhibitor lapatinib. Moreover, compared with single-agent therapies, combining MEK1/2 degraders with lapatinib improved growth inhibition of MDR1-overexpressing KRAS-mutant colorectal cancer xenografts in mice. Together, our findings suggest that concurrent blockade of MDR1 will likely be required with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

Objective The aim of this study was to retrospectively review the midface and orbital floor fractures treated at our institution with regard to epidemiological aspects, surgical treatment options and postoperative complications and discuss this data with the current literature. Study design One thousand five hundred and ninety-four patients with midface and orbital fractures treated at the Department of Oral, Cranio-Maxillofacial and Facial Plastic Surgery of the Goethe University Hospital in Frankfurt (Germany) between 2007 and 2017 were retrospectively reviewed. The patients were evaluated by age, gender, etiology, fracture pattern, defect size, surgical treatment and complications. Results The average patient age was 46.2 (± 20.8). Most fractures (37.5%) occurred in the age between 16 and 35. Seventy-two percent of patients were male while 28% were female. The most common cause of injury was physical assault (32.0%) followed by falls (30.8%) and traffic accidents (17.0%). The average orbital wall defect size was 297.9 mm2 (± 190.8 mm2). For orbital floor reconstruction polydioxanone sheets (0.15 mm 38.3%, 0.25 mm 36.2%, 0.5 mm 2.8%) were mainly used, followed by titanium meshes (11.5%). Reconstructions with the 0.15 mm polydioxanone sheets showed the least complications (p r = 0.15). Eighteen percent of patients who showed persistent symptoms and post-operative complications: 12.9% suffered from persistent hypoesthesia, 4.4% suffered from post-operative diplopia and 3.9% showed intra-orbital hematoma. Conclusion Results of the clinical outcome in our patients show that 0.15 mm resorbable polydioxanone sheets leads to significantly less post-operative complications for orbital floor defects even for defects beyond the recommended 200 mm2.

Genetic variants in YWHAZ contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we have used zebrafish to investigate the mechanisms by which YWHAZ contributes to neurodevelopmental disorders. We observed that ywhaz expression was pan-neuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum, cells that are described to be reduced in number and size in autistic patients. GCaMP6s albino zebrafish embryos were generated by the National Institute of Genetics (Japan) and obtained from Dr. Matt Parker from the University of Portsmouth, UK. The Tg(aldoca:gap43-Venus) line was obtained from Masahiko Hibi from the Bioscience and Biotechnology Center of Nagoya University, Japan. Tg(olig2:egfp)vu12 brains were obtained from the Center for Developmental Biology, UMR 5547 CNRS, Toulouse, France. Major financial support for this research was received by BC from the Spanish ‘Ministerio de Ciencia, Innovación y Universidades’ (RTI2018-100968-B-100, PID2021-1277760B-I100), the ‘Ministerio de Sanidad, Servicios Sociales e Igualdad/Plan Nacional Sobre Drogas’ (PNSD-2017I050 and PNSD-2020I042), ‘Generalitat de Catalunya/AGAUR’ (2017-SGR-738), ICREA Academia 2021, and the European Union H2020 Program [H2020/2014-2020] under grant agreements n° 667302 (CoCA) and Eat2beNICE (728018). E.A-G was supported by the Ministerio de Economía y Competitividad (Spanish Government) and the EU H2020 program (Eat2beNICE-728018). G.C., E.G. and P.L-A acknowledge financial support from the Spanish Ministerio de Economía y Competitividad (MINECO) through the “Severo Ochoa” program for Centres of Excellence in R&D CEX2019-000910-S), MINECO/FEDER Ramon y Cajal program (RYC-2015-17935); Laserlab-Europe EU-H2020 GA no. 871124, Fundació Privada Cellex, Fundación Mig-Puig and from the Generalitat de Catalunya through the CERCA program. F.A. acknowledges financial support from the Spanish ‘Ministerio de Ciencia, Innovación y Universidades’ (PID2019-107738RB-I00, MICINN/FEDER) and SGR (2017SGR1255).

In COVID-19, the inflammatory cytokine-release syndrome is associated with the progression of the disease. Itolizumab is a monoclonal antibody that recognizes human CD6 expressed in activated T cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of pro-inflammatory cytokines release, including IFN-γ, IL-6 and TNF-α. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access protocol. Itolizumab was able to reduce IL-6 concentrations in all the patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality., Lay abstract In COVID-19 patients, inflammation is associated with the progression of the disease. This inflammation comes from immune system activation in response to SARS-COV-2. Itolizumab is an antibody that recognizes a protein expressed in immune cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of inflammation and immune system activation. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access clinical protocol. Itolizumab was able to reduce inflammation in all patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality.

