miRNA Expression Associated with HbF in Saudi Sickle Cell Anemia.

Background and Objectives: Sickle cell anemia (SCA) is a hereditary monogenic disease due to a single ß-globin gene mutation that codes for the production of sickle hemoglobin. Its phenotype is modulated by fetal hemoglobin (HbF), a product of γ-globin genes. Exploring the molecules that regulate γ-globin genes at both transcriptional and translational levels, including microRNA (miRNA), might help identify alternative therapeutic targets. Materials and Methods: Using next-generation sequencing we identified pre-miRNAs and mature miRNA expression signatures associated with different HbF levels in patients homozygous for the sickle hemoglobin gene. The involvement of identified miRNAs in potential SCD-related pathways was investigated with the DIANA TOOL and miRWalk 2.0 database. Results: miR-184 were most highly upregulated in reticulocytes. miR-3609 and miR-483-5p were most highly downregulated in sickle cell anemia with high HbF. miR-370-3p that regulates LIN28A, and miR-451a which is effective in modulating α- and ß- globin levels were also significantly upregulated. miRNA targeted gene pathway interaction identified BCL7A, BCL2L1, LIN28A, KLF6, GATA6, solute carrier family genes and ZNF genes associated with erythropoiesis, cell cycle regulation, glycosphingolipid biosynthesis, cAMP, cGMP-PKG, mTOR, MAPK and PI3K-AKT signaling pathways and cancer pathways. Conclusions: miRNA signatures and their target genes identified novel miRNAs that could regulate fetal hemoglobin production and might be exploited therapeutically.

Gammaglobulina subcutánea: Revisión sistemática / Subcutaneous gamma globulin: A systematic review

Las inmunodeficiencias primarias constituyen enfermedades determinadas genéticamente, caracterizadas por la alteración cuantitativa y/o funcional de distintos mecanismos implicados en la respuesta inmunitaria. Algunas de ellas se caracterizan por una alteración en la producción de anticuerpos, por lo que algunos pacientes se benefician con la administración supletoria de gammaglobulina, la cual se administra mayormente por vía endovenosa, siendo la vía subcutánea una alternativa terapéutica. La siguiente revisión sistemática tiene por objetivo determinar si la gammaglobulina subcutánea tiene alguna ventaja frente al clásico uso de gammaglobulina endovenosa, en pacientes pediátricos con inmunodeficiencias primarias, revisando la bibliografía disponible hasta la actualidad (AU)

Primary immunodeficiencies are genetically determined diseases characterized by the quantitative and/or functional alteration of different mechanisms involved in the immune response. Some of these diseases are characterized by an alteration in the antibody production and therefore some patients benefit from the supplementary administration of gamma globulin, which is mostly administered intravenously, with the subcutaneous route being a therapeutic alternative. The following systematic literature review aims to determine whether subcutaneous gamma globulin has any advantage over the classic use of intravenous gamma globulin in pediatric patients with primary immunodeficiencies (AU)

Hemoglobin F (HbF) Inducers; History, Structure and Efficacies.

Inherited beta-thalassemia is caused by irregular production of hemoglobin through reducing beta-globin chains. It has been observed that increasing fetal hemoglobin (HbF) production improves symptoms in the patients; thus, it has been an operative approach to treat patients with betathalassemia. This review represents compounds with biological activities and pharmacological properties that can be useful in promoting the HBF level in ß-thalassemia patients. Various natural products with different mechanisms of action can be helpful in this medication cure. Clinical trials were efficient in improving the signs of patients. Association of in vivo, and in vitro studies of HbF induction and γ-globin mRNA growth displays that in vitro experiments could be an indicator of the in vivo response. The current study resulted that; (a) HbF inducers can be grouped into several classes based on their chemical structures and mechanism of actions; (b) According to several clinical trials, wellknown drugs such as hydroxyurea and decitabine are useful HbF inducers. (c) The cellular biosensor K562 carrying genes under the control of the human γ-globin and ß-globin gene promoters were applied during the researches. (d) New natural products and lead compounds were found based on various studies as HbF inducers.

Wake-up Sleepy Gene: Reactivating Fetal Globin for ß-Hemoglobinopathies.

