HEMATOPOIETIC STEM CELL TRANSPLANTATION AND CROHN'S DISEASE: POSITION PAPER FROM THE TRANSPLANTATION COMMITTEE OF THE BRAZILIAN GROUP FOR THE STUDY OF INFLAMMATORY BOWEL DISEASES (GEDIIB).

Crohn's disease (CD) is a relapse-remitting inflammatory bowel disease that can affect any part of the digestive system. This heterogeneous disease has multiple factors that contribute to an abnormal immune response to intestinal microorganisms. Treatment is based on the use of anti-inflammatories, corticosteroids, immunosuppressants and biologic biologic agents either alone or in combination. Surgical treatment is usual and, ten years after diagnosis, more than 80% of patients report having undergone surgical procedures related to the disease. Unfortunately, none of the treatments described offer a cure, and many cases become refractory or without therapeutic options. In this scenario, hematopoietic stem cell transplantation has been suggested because clinical remission was obtained in patients who had CD associated with malignant hematological diseases and an alternative since the first reports in 2010. In this report, the Transplantation Committee of the Brazilian Group for the Study of Inflammatory Bowel Diseases reviews the history and results of the procedure in patients with CD, detailing and discussing the various relevant points that permeate hematopoietic stem cell transplantation and cell therapy in this disease.

Transplante de células tronco hematopoiéticas e doença de Crohn: posição do Comitê de Transplantes do Grupo Brasileiro para estudo das doenças inflamatórias do intestino (GEDIIB) / Hematopoietic stem cell transplantation and crohn's disease: position paper from the transplantation committee of the brazilian group for the study of inflammatory bowel diseases (gediib)

ABSTRACT Crohn's disease (CD) is a relapse-remitting inflammatory bowel disease that can affect any part of the digestive system. This heterogeneous disease has multiple factors that contribute to an abnormal immune response to intestinal microorganisms. Treatment is based on the use of anti-inflammatories, corticosteroids, immunosuppressants and biologic biologic agents either alone or in combination. Surgical treatment is usual and, ten years after diagnosis, more than 80% of patients report having undergone surgical procedures related to the disease. Unfortunately, none of the treatments described offer a cure, and many cases become refractory or without therapeutic options. In this scenario, hematopoietic stem cell transplantation has been suggested because clinical remission was obtained in patients who had CD associated with malignant hematological diseases and an alternative since the first reports in 2010. In this report, the Transplantation Committee of the Brazilian Group for the Study of Inflammatory Bowel Diseases reviews the history and results of the procedure in patients with CD, detailing and discussing the various relevant points that permeate hematopoietic stem cell transplantation and cell therapy in this disease.

RESUMO A doença de Crohn (DC) é uma doença inflamatória intestinal (DII) recidivante recorrente que pode afetar qualquer parte do sistema digestivo. É doença heterogênea e possui múltiplos fatores que contribuem para uma resposta imune anormal aos microrganismos intestinais. O tratamento baseia-se no uso de anti-inflamatórios, corticosteroides e imunossupressores e imunobiológicos que são utilizados isoladamente ou em combinação. O tratamento cirúrgico é frequente e 10 anos após o diagnóstico, mais de 50% dos pacientes relatam terem sido submetidos a procedimentos cirúrgicos relacionados à doença. Infelizmente, nenhum dos tratamentos descritos oferece cura, e inúmeros casos tornam-se refratários ou sem opções terapêuticas. Nesse cenário, o transplante de células-tronco hematopoéticas (TCTH) em decorrência da remissão clínica de pacientes que apresentavam DC associada a doenças hematológicas malignas, passou a ser alternativa desde os primeiros resultados em 2010. Neste relato, a Comissão de Transplantes do Grupo Brasileiro de Estudo das Doenças Inflamatórias Intestinais revisa a história e os resultados do procedimento em pacientes com DC, detalhando e discutindo os diversos pontos relevantes que permeiam o TCTH e a terapia celular no tratamento da moléstia.

Magnetohydrodynamic Simulations of Self-Consistent Rotating Neutron Stars with Mixed Poloidal and Toroidal Magnetic Fields.

We perform the first magnetohydrodynamic simulations in full general relativity of self-consistent rotating neutron stars (NSs) with ultrastrong mixed poloidal and toroidal magnetic fields. The initial uniformly rotating NS models are computed assuming perfect conductivity, stationarity, and axisymmetry. Although the specific geometry of the mixed field configuration can delay or accelerate the development of various instabilities known from analytic perturbative studies, all our models finally succumb to them. Differential rotation is developed spontaneously in the cores of our magnetars which, after sufficient time, is converted back to uniform rotation. The rapidly rotating magnetars show a significant amount of ejecta, which can be responsible for transient kilonova signatures. However, no highly collimated, helical magnetic fields or incipient jets, which are necessary for γ-ray bursts, arise at the poles of these magnetars by the time our simulations are terminated.