Background The high-oblique sagittal osteotomy (HOSO) is an alternative to a bilateral sagittal split osteotomy (BSSO). Due to its novelty, there are no long-term studies which have focused on describing the incidence and type of complications encountered in the post-operative follow-up. The aim of this retrospective study is to analyze patients operated on with this surgical technique and the post-operative complications encountered. Patient and methods The electronic medical records of all patients treated with orthognathic surgery at the Department of Oral, Maxillofacial and Facial Plastic Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany, between the years 2009 and 2016 were retrospectively reviewed. Results A total of 116 patients fulfilled the inclusion criteria. The cases operated on with the standard osteosynthesis (X, Y, and straight) showed a complication rate of 36.37% (n = 4/11). The cases operated on with the HOSO-dedicated plates (HOSO-DP) showed, in total, a complication rate of 6.67% (n = 7/105). The most common post-operative complication resulting from both fixation methods was a reduction in mouth opening and TMJ pain for 4.3%. During the first years of performing the surgery (2009–211), a variety of standard plates had material failure causing non-union or pseudarthrosis. No cases of material failure were observed in the cases operated on with the HOSO-DP. The statistical results showed a highly significant dependence of a reduction in OP-time over the years, when the HOSO was performed without additional procedures (R2 > 0.83, P < 0.0015). Conclusion The rate of complications in the HOSO were shown to be comparable to the rate of complications from the BSSO reported in the literature. Moreover, the use of the ramus dedicated plate appears to provide enough stability to the bone segments, making the surgery safer. Clinical relevance The HOSO needs to be considered by surgeons as an alternative to BSSO. Once the use of the HOSO-DP was established, the rate of complications and the operation time reduced considerably.

Background: The feedback given to students plays an important role concerning their efficiency related to learning practical skills. In the present literature, diverse feedback modalities have been investigated. Our hypothesis is that individualized and unsupervised video feedback can produce a similar learning experience as performing practical skills in the setting of oral and maxillofacial surgery as conventional direct expert feedback (control group). Methods: This prospective, randomized, controlled and blinded study compared direct expert feedback (DEF), individualized video feedback (IVF) and unsupervised video feedback (UVF). The participants were fourth-year dental students from University Goethe in Frankfurt. The students were assigned to one of the three feedback methods (n = 20) using simple randomization. All of the participants received an instruction video for an interdental (‘Ernst’) ligature and periphery venous catheterization. Subsequently, the students were video recorded performing the tasks by themselves (pre-test). Following this, every student received feedback using one of the above-mentioned modalities of feedback. The participants then performed the same task again while being video recorded (post-test) to measure the acquired competence. Six weeks later, the students participated in an objective structured clinical examination (OSCE) where their long-term knowledge retention was evaluated. All of the examiners were blinded regarding the students’ instructional approach and their affiliation in terms of learning group. Results: For the interdental ligature, significant performance improvements for each feedback modality between the pre-test and post-test were found (p p = 0.33). All groups showed a satisfying level of knowledge retention from the post-test through to the long-term knowledge retention test. Conclusion: This study showed that IVF and UVF can be considered an alternative or adjunct to conventional methods (i.e. DEF) when learning procedural skills in oral and maxillofacial surgery as no quantitative difference was found between them in the short- and long-term.

Background In South Africa, there are limited data on the burden of diarrhoea at a community level, specifically in older children and adults. This community survey estimated rates of and factors associated with diarrhoea across all ages and determined the proportion of cases presenting to healthcare facilities. Methods Households were enrolled from an existing urban health and demographic surveillance site. A household representative was interviewed to determine associated factors and occurrence of diarrhoea in the household, for all household members, in the past 2 weeks (including symptoms and health seeking behaviour). Diarrhoeal rate of any severity was calculated for 15 years age groups. Factors associated with diarrhoea and health seeking behaviour were investigated using binomial logistic regression. Results Diarrhoeal rate among respondents (2.5 episodes/person-year (95% CI, 1.8–3.5)) was significantly higher than for other household members (1.0 episodes/person-year (95% CI, 0.8–1.4); IRR = 2.4 (95% CI, 1.5–3.7) p p = 0.039). Oral rehydration solution was used in 44.8% of cases. Having a child between 5 and 15 years in the household was associated with diarrhoea (OR = 2.3 (95% CI, 1.3–3.9), p = 0.003) and, while 26.4% of cases sought healthcare, only 4.6% were hospitalised and only 3.4% of cases had a stool specimen collected. While the majority of cases were mild, 13.8% of cases felt they required healthcare but were unable to access it. Conclusion Diarrhoeal rate was high across all age groups in this community; however, older children and adults were less likely to present to healthcare, and are therefore underrepresented through facility-based clinical surveillance. Current diarrhoeal surveillance represents a fraction of the overall cases occurring in the community.

Platelet-rich fibrin is a blood concentrate system used for soft tissue and bone tissue regeneration. In the last decade, platelet rich fibrin (PRF) has been widely used in different indication fields, particularly in oral and maxillofacial surgery. This review investigates the level of scientific evidence of published articles related to the use of PRF for bone and soft tissue regeneration in dentistry and maxillofacial surgery. An electronic literature research using the biomedical search engine “National Library of Medicine” (PubMed-MEDLINE) was performed in May 2017. A total of 392 articles were found, 72 of which were classified for each indication field. When comparing PRF with biomaterials vs biomaterial alone in sinus lift (5 studies; IIa), no statistically significant differences were detected. Socket preservation and ridge augmentation using PRF significantly enhanced new bone formation compared to healing without PRF (7 studies Ib, IIa, IIb). Reepithelialization and bone regeneration was achieved in 96 of 101 patients diagnosed with medication-related osteonecrosis of the jaw (5 studies, III). In periodontology, PRF alone (6 studies; Ib, IIa, IIb) or its combination with biomaterials (6 studies; Ib, IIa, IIb) significantly improved the pocket depth and attachment loss compared to a treatment without PRF. Over 70% of the patients were part of studies with a high level of scientific evidence (randomized and controlled prospective studies). This published evidence (38 articles), with a high scientific level, showed that PRF is a beneficial tool that significantly improves bone and soft tissue regeneration. However, the clinical community requires a standardization of PRF protocols to further examine the benefit of PRF in bone and soft tissue regeneration in reproducible studies, with a higher scientific level of evidence.