Disorders in hemoglobin (hemoglobinopathies) were the first monogenic diseases to be characterized and remain among the most common and best understood genetic conditions. Moreover, the study of the ß-globin locus provides a textbook example of developmental gene regulation. The fetal γ-globin genes (HBG1/HBG2) are ordinarily silenced around birth, whereupon their expression is replaced by the adult ß-globin genes (HBB primarily and HBD). Over 50 years ago it was recognized that mutations that cause lifelong persistence of fetal γ-globin expression ameliorate the debilitating effects of mutations in ß-globin. Since then, research has focused on therapeutically reactivating the fetal γ-globin genes. Here, we summarize recent discoveries, focusing on the influence of genome editing technologies, including CRISPR-Cas9, and emerging gene therapy approaches.

[γ-Globin Inductive Therapy of ß-thalassemia and Its Relationship with MicroRNA].

ß-thalassemia is a chronic hemolytic anemia characterized by the reduction or absence of synthesis of ß-globin chains because of the ß-globin gene mutations. ß-thalassemia belongs to the inherited hemoglobin disease, and occurs in some provinces of China, such as in Guangdong, Guangxi, Fujian, its prevalence is about 2%. The treatment of this disease include transfusion, iron chelating agent, hematopoietic stem cell transplantation, splenectomy, induced expression of Fetal Hemoglobin (HbF) and gene therapies. However, the mortality rate of this disease is still higher, thus some new treatments are urgently needed. In recent years, the study was mainly concentrated in 2 aspects: the normal ß-globin gene transfer and endogenous γ-globin re-activation. Some studies showed that the expression of miRNAs was dysregulated in ß-thalassemia. Some miRNAs could regulate γ-globin at posttranscriptional level, thus, the clarification of relationship between miRNAs and ß-thalassemia is expected to provide experimental bases to ß-thalassemia therapy. In this review, the induced therapy of γ-globin for ß-thalassemia and its relationship with the miRNA are summarized.

Tratamiento con gammaglobulinas intravenosas en las enfermedades inflamatorias sistémicas autoinmunitarias: ¿nuevas indicaciones? / Therapy with intravenous gammaglobulins in systemic inflammatory autoimmune diseases: New indications?

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Síndrome de Guillain-Barré: variante faringo-cervico-braquial / Guillain- Barré syndrome: pharyngeal-cervical-brachial variant

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Síndrome de Guillain-Barré en trasplante renal / No disponible

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[Cryptosporidiose (C. parvum) in a foal with diarrhea]. / Cryptosporidiose (C. parvum) bei einem Fohlen mit Durchfall.

The protozoon parasite Cryptosporidium parvum is an important cause of diarrhea in farm animals, but it can also infect other animals and humans. In this case report, oocysts of Cryptosporidium spp. were microscopically detected by modified Ziehl-Neelsen staining in the feces of a 9 day old Arabian colt presented with yellowish, foul smelling, diarrhea and fever of 40 degrees C. PCR and sequencing of the isolate revealed C. parvum (bovine genotype). Hemato-chemical analysis of the foals blood revealed a marked hypogammaglobulinaemia (IgG 108mg/dl). The colt responded well to a supportive therapy and administration of plasma (until a gammaglobulin-concentration of 620 mg/dl was reached) and was released in good health from the clinic after 10 days. Follow-up testing for Cryptosporidium oocycsts remained negative. Cryptosporidiosis with life-threatening diarrhea is a rare diagnosis in foals in Switzerland. Immunodeficiency increases the risk for cryptosporidiosis. We hypothesize that the low concentration of gammaglobulins together with the weak INF-gamma response normally observed in young foals may have favored the clinical manifestation with diarrhea. Foals with diarrhea should be screened for cryptosporidia with specific tests.

[Case report of anti-NMDA receptor encephalitis suspected of schizophrenia].