Multimessenger Binary Mergers Containing Neutron Stars: Gravitational Waves, Jets, and γ-Ray Bursts.

Neutron stars (NSs) are extraordinary not only because they are the densest form of matter in the visible Universe but also because they can generate magnetic fields ten orders of magnitude larger than those currently constructed on earth. The combination of extreme gravity with the enormous electromagnetic (EM) fields gives rise to spectacular phenomena like those observed on August 2017 with the merger of a binary neutron star system, an event that generated a gravitational wave (GW) signal, a short γ -ray burst (sGRB), and a kilonova. This event serves as the highlight so far of the era of multimessenger astronomy. In this review, we present the current state of our theoretical understanding of compact binary mergers containing NSs as gleaned from the latest general relativistic magnetohydrodynamic simulations. Such mergers can lead to events like the one on August 2017, GW170817, and its EM counterparts, GRB 170817 and AT 2017gfo. In addition to exploring the GW emission from binary black hole-neutron star and neutron star-neutron star mergers, we also focus on their counterpart EM signals. In particular, we are interested in identifying the conditions under which a relativistic jet can be launched following these mergers. Such a jet is an essential feature of most sGRB models and provides the main conduit of energy from the central object to the outer radiation regions. Jet properties, including their lifetimes and Poynting luminosities, the effects of the initial magnetic field geometries and spins of the coalescing NSs, as well as their governing equation of state, are discussed. Lastly, we present our current understanding of how the Blandford-Znajek mechanism arises from merger remnants as the trigger for launching jets, if, when and how a horizon is necessary for this mechanism, and the possibility that it can turn on in magnetized neutron ergostars, which contain ergoregions, but no horizons.

Gravitational waves from disks around spinning black holes: Simulations in full general relativity.

We present fully general-relativistic numerical evolutions of self-gravitating tori around spinning black holes with dimensionless spin a/M = 0.7 parallel or antiparallel to the disk angular momentum. The initial disks are unstable to the hydrodynamic Papaloizou-Pringle instability which causes them to grow persistent orbiting matter clumps. The effect of black hole spin on the growth and saturation of the instability is assessed. We find that the instability behaves similarly to prior simulations with nonspinning black holes, with a shift in frequency due to spin-induced changes in disk orbital period. Copious gravitational waves are generated by these systems, and we analyze their detectability by current and future gravitational wave observatories for a large range of masses. We find that systems of 10 M ⊙-relevant for black hole-neutron star mergers-are detectable by Cosmic Explorer out to ~300 Mpc, while DECIGO (LISA) will be able to detect systems of 1000 M ⊙ (105 M ⊙)-relevant for disks forming in collapsing supermassive stars-out to cosmological redshift of z ~ 5 (z ~ 1). Computing the accretion rate of these systems we find that these systems may also be promising sources of coincident electromagnetic signals.

A novel algorithm for high compression rates focalized on electrical power quality signals.

This research proposes a high-performance algorithm for the compression rate of electrical power quality signals, using wavelet transformation. To manage the massive amount of data the telecommunications networks are constantly acquiring it is necessary to study techniques for data compression, which will save bandwidth and reduce costs extensively by avoiding having massive data storage facilities. First biorthogonal wavelet level six transform is applied, however after compression, the reconstructed signal will have a different amplitude and it will be shifted when compared to the original one. Then, normalization is used (for amplitude correction between the original signal and reconstructed one) by multiplying the reconstructed signal by the result of the division between the original signal maximum magnitude and the reconstructed signal maximum magnitude. Thirdly, the ripple in the reconstructed signal is eliminated by applying a moving average filter. Finally, the shifting is corrected by finding the difference between the maximum points in a cycle of the original signal and the reconstructed one. After the compression algorithm was performed the best rates are 99.803% for compression rate, RTE 99.9479%, NMSE 0.000434, and Cross-Correlation 0.999925. Finally, this works presents two new performance criteria, compression time and recovery time, both of them in a real scenario will determinate how fast the algorithm can perform.

A review of hematopoietic stem cell transplantation for autoimmune diseases: multiple sclerosis, systemic sclerosis and Crohn's disease. Position paper of the Brazilian Society of Bone Marrow Transplantation

ABSTRACT Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.