Background Recent advances in 3D printing technology have enabled the emergence of new educational and clinical tools for medical professionals. This study provides an exemplary description of the fabrication of 3D-printed individualised patient models and assesses their educational value compared to cadaveric models in oral and maxillofacial surgery. Methods A single-stage, controlled cohort study was conducted within the context of a curricular course. A patient's CT scan was segmented into a stereolithographic model and then printed using a fused filament 3D printer. These individualised patient models were implemented and compared against cadaveric models in a curricular oral surgery hands-on course. Students evaluated both models using a validated questionnaire. Additionally, a cost analysis for both models was carried out. P-values were calculated using the Mann-Whitney U test. Results Thirty-eight fourth-year dental students participated in the study. Overall, significant differences between the two models were found in the student assessment. Whilst the cadaveric models achieved better results in the haptic feedback of the soft tissue, the 3D-printed individualised patient models were regarded significantly more realistic with regard to the anatomical correctness, the degree of freedom of movement and the operative simulation. At 3.46 € (compared to 6.51 €), the 3D-printed patient individualised models were exceptionally cost-efficient. Conclusions 3D-printed patient individualised models presented a realistic alternative to cadaveric models in the undergraduate training of operational skills in oral and maxillofacial surgery. Whilst the 3D-printed individualised patient models received positive feedback from students, some aspects of the model leave room for improvement.

Background: Recent advances in 3D printing technology have enabled the emergence of new educational and clinical tools for medical professionals. This study provides an exemplary description of the fabrication of 3D‐printed individualised patient models and assesses their educational value compared to cadaveric models in oral and maxillofacial surgery. Methods: A single‐stage, controlled cohort study was conducted within the context of a curricular course. A patient's CT scan was segmented into a stereolithographic model and then printed using a fused filament 3D printer. These individualised patient models were implemented and compared against cadaveric models in a curricular oral surgery hands‐on course. Students evaluated both models using a validated questionnaire. Additionally, a cost analysis for both models was carried out. P‐values were calculated using the Mann‐Whitney U test. Results: Thirty‐eight fourth‐year dental students participated in the study. Overall, significant differences between the two models were found in the student assessment. Whilst the cadaveric models achieved better results in the haptic feedback of the soft tissue, the 3D‐printed individualised patient models were regarded significantly more realistic with regard to the anatomical correctness, the degree of freedom of movement and the operative simulation. At 3.46 € (compared to 6.51 €), the 3D‐printed patient individualised models were exceptionally cost‐efficient. Conclusions: 3D‐printed patient individualised models presented a realistic alternative to cadaveric models in the undergraduate training of operational skills in oral and maxillofacial surgery. Whilst the 3D‐printed individualised patient models received positive feedback from students, some aspects of the model leave room for improvement.

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer with few effective, targeted therapies. HGSOC tumors exhibit genomic instability with frequent alterations in the protein kinome; however, only a small fraction of the kinome has been therapeutically targeted in HGSOC. Using multiplexed inhibitor beads and mass spectrometry (MIB-MS), we mapped the kinome landscape of HGSOC tumors from patients and patient-derived xenograft (PDX) models. The data revealed a prevalent signature consisting of established HGSOC-driver kinases, as well as several kinases previously unexplored in HGSOC. Loss-of-function analysis of these kinases in HGSOC cells indicated MRCKA (also known as CDC42BPA) as a putative therapeutic target. Characterization of the effects of MRCKA knockdown in established HGSOC cell lines demonstrated that MRCKA was integral to signaling that regulated the cell cycle checkpoint, focal adhesion and actin remodeling, as well as cell migration, proliferation, and survival. Moreover, inhibition of MRCKA using the small molecule BDP9066 decreased cell proliferation and spheroid formation and induced apoptosis in HGSOC cells, suggesting that MRCKA may be a promising therapeutic target for the treatment of HGSOC.

RNA editing is a relatively unexplored process in which transcribed RNA is modified at specific nucleotides before translation, adding another level of regulation of gene expression. Cephalopods use it extensively to increase the regulatory complexity of their nervous systems, and mammals use it too, but less prominently. Nevertheless, little is known about the specifics of RNA editing in most of the other clades and the relevance of RNA editing from an evolutionary perspective remains unknown. Here we analyze a key element of the editing machinery, the ADAR (adenosine deaminase acting on RNA) gene family, in an animal with a key phylogenetic position at the root of chordates: the cephalochordate amphioxus. We show, that as in cephalopods, ADAR genes in amphioxus are predominantly expressed in the nervous system, we identify a number of RNA editing events in amphioxus, and we provide a newly developed method to identify RNA editing events in highly polymorphic genomes using orthology as a guide. Overall, our work lays the foundations for future comparative analysis of RNA-editing events across the metazoan tree.