Recently, paraneoplastic encephalitis associated with ovarian teratoma, which predomi nantly affects young women, has been reported. Its symptoms are severe but often treatment-responsive and reversible. Various psychiatric symptoms occurring shortly after onset are characteristic of this encephalitis. A 22-year-old female who had a fever and common cold-like symptoms presented with short-term memory loss. She was suspected to have viral encephalitis, but the cerebrospinal fluid (CSF) showed no marked change. Shortly after that, she developed delusions and hallucinations and presented with psychomotor excitement. She was suspected of having schizophrenia and admitted to the psychiatry department. However, several days after admission, she showed upper limb convulsion, orofacial dyskinesias, and central hypoventilation and became unresponsive. The results of laboratory tests were within the normal range, and there was no marked elevation of anti-viral antibody titers. Brain imaging was normal, but a solid tumor containing soft tissue and calcified components, probably an ovarian teratoma, was discovered on an abdominal CT scan. Anti-N-methyl-D-aspartate (NMDA) receptor antibody was positive in her CSF and blood serum, and we diagnosed her with "Anti-NMDA receptor encephalitis". Gamma globulin was very effective, and the ovarian teratoma was removed. Finally, she could be discharged from our hospital without any sequela, and returned to her job. Psychiatrists often encounter encephalitis patients with psychiatric symptoms. If the type of encephalitis is unknown, we should keep this disease in mind.

[Integrated Chinese and western medicinal treatment on systemic lupus erythematosus characterized by hypoplastic bone marrow].

OBJECTIVE: To study the clinical effect of combined treatment with gamma-globulin, corticosteroids, immunosuppressor and Chinese medicines on systemic lupus erythematosus (SLE) patients characterized by hypoplastic bone marrow (HBM). METHODS: Nineteen patients were randomly assigned to two groups, the treated group (10 cases) received combined therapy of prednisone and cyclophosphamide (CTX) plus Chinese medicine Langchuang Recipe after being treated impactively with gamma-globulin. The control group (9 cases) was treated with prednisone and CTX. Changes of hypoplastic bone marrow, peripheral white blood cell (WBC), complement C3, 24 h urinary protein excretion, and lupus activity index (LAI) were observed, and a follow-up was carried out for one year. RESULTS: After one-month treatment, the bone marrow hypoplasia was relieved significantly in the treated group (P < 0.05, P < 0.01), showing an improvement superior to that in the control group (P < 0.05, P < 0.01); after three months treatment, the level of complement C3 increased (P < 0.01), while the 24 h urinary protein excretion and LAI decreased in the treated group (P < 0.05), showing significant difference as compared with those in the control group (P < 0.05, P < 0.01). In the follow-up period, 3 cases withdrew from the trial because of infection and 4 cases manifested full moon-face and acne in the control group, while no adverse reaction was found in the treated group. CONCLUSION: Treatment with integrated Chinese and Western medicine could effectively improve bone marrow hypoplasia, alleviate the clinical symptoms, suppress the activity of lupus in patients, and reduce the adverse reaction of treatment, showing a superiority to the treatment with prednisone combining with CTX.

Formas incompletas de enfermedad de Kawasaki / Incomple Kawasaki disease

La enfermedad de Kawasaki (EK) es una vasculitis aguda que se manifiesta por fiebre y signos de inflamación mucocutánea. Sin el tratamiento adecuado, uno de cada cuatro a cinco niños desarrollan aneurismas de las arterias coronarias. Este riesgo se reduce considerablemente por la administración de altas dosis de gamaglobulina intravenosa en la fase aguda de la enfermedad. La EK no se puede diagnosticar por ningún test específico de laboratorio ni tiene signos clínicos patognomónicos. En las formas incompletas a atípicas de EK, no existen los criterios diagnósticos clásicos en su totalidad, pero también hay riesgo del desarrollo de aneurismas coronarios. Debe considerarse el diagnóstico de forma incompleta de EK en los niños con fiebre inexplicada de por lo menos 5 días de duración y que además presenten dos o tres de los cinco signos clínicos de EK y además datos de laboratorio sugestivos como son la elevación de los marcadores de inflamación, PCR o VSG (au)

Kawasaki disease is an acute vasculitis manifested by fever and signs of mucocutaneous inflammation. Without treatment, coronary artery aneurysms develop in one of every four to five children. This risk is reduced by the administration of high-dose intravenous gammaglobulin in the acute phase of the disease. The diagnosis of Kawasaki disease cannot be made by a laboratory test or pathognomonic clinical finding. In incomplete or atypical Kawasaki disease patients lack sufficient clinical signs to fulfill the classic criteria for Kawasaki disease but are at risk for the development of coronary aneurysms. Incomplete Kawasaki disease should be considered in children with unexplained fever for at least 5 days that is associated with two or three principal clinical features of the disease and consistent laboratory data such as elevation of inflammatory markers such as CRP and/or ESR (AU)