A review of hematopoietic stem cell transplantation for autoimmune diseases: multiple sclerosis, systemic sclerosis and Crohn's disease. Position paper of the Brazilian Society of Bone Marrow Transplantation.

Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.

Medical, ethical, and legal aspects of hematopoietic stem cell transplantation for Crohn's disease in Brazil.

Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract. The etiology of CD is unknown; however, genetic, epigenetic, environmental, and lifestyle factors could play an essential role in the onset and establishment of the disease. CD results from immune dysregulation due to loss of the healthy symbiotic relationship between host and intestinal flora and or its antigens. It affects both sexes equally with a male to female ratio of 1.0, and its onset can occur at any age, but the diagnosis is most commonly observed in the range of 20 to 40 years of age. CD diminishes quality of life, interferes with social activities, traumatizes due to the stigma of incontinence, fistulae, strictures, and colostomies, and in severe cases, affects survival when compared to the general population. Symptoms fluctuate between periods of remission and activity in which complications such as fistulas, strictures, and the need for bowel resection, surgery, and colostomy implantation make up the most severe aspects of the disease. CD can be progressive and the complications recurrent despite treatment with anti-inflammatory drugs, corticosteroids, immunosuppressants, and biological agents. However, over time many patients become refractory without treatment alternatives, and in this scenario, hematopoietic stem cell transplantation (HSCT) has emerged as a potential treatment option. The rationale for the use of HSCT for CD is anchored in animal studies and human clinical trials where HSCT could reset a patient's immune system by eliminating disease-causing effector cells and upon immune recovery increase regulatory and suppressive immune cells. Autologous HSCT using a non-myeloablative regimen of cyclophosphamide and anti-thymocyte globulin without CD34+ selection has been to date the most common transplant conditioning regimen adopted. In this review we will address the current situation regarding CD treatment with HSCT and emphasize the medical, ethical, and legal aspects that permeate the procedure in Brazil.

Great Impostors: Extremely Compact, Merging Binary Neutron Stars in the Mass Gap Posing as Binary Black Holes.

Can one distinguish a binary black hole undergoing a merger from a binary neutron star if the individual compact companions have masses that fall inside the so-called mass gap of 3-5 M_{⊙}? For neutron stars, achieving such masses typically requires extreme compactness and in this work we present initial data and evolutions of binary neutron stars initially in quasiequilibrium circular orbits having a compactness C=0.336. These are the most compact, nonvacuum, quasiequilibrium binary objects that have been constructed and evolved to date, including boson stars. The compactness achieved is only slightly smaller than the maximum possible imposed by causality, C_{max}=0.355, which requires the sound speed to be less than the speed of light. By comparing the emitted gravitational waveforms from the late inspiral to merger and postmerger phases between such a binary neutron star vs a binary black hole of the same total mass we identify concrete measurements that serve to distinguish them. With that level of compactness, the binary neutron stars exhibit no tidal disruption up until merger, whereupon a prompt collapse is initiated even before a common core forms. Within the accuracy of our simulations the black hole remnants from both binaries exhibit ringdown radiation that is not distinguishable from a perturbed Kerr spacetime. However, their inspiral leads to phase differences of the order of ∼5 rad over an ∼81 km separation (1.7 orbits) while typical neutron stars exhibit phase differences of ≥20 rad. Although a difference of ∼5 rad can be measured by current gravitational wave laser interferometers (e.g., aLIGO/Virgo), uncertainties in the individual masses and spins will likely prevent distinguishing such compact, massive neutron stars from black holes.

Magnetohydrodynamic simulations of binary neutron star mergers in general relativity: Effects of magnetic field orientation on jet launching.

Binary neutron star mergers can be sources of gravitational waves coincident with electromagnetic counterpart emission across the spectrum. To solidify their role as multimessenger sources, we present fully 3D, general relativistic, magnetohydrodynamic simulations of highly spinning binary neutrons stars initially on quasicircular orbits that merge and undergo delayed collapse to a black hole. The binaries consist of two identical stars modeled as Γ = 2 polytropes with spin χ NS = 0.36 aligned along the direction of the total orbital angular momentum L. Each star is initially threaded by a dynamical unimportant interior dipole magnetic field. The field is extended into the exterior where a nearly force-free magnetosphere resembles that of a pulsar. The magnetic dipole moment µ is either aligned or perpendicular to L and has the same initial magnitude for each orientation. For comparison, we also impose symmetry across the orbital plane in one case where µ in both stars is aligned along L. We find that the lifetime of the transient hypermassive neutron star remnant, the jet launching time, and the ejecta (which can give rise to a detectable kilonova) are very sensitive to the magnetic field orientation. By contrast, the physical properties of the black hole + disk remnant, such as the mass and spin of the black hole, the accretion rate, and the electromagnetic (Poynting) luminosity, are roughly independent of the initial magnetic field orientation. In addition, we find imposing symmetry across the orbital plane does not play a significant role in the final outcome of the mergers. Our results suggest that, as in the black hole-neutron star merger scenario, an incipient jet emerges only when the seed magnetic field has a sufficiently large-scale poloidal component aligned to the initial orbital angular momentum. The lifetime [Δt ≳ 140(M NS/1.625 M ⊙) ms] and Poynting luminosities [L EM ≃ 1052 erg/s] of the jet, when it forms, are consistent with typical short gamma-ray bursts, as well as with the Blandford-Znajek mechanism for launching jets.