[Background]: One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood., [Results]: Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes., [Conclusions]: We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders., Major financial support for this research was received from Spanish “Ministerio de Ciencia, Innovación y Universidades.” Grants BFU2015-68655-P and BFU2017-861152-P to J.G.F., RTI2018-100968-B-I00, 2017-SGR-738, H2020/2014-2020 under grant agreements n°667302, n°643051, and n°728018 to B.C., PGC2018-098229-B-I00 to J.L.F., BES-2016-077374 to E.A.-G., CVI-7290 Junta de Andalucía to A.R.M., SAF2016-80937-R (Ministerio de Economía y Competitividad/FEDER) to G.M., Institutional Grant MDM-2016-0687 (Maria de Maeztu Excellence Unit, Department of Gene Regulation and Morphogenesis at CABD) and BFU2017-83150-P to J.J.C, BFU2017-89780-R and P12-CTS-2257 to A.M.C. and SAF2016-76340-R and María de Maeztu Excellence Unit, Institute of Neurosciences to E.S.. E.N.P. held an FPI pre-doctoral fellowship (Spanish “Ministerio de Ciencia, Innovación y Universidades”). S.M. was first supported by a contract with the “Centro de Investigación Biomédica en Enfermedades Neurodegenerativas,” and later by “Centro de Investigación Biomédica en Red de Enfermedades Raras” (CIBERER). N.F.C. is also under contract by CIBERER.

Ciguatera is a food intoxication caused by the consumption of primarily coral fish; these species exist in large numbers in the seas that surround the Colombian territory. The underreported diagnosis of this clinical entity has been widely highlighted due to multiple factors, such as, among others, ignorance by the primary care practitioner consulted for this condition as well as clinical similarity to secondary gastroenteric symptoms and common food poisonings of bacterial, parasitic or viral etiology. Eventually, it was found that people affected by ciguatoxins had trips to coastal areas hours before the onset of symptoms. Thanks to multiple studies over the years, it has been possible to identify the relation between toxigenic dinoflagellates and seagrasses, as well as its incorporation into the food chain, starting by fish primarily inhabiting reef ecosystems and culminating in the intake of these by humans. Identifying the epidemiological link, its cardinal symptoms and affected systems, such as gastrointestinal, the peripheral nervous system and, fortunately with a low frequency, the cardiovascular system, leads to a purely clinical diagnostic impression without necessitating further complementary studies; in addition, what would also help fight ciguatera poisoning is performing an adequate treatment of the symptoms right from the start, without underestimating or overlooking any associated complications.

Large bone defects have always been a big challenge. The use of bone marrow mononuclear cells (BMCs) combined with an osteoconductive scaffold has been proved a good alternative for the treatment of large bone defects. Another autologous source for tissue engineering is platelet rich fibrin (PRF). PRF is a blood concentrate system obtained through a one-step centrifugation. The generated 3D matrix of the PRF clot serves as a reservoir of growth factors. Those growth factors might support the regenerative response of BMC, and therefore the effect of PRF, centrifuged with either high medium (208 g) or low (60 g) relative centrifugation force (RCF) on BMCs was evaluated

To evaluate the clinical benefits of liquid platelet-rich fibrin (PRF) in patients with temporomandibular joint (TMJ) pain and dysfunction.Forty-eight TMJs in 37 patients with painful internal derangement (ID) (Wilkes' I-V) were included. Patients were injected with 1.5-2cc of PRF within the superior joint space at 2-week intervals. Pain and subjective dysfunction were recorded using a visual analog scale. Statistical analyses were done using the ANOVA test.Thirty-three of 48 TMJs (69%) showed significant reduction in pain at 8 weeks, and at 3, 6, and 12 months (Responders). Fifteen of 48 TMJs (31%) did not improve (Non-responders). The best Responders to liquid PRF injections were ID stages Wilkes' IV (78.5%) and V (100%), compared to Wilkes' I (0%), II (47%), and III (33%). A non-significant, but notable decrease in dysfunction was found.Preliminary findings support that liquid PRF exhibits long-term analgesic effects in most patients with painful TMJ ID.

Background The present study evaluated the cellular tissue reaction of two equine-derived collagen hemostatic sponges (E-CHS), which differed in thickness after pressing, over 30 days in vivo. The inflammatory response during physiological wound healing in sham-operated animals was used as control group. Material and methods First, the E-CHS was pressed by applying constant pressure (6.47 ± 0.85 N) for 2 min using a sterile stainless-steel cylinder until the material was uniformly flattened. Consequently, the original (E-CHS), the pressed (P-E-CHS), as well as the control group (CG; sham operation) were studied independently. The 3 groups were evaluated in vivo after subcutaneous implantation in Wistar rats during 3, 15, and 30 days. Histochemical and immunohistochemical methods provided observations of biomaterial degradation rate, cellular inflammatory response, and vascularization pattern. A derivative of human blood known as platelet-rich fibrin (PRF) was used as an ex vivo model to simulate the initial biomaterial-cell interaction. Segments of E-CHS and P-E-CHS were cultivated for 3 and 6 days with PRF, and the release of pro-inflammatory proteins was measured using ELISA. PRF cultivated alone was used as a control group. Results At day 3, the CG induced a statistically significant higher presence of monocytes/macrophages (CD68+), pro-inflammatory macrophages (M1; CCR7+), and pro-wound healing macrophages (M2; CD206+) compared to E-CHS and P-E-CHS. At the same time point, P-E-CHS induced a statistically significant higher presence of CD68+ cells compared to E-CHS. After 15 days, E-CHS was invaded by cells and vessels and showed a faster disintegration rate compared to P-E-CHS. On the contrary, cells and vessels were located only in the outer region of P-E-CHS and the biomaterial did not lose its structure and accordingly did not undergo disintegration. The experimental groups induced similar inflammatory reaction primarily with positive pro-inflammatory CD68+/CCR7+ macrophages and a low presence of multinucleated giant cells (MNGCs). At this time point, significantly lower CD68+/CCR7+ macrophages and no MNGCs were detected within the CG when compared to the experimental groups (P Conclusion Altering the original presentation of a hemostatic sponge biomaterial by pressing modified the initial biomaterial-cell interaction, delayed the early biomaterial’s degradation rate, and altered the vascularization pattern. A pressed biomaterial seems to induce a higher inflammatory reaction at early time points. However, altering the biomaterial did not modify the polarization pattern of macrophages compared to physiologic wound healing. The ex vivo model using PRF was shown to be an effective model to simulate the initial biomaterial-cell interaction in vivo. Clinical relevance A pressed hemostatic sponge could be applied for guided tissue regeneration and guided bone regeneration. In that sense, within the limitations of this study, the results show that the same biomaterial may have two specific clinical indications.

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes., Kras is often mutated in colorectal cancer but how this oncogenic mutation alters signalling pathways globally is undetermined. Here, the authors analyse how this mutation affects protein interaction networks and signal flow showing an extensive re‐wiring of signalling in response to KRas mutation

Mutation or deletion of Neurofibromin 1 (NF1), an inhibitor of RAS signaling, frequently occurs in epithelial ovarian cancer (EOC), supporting therapies that target downstream RAS effectors, such as the RAF–MEK–ERK pathway. However, no comprehensive studies have been carried out testing the efficacy of MEK inhibition in NF1-deficient EOC. Here, we performed a detailed characterization of MEK inhibition in NF1-deficient EOC cell lines using kinome profiling and RNA sequencing. Our studies showed MEK inhibitors (MEKi) were ineffective at providing durable growth inhibition in NF1-deficient cells due to kinome reprogramming. MEKi-mediated destabilization of FOSL1 resulted in induced expression of receptor tyrosine kinases (RTK) and their downstream RAF and PI3K signaling, thus overcoming MEKi therapy. MEKi synthetic enhancement screens identified BRD2 and BRD4 as integral mediators of the MEKi-induced RTK signatures. Inhibition of bromo and extra terminal (BET) proteins using BET bromodomain inhibitors blocked MEKi-induced RTK reprogramming, indicating that BRD2 and BRD4 represent promising therapeutic targets in combination with MEKi to block resistance due to kinome reprogramming in NF1-deficient EOC. Implications: Our findings suggest MEK inhibitors will likely not be effective as single-agent therapies in NF1-deficient EOC due to kinome reprogramming. Cotargeting BET proteins in combination with MEKis to block reprogramming at the transcriptional level may provide an epigenetic strategy to overcome MEKi resistance in NF1-deficient EOC.

Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus (Branchiostoma lanceolatum) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis-regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that—in vertebrates—over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations., This research was funded primarily by the European Research Council (ERC) under the European Union’s Horizon 2020 and Seventh Framework Program FP7 research and innovation programs (ERC-AdG-LS8-740041 to J.L.G.-S., ERC-StG-LS2-637591 to M.I., a Marie Sklodowska-Curie Grant (658521) to I.M. and a FP7/2007-2013-ERC-268513 to P.W.H.H.), the Spanish Ministerio de Economía y Competitividad (BFU2016-74961-P to J.L.G.-S., RYC-2016-20089 to I.M., BFU2014-55076-P and BFU2017-89201-P to M.I. and BFU2014-55738-REDT to J.L.G.-S, M.I. and J.R.M.-M), the ‘Centro de Excelencia Severo Ochoa 2013-2017’(SEV-2012-0208), the ‘Unidad de Excelencia María de Maetzu 2017-2021’(MDM-2016-0687), the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program FP7 under REA grant agreement number 607142 (DevCom) to J.L.G.-S., and the CNRS and the ANR (ANR16-CE12-0008-01) to H.E. O.B. was supported by an Australian Research Council Discovery Early Career Researcher Award (DECRA; DE140101962).

Argentina has recognized women's right to not be subjected to obstetric violence, the violence exercised by health personnel on the body and reproductive processes of pregnant women, as expressed through dehumanizing treatment, medicalization abuse, and the conversion of natural processes of reproduction into pathological ones. Argentina's legislative decision to frame this abuse and mistreatment of women under the rubric of gender-based violence permits the identification of failures in both the healthcare system and women's participation in society. This article examines how applying the Violence Against Women framework to address issues of abuse and mistreatment of women during maternal health care provides a beneficial approach for analyzing such embedded structural problems from public health, human rights, and ethics perspectives. The framework of Violence Against Women seeks to transform existing harmful cultural practices, not only through the protection of women's reproductive autonomy, but also through the empowerment of women's participation in society.