Black hole-neutron star coalescence: Effects of the neutron star spin on jet launching and dynamical ejecta mass.

Black hole-neutron star (BHNS) mergers are thought to be sources of gravitational waves (GWs) with coincident electromagnetic (EM) counterparts. To further probe whether these systems are viable progenitors of short gamma-ray bursts (SGRBs) and kilonovas, and how one may use (the lack of) EM counterparts associated with LIGO/Virgo candidate BHNS GW events to sharpen parameter estimation, we study the impact of neutron star spin in BHNS mergers. Using dynamical spacetime magnetohydrodynamic simulations of BHNSs initially on a quasicircular orbit, we survey configurations that differ in the BH spin (a BH/M BH = 0 and 0.75), the NS spin (a NS/M NS = -0.17, 0, 0.23, and 0.33), and the binary mass ratio (q = M BH:M NS = 3:1 and 5:1). The general trend we find is that increasing the NS prograde spin increases both the rest mass of the accretion disk onto the remnant black hole, and the rest mass of dynamically ejected matter. By a time Δt ~ 3500-5500M ~ 88-138(M NS/1.4 M ⊙) ms after the peak gravitational-wave amplitude, a magnetically driven jet is launched only for q = 3:1 regardless of the initial NS spin. The lifetime of the jets [Δt ~ 0.5-0.8(M NS/1.4 M ⊙) s] and their outgoing Poynting luminosity [L Poyn ~ 1051.5±0.5 erg/s] are consistent with typical SGRBs' luminosities and expectations from the Blandford-Znajek mechanism. By the time we terminate our simulations, we do not observe either an outflow or a large-scale magnetic-field collimation for the other systems we consider. The mass range of dynamically ejected matter is 10-4.5-10-2(M NS/1.4 M ⊙) M ⊙, which can power kilonovas with peak bolometric luminosities L knova ~ 1040-1041.4 erg/s with rise times ≲6.5 h and potentially detectable by the LSST.

Dynamically Stable Ergostars Exist: General Relativistic Models and Simulations.

We construct the first dynamically stable ergostars (equilibrium neutron stars that contain an ergoregion) for a compressible, causal equation of state. We demonstrate their stability by evolving both strict and perturbed equilibrium configurations in full general relativity for over a hundred dynamical timescales (≳30 rotational periods) and observing their stationary behavior. This stability is in contrast to earlier models which prove radially unstable to collapse. Our solutions are highly differentially rotating hypermassive neutron stars with a corresponding spherical compaction of C=0.3. Such ergostars can provide new insights into the geometry of spacetimes around highly compact, rotating objects and on the equation of state at supranuclear densities. Ergostars may form as remnants of extreme binary neutron star mergers and possibly provide another mechanism for powering short gamma-ray bursts.

Hematopoietic stem cell transplantation for Crohn's disease: Gaps, doubts and perspectives.

Crohn's disease (CD) is an inflammatory bowel disease that can affect any site of the digestive system. It occurs due to an immunological imbalance and is responsible for intestinal mucosal lesions and complications such as fistulas and stenoses. Treatment aims to stabilize the disease, reducing the symptoms and healing intestinal lesions. Surgical procedures are common in patients. Cell therapy was initially used to treat this disease in patients who also suffered from lymphoma and leukemia and were considered to be good candidates for autologous and allogeneic transplantation. After transplantation, an improvement was also observed in their CD. In 2003, the procedure began to be used to treat the disease itself, and several case series and randomized studies have been published since then; this approach currently comprises a new option in the treatment of CD. However, considerable doubt along with significant gaps in our knowledge continue to exist in relation to cell therapy for CD. Cell therapy is currently restricted to the autologous modality of hematopoietic stem cell transplantation and, experimentally, to mesenchymal stromal cells to directly treat lesions of the anal mucosa. This article presents the supporting claims for transplantation as well as aspects related to the mobilization regime, conditioning and perspectives of cell therapy.