Resumen Introducción. La etapa posprandial se asocia con el incremento de marcadores relacionados con el riesgo cardiovascular, cuya intensidad depende del estado metabólico. Objetivo. Determinar el impacto de la ingestión de una comida rica en grasas saturadas sobre el perfil metabólico e inflamatorio y su relación con la obesidad abdominal. Materiales y métodos. Se hizo un ensayo clínico en 42 individuos (21 con obesidad abdominal). Se midieron, en sangre, la glucosa, la insulina, el perfil lipídico, la proteína C reactiva, los lipopolisacáridos y la interleucina 6, en ayunas y después de la ingestión. Resultados. Además de la obesidad, se registró la presencia de resistencia a la insulina y de niveles elevados de triacilglicéridos y proteína C reactiva en ayunas. Asimismo, se detectaron niveles posprandiales más elevados de glucosa, insulina y triacilglicéridos. La interleucina 6 disminuyó en el grupo de personas sin obesidad y los lipopolisacáridos aumentaron en ambos grupos. Conclusión. La ingestión de una comida rica en grasas saturadas produjo un mayor impacto en las variables glucémicas en el grupo con obesidad y, aunque afectó de forma similar los lípidos en ambos grupos, el incremento de triacilglicéridos fue mayor en presencia de una concentración basal elevada y promovió el aumento de lipopolisacáridos. El estado inflamatorio basal y posprandial afectó en mayor medida al grupo con obesidad. El momento posprandial reflejó el estado más frecuente de los individuos en un día normal y permitió evidenciar la capacidad de respuesta metabólica frente a la ingestión de alimentos, así como los estados tempranos de riesgo metabólico. Abstract Introduction: The postprandial stage is associated with the increase of markers related to cardiovascular risk, and its intensity depends on the metabolic state. Objective: To determine the impact of a high-fat meal intake on the metabolic and inflammatory profile, and its relationship to abdominal obesity. Materials and methods: This clinical trial included 42 individuals (21 with abdominal obesity). We measured glucose, insulin, lipid profile, reactive C protein, lipopolysaccharides, and interleukin 6 in fasting blood, and four hours after eating. Results: Besides obesity, we found insulin resistance and higher levels of fasting triacylglycerides and C-reactive protein. There were higher postprandial responses to glucose, insulin, and triacylglycerides. Interleukin 6 decreased in the non-obese group, and lipopolysaccharides increased in both groups. Conclusions: A saturated high-fat food intake produced a greater impact on the glycemic variables in the group with obesity, while it affected the lipids in both groups. However, the increase of triacylglycerides was higher in the presence of a high basal concentration, and it promoted the increase of lipopolysaccharides. The basal and postprandial inflammatory state affected the group with obesity more. The postprandial moment reflected the most frequent state of the individuals on a normal day and evidenced the capacity of the metabolic response to food intake, as well as early metabolic risk states.

International audience; Toll-like receptors (TLRs) are important for raising innate immune responses in both invertebrates and vertebrates. Amphioxus belongs to an ancient chordate lineage which shares key features with vertebrates. The genomic research on TLR genes in Branchiostoma floridae and Branchiostoma belcheri reveals the expansion of TLRs in amphioxus. However, the repertoire of TLRs in Branchiostoma lanceolatum has not been studied and the functionality of amphioxus TLRs has not been reported. We have identified from transcriptomic data 30 new putative TLRs in B. lanceolatum and all of them are transcribed in adult amphioxus. Phylogenetic analysis showed that the repertoire of TLRs consists of both non-vertebrate and vertebrate-like TLRs. It also indicated a lineage-specific expansion in orthologous clusters of the vertebrate TLR11 family. We did not detect any representatives of the vertebrate TLR1, TLR3, TLR4, TLR5 and TLR7 families. To gain insight into these TLRs, we studied in depth a particular TLR highly similar to a B. belcheri gene annotated as bbtTLR1. The phylogenetic analysis of this novel BlTLR showed that it clusters with the vertebrate TLR11 family and it might be more related to TLR13 subfamily according to similar domain architecture. Transient and stable expression in HEK293 cells showed that the BlTLR localizes on the plasma membrane, but it did not respond to the most common mammalian TLR ligands. However, when the ectodomain of BlTLR is fused to the TIR domain of human TLR2, the chimeric protein could indeed induce NF-κB transactivation in response to the viral ligand Poly I:C, also indicating that in amphioxus, specific accessory proteins are needed for downstream activation. Based on the phylogenetic, subcellular localization and functional analysis, we propose that the novel BlTLR might be classified as an antiviral receptor sharing at least partly the functions performed by vertebrate TLR22. TLR22 is thought to be viral teleost-specific TLR but here we demonstrate that teleosts and amphioxus TLR22-like probably shared a common ancestor. Additional functional studies with other lancelet TLR genes will enrich our understanding of the immune response in amphioxus and will provide a unique perspective on the evolution of the immune system.

This study has retrospectively analyzed the efficacy of single-agent prednisone, usually given after failure of other therapies, in 30 patients with myelofibrosis (MF) and severe anemia. Initial dose was 0.5-1 mg/kg daily, with tapering to the minimum effective dose in responders. Twelve patients (40%) achieved anemia response according to the revised International Working Group for Myelofibrosis Research and Treatment criteria, after a median time of 1.1 months on treatment. Median response duration was 12.3 months. Patients with constitutional symptoms or > 2% circulating blasts had a trend for a lower response rate. A platelet increase > 50 × 10(9)/L was observed in three out of 11 patients with baseline counts < 100 × 10(9)/L. Median survival from prednisone start was significantly longer in anemia responders (5.0 years, 95% CI = 3.5-6.5, vs 1.5 years, 95% CI = 0.2-2.8; p = 0.002). Prednisone can improve the anemia and thrombocytopenia in selected MF patients after failure to standard therapies.

The two-dimensional (2D) derivative of graphite termed graphene has widespread applications in various frontiers areas of nanoscience and nanotechnologies. Graphene in its oxidized form named as graphene oxide (GO) has a mixed structure equipped with various oxygen containing functional groups (epoxy, hydroxyl, carboxylic and carbonyl etc.) provides attachment sites to various biological molecules including protein, deoxyribonucleic acid (DNA), ribonucleic acid (RNA) etc. The attached biological molecules with the help of functional groups make it a promising candidate in research field of biotechnological and biomedical applications. The ease of processability and functionalization in aqueous solution due to available functional groups, amphiphilicity, better surface enhanced Raman scattering (SERS), fluorescence and its quenching ability better than graphene make GO a promising candidate for various biological applications. The amphipathetic nature and high surface area of the GO not only prepare it as a biocompatible, soft and flexible intra/inter cellular carrier but also provides long-term biocompatibility with very low cytotoxicity. Inspite of this, still we lack a very recent review for advanced biological applications of graphene oxide. This review deals the bio application of GO and the recent advancement as a biosensors, antibacterial agent, early detection of cancer, cancer cell imaging/mapping, targeted drug delivery and gene therapy etc.

Although obesity is related to socioeconomic level, studies are inconclusive.To determine obesity risk according to socioeconomic vulnerability among Chilean children (1st grade) in 2009 and 2013 and assess its change during that period, by sex and geographical area.Cross-sectional study (N = 175,462 in 2009) and (N = 189,055 in 2013) which included: weight, height, rural / urban, gender and vulnerability obtained from JUNAEB's survey. BMI Z, % obesity and 3 categories of vulnerability (very vulnerable, moderate, non-vulnerable) were determined. For the descriptive analyses, we used t tests and for predictor variables (2 categories of vulnerability) and outcome (obesity) by sex and area, we used %2. Logistic regression models determined OR to develop obesity by.% obesity was 19.6% and 24.1% in 2009 and 2013, higher in boys. In urban and rural areas respectively, OR to develop obesity were: 0.85 (0.82-0.88) and 0.70 (0.64-0.75) in the most vulnerable students and 0.94 (0.91-0.97) and 0.81 (0.74-0.88) in those with moderate vulnerability in 2009 and 0.96 (0.93-0.98) and 0.89 (0.82-0.96) in the most vulnerable students and 0.99 (0.96-1.02) and 0.94 (0.86-1.02) in students with moderate vulnerability in 2013. The highest increase in obesity was observed among the most vulnerable group from rural areas (16, 6 to 24.3%). vulnerability.The non-vulnerable group had the highest % obesity. Although the most vulnerable students in rural areas had the lowest obesity risk in both years, the highest increase in obesity during the period, occurred in that group.

We argue for a morphofunctional approach to emotion modeling that can also aid the design of adaptive embodied systems. By morphofunctionality we target the online change in both structure and function of a system, and relate it to the notion of physiology and emotion in animals. Besides the biological intuition that emotions serve the function of preparing the body, we investigate the control requirements that any morphofunctional autonomous system must face. We argue that changes in morphology modify the dynamics of the system, thus forming a variable structure system (VSS). We introduce some of the techniques of control theory to deal with VSSs and derive a twofold hypothesis: first, the loose coupling between two control systems, in charge of action and action readiness, respectively; second, the formation of patterned metacontrol. Emotional phenomena can be seen as emergent from this control setup.

Numerous initiatives have contributed to health data transparency in the Americas, but further coordinated effort is needed to ensure the reliability of research for health, argue Trudo Lemmens and Carlos Herrera Vacaflor

Studies using massive, passively collected data from communication technologies have revealed many ubiquitous aspects of social networks, helping us understand and model social media, information diffusion and organizational dynamics. More recently, these data have come tagged with geographical information, enabling studies of human mobility patterns and the science of cities. We combine these two pursuits and uncover reproducible mobility patterns among social contacts. First, we introduce measures of mobility similarity and predictability and measure them for populations of users in three large urban areas. We find individuals' visitations patterns are far more similar to and predictable by social contacts than strangers and that these measures are positively correlated with tie strength. Unsupervised clustering of hourly variations in mobility similarity identifies three categories of social ties and suggests geography is an important feature to contextualize social relationships. We find that the composition of a user's ego network in terms of the type of contacts they keep is correlated with mobility behaviour. Finally, we extend a popular mobility model to include movement choices based on social contacts and compare its ability to reproduce empirical measurements with two additional models of mobility., National Science Foundation (U.S.). Graduate Research Fellowship Program, King Abdulaziz City of Science and Technology (Saudia Arabia)

Bone marrow infiltration (BMI), categorized as an extra-nodal site, affects stage and is associated with poor prognosis in newly diagnosed lymphoma patients. We have evaluated the accuracy of PET/CT and bone marrow biopsy (BMB) to assess BMI in 372 lymphoma patients [140 Hodgkin Lymphoma (HL) and 232 High Grade B-cell non-Hodgkin Lymphoma (HG B-NHL), among them 155 Diffuse Large B-Cell Lymphoma (DLCL)]. For HL cases, and taking into account PET/CT, sensitivity, negative predictive value (NPV) and accuracy were 96.7, 99.3, and 99.3% while those of BMB were 32.3, 83.8, and 85%, respectively. For HG B-NHL and considering PET/CT, sensitivity, NPV, and accuracy were 52.7, 81.7, and 84.1%, while those of BMB were 77.6, 90.2, and 90.7%, respectively. In the HG B-NHL group, 25 patients would have been under-staged without BMB. These results lead us to recommend PET/CT and the avoidance of BMB to assess BMI in HL. In the case of HG B-NHL, bone marrow status should be assessed firstly by means of PET/CT; only in either focal or diffuse PET/CT with low borderline SUV max values or in negative cases, should BMB be carried out afterwards. In the HG B-NHL setting and at the present moment, both techniques are complementary. Am. J. Hematol. 90:686-690, 2015. (c) 2015 Wiley Periodicals, Inc.