Disks around merging binary black holes: From GW150914 to supermassive black holes.

We perform magnetohydrodynamic simulations in full general relativity of disk accretion onto nonspinning black hole binaries with mass ratio q = 29/36. We survey different disk models which differ in their scale height, total size and magnetic field to quantify the robustness of previous simulations on the initial disk model. Scaling our simulations to LIGO GW150914 we find that such systems could explain possible gravitational wave and electromagnetic counterparts such as the Fermi GBM hard x-ray signal reported 0.4 s after GW150915 ended. Scaling our simulations to supermassive binary black holes, we find that observable flow properties such as accretion rate periodicities, the emergence of jets throughout inspiral, merger and postmerger, disk temperatures, thermal frequencies, and the time delay between merger and the boost in jet outflows that we reported in earlier studies display only modest dependence on the initial disk model we consider here.

GW170817, general relativistic magnetohydrodynamic simulations, and the neutron star maximum mass.

Recent numerical simulations in general relativistic magnetohydrodynamics (GRMHD) provide useful constraints for the interpretation of the GW170817 discovery. Combining the observed data with these simulations leads to a bound on the maximum mass of a cold, spherical neutron star (the TOV limit): Mmaxsph≲2.74/ß , where ß is the ratio of the maximum mass of a uniformly rotating neutron star (the supramassive limit) over the maximum mass of a nonrotating star. Causality arguments allow ß to be as high as 1.27, while most realistic candidate equations of state predict ß to be closer to 1.2, yielding Mmaxsph in the range 2.16-2.28M⊙. A minimal set of assumptions based on these simulations distinguishes this analysis from previous ones, but leads a to similar estimate. There are caveats, however, and they are enumerated and discussed. The caveats can be removed by further simulations and analysis to firm up the basic argument.

The relationship between of ACE I/D and the MTHFR C677T polymorphisms in the pathophysiology of type 2 diabetes mellitus in a population of Brazilian obese patients.

Objectives This study aimed to evaluate the frequencies of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms in obese patients with and without type 2 diabetes mellitus (T2DM). Subjects and methods These polymorphisms were analyzed by polymerase chain reaction in 125 patients with obesity, 47 (T2DM) and 78 (Control Group). Results No significant difference was found on comparing the T2DM and Control Groups in respect to the genotypic frequencies of the polymorphisms - (II: 13.3% vs. 12.0%; ID: 37.8% vs. 37.3; DD: 48.9% vs. 50.7%; CC: 36.2% vs. 39.0%; CT: 46.8% vs. 49.3%; TT: 17.0% vs. 11.7%), and alleles (I: 32.2% vs. 30.7%; D: 67.8% vs. 69.3%; C: 59.6% vs. 63.6%; T: 40.4% vs. 36.4%) and their synergisms in the pathophysiology of T2DM. On analyzing the T2DM Group, there were no significant differences in the presence of complications. In this population of Brazilian obese patients, no correlation was found between the ACE and MTHFR polymorphisms in the development of T2DM. Conclusion Analyzing only the group with diabetes, there was also no relationship between these polymorphisms and comorbidities.

The relationship between of ACE I/D and the MTHFR C677T polymorphisms in the pathophysiology of type 2 diabetes mellitus in a population of Brazilian obese patients

ABSTRACT Objectives This study aimed to evaluate the frequencies of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms in obese patients with and without type 2 diabetes mellitus (T2DM). Subjects and methods These polymorphisms were analyzed by polymerase chain reaction in 125 patients with obesity, 47 (T2DM) and 78 (Control Group). Results No significant difference was found on comparing the T2DM and Control Groups in respect to the genotypic frequencies of the polymorphisms - (II: 13.3% vs. 12.0%; ID: 37.8% vs. 37.3; DD: 48.9% vs. 50.7%; CC: 36.2% vs. 39.0%; CT: 46.8% vs. 49.3%; TT: 17.0% vs. 11.7%), and alleles (I: 32.2% vs. 30.7%; D: 67.8% vs. 69.3%; C: 59.6% vs. 63.6%; T: 40.4% vs. 36.4%) and their synergisms in the pathophysiology of T2DM. On analyzing the T2DM Group, there were no significant differences in the presence of complications. In this population of Brazilian obese patients, no correlation was found between the ACE and MTHFR polymorphisms in the development of T2DM. Conclusion Analyzing only the group with diabetes, there was also no relationship between these polymorphisms and comorbidities.