A Framework Convention on Global Health (FCGH) seeks to have a profound, effective, and broad impact: bringing access to health rights to the largest global community possible. One of the main issues the FCGH will address is how to make the right to health justiciable. An FCGH must articulate functional remedies for violations of the right to health by state or non-state actors. This paper analyzes one approach to ensuring the recognition of the rights defended in a future FCGH. Following the incremental development approach inspired by the architecture of other successful framework convention protocols, we propose the inclusion of access to health justice guidelines in an FCGH. This proposal is based on the amparo remedy, a figure already extant in the legislation of several Latin American countries; since its incorporation, these countries have witnessed a significant increase in litigation defending health rights. This is only one of many important advantages to broadly adopting guidelines based on the amparo remedy. The proposed guidelines would serve as a basic agreement on broad principles on access to health justice.

TP53 is a tumor suppressor gene located on chromosome 17p13.1. This gene is essential for the control of cell cycle and has been found altered in about 50% of all tumor types.The presence of aneuploidy of chromosome 17 and TP53 gene deletion at 17p13.1 locus was determined in primary solid tumors using the dual-color FISH (fluorescence in situ hybridization).Thirty-eight samples consisted of several types of primary solid tumors. All samples were mechanically and enzymatically disaggregated with 0.2% collagenase prior to obtaining interphase nuclei. The dual-color FISH was performed using direct fluorescent labeling probes for the chromosome 17 centromere (green signal) and for the TP53 gene locus-specific (orange signal).Characteristic aneuploidy on chromosome 17 was found in 63% (24/38) of the samples. Monosomy occurred most frequently (75%, 18/24), followed by trisomy (17%, 4/24); nullisomy and tetrasomy were less frequent. TP53 gene deletion was found in 89.5% (34/38) of cases. Only four tumors were normal for copy number of chromosome 17 and TP53 gene. The histopathologic study showed that most of the samples were malignant tumors.Aneuploidy of chromosome 17 and deletion at 17p13.1 locus of TP53 gene were genetic alterations found to be very frequent in solid tumors. The dual-color FISH was able to detect both numerical and structural chromosomal abnormalities in interphase nuclei.

IN 1 7 6 7 K I N G C A R L O S I II OF S PA I N called for vecinos (citizens) of the colonial province of Sonora (now in northwestern Mexico) to wage war against a loose confederation of Seri warrior clans that inhabited the coastal fringes of the province.' Jose Antonio Vild6sola was among those who answered the king's summons, and the company of mounted troops he led into battle took the fight into the enemy's homeland. When the odds favored the invaders, the Seris retreated to hideaways, thus forcing the Spaniards to hunt them down in mountain ravines and rugged terrain that neutralized the Spaniards' effective use of cavalry.2 By the end of 1769 the war seemed

Preemptive therapy reduces the risk of cytomegalovirus disease in high-risk kidney transplant patients. The advantage of this strategy is that only a fraction of patients receive antiviral drugs for a limited time, which decreases costs and toxicity but requires frequent monitoring and may not prevent complications of asymptomatic cytomegalovirus replication.Long-term graft-function and patient survival of high-risk kidney transplant patients who received preemptive therapy guided by pp65 antigenemia was compared to those whose assay remained negative throughout the first post-transplant year.Between August 1997 and March 2005, 24 of 272 patients were CMV D+/R-. Thirteen of the 24 (54.2%) developed a positive CMV assay during follow-up; the time between transplant and first positive antigenemia was 66.7 +/- 58.3 days (range 29-251 days). Four patients developed symptoms associated with CMV, one of whom succumbed from complications of CMV neumonitis. Overall, no significant differences were observed in SCr, eGFR, delta SCr, and delta eGFR during a 60-month followup between patients who developed CMV infection or disease and those who remained pp65 antigenemia-negative throughout the first 12 post-transplant months. Additionally, no deaths or graft loss occurred during the long-term follow up of this cohort.Our results suggest that in this high risk group of kidney transplant recipients, treating CMV replication using a preemptive strategy during the first posttransplant year is associated with a low rate of CMV complications and probably interferes with the alleged long-term negative indirect effects of CMV on kidney function and survival.

Hypochondroplasia is an inherited chondrodystrophy that is characterized by disproportionate short stature. A recent linkage study by LeMerrer et al. suggested that hypochondroplasia and achondroplasia are allelic conditions. Three groups have now mapped the achondroplasia locus to the telomeric region of chromosome 4. Recently, two mutations in fibroblast growth factor receptor 3 (FGFR3) at nucleotide 1138, in the transmembrane domain, were identified in 169 of 170 unrelated individuals with achondroplasia. Here, we report the results of a linkage study in 4 multigenerational families with hypochondroplasia and mutational analysis of nucleotide 1138 in one individual from each of these families, two nonfamilial hypochondroplasia individuals and sequencing of the transmembrane domain of the FGFR3 in three affected unrelated individuals. 13 refs., 1 tab.