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1.
Osteoarthr Cartil Open ; 6(1): 100434, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38322145

RESUMEN

Objectives: Modic type 1 changes (MC1) are vertebral endplate bone marrow (BM) lesions observed on magnetic resonance images in sub-populations of chronic low back pain (CLBP) patients. The etiopathogenesis remains unknown and treatments that modify the underlying pathomechanisms do not exist. We hypothesized that two biological MC1 subtypes exist: a bacterial and a non-bacterial. This would have important implications for developing treatments targeting the underlying pathomechanisms. Methods: Intervertebral disc (IVD) samples adjacent to MC1 (n â€‹= â€‹34) and control (n â€‹= â€‹11) vertebrae were collected from patients undergoing spinal fusion. Cutibacterium acnes (C.acnes) genome copy numbers (GCNs) were quantified in IVD tissues with 16S qPCR, transcriptomic signatures and cytokine profiles were determined in MC1 and control BM by RNA sequencing and immunoassay. Finally, we assessed if C.acnes GCNs are associated with blood plasma cytokines. Results: IVD tissues from control levels had <870 â€‹C.acnes GCNs/gram IVD. MC1-adjacent IVDs had either "low" (<870) or "high" (>870) C.acnes GCNs. MC1 patients with "high" C.acnes GCNs had upregulated innate immune cell signatures (neutrophil, macrophage/monocyte) and pro-inflammatory cytokines related to neutrophil and macrophage/monocyte function in the BM, consistent with a host defense against bacterium. MC1 patients with "low" C.acnes GCNs had increased adaptive immune cell signatures (T-and B-cell) in the BM and elevated IL-13 blood plasma levels. Conclusion: Our study provides the first evidence for the existence of bacterial (C.acnes "high") and non-bacterial (C.acnes "low") subtypes in MC1 patients with CLBP. This supports the need for different treatment strategies.

2.
Clin Exp Immunol ; 203(3): 448-457, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33040328

RESUMEN

Severe combined immunodeficiency (SCID) is fatal if not treated with immune reconstitution. In Egypt, T- B+ SCID accounts for 38·5% of SCID diagnoses. An accurate genetic diagnosis is essential for choosing appropriate treatment modalities and for offering genetic counseling to the patient's family. The objectives of this study were to describe the clinical, immunological and molecular characteristics of a cohort of twenty Egyptian patients with T- B+ SCID. The initial diagnosis (based on clinical features and flow cytometry) was followed by molecular investigation (whole-exome sequencing). All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2). The onset of manifestations was at the age of 2·4 ± 1·6 months and diagnosis at the age of 6·7 ± ·5 months, giving a diagnostic delay of 4·3 months. JAK3 gene variants were most frequent (n = 12) with three novel variants identified, followed by IL2Rγ variants (n = 6) with two novel variants. IL7Rα and CD3ε variants were found once, with a novel variant each. T- B+ NK- SCID accounted for approximately 90% of the Egyptian patients with T- B+ SCID. Of these T- B+ NK- SCID cases, 60% were autosomal recessive syndromes caused by JAK3 mutations and 30% were X-linked syndromes. It might be useful to sequence the JAK3 gene (i.e. targeted Sanger sequencing) in all T- B+ SCID patients, especially after X-linked SCID has been ruled out. Hence, no more than 10% of T- B+ SCID patients might require next-generation for a molecular diagnosis.


Asunto(s)
Secuenciación del Exoma/métodos , Janus Quinasa 3/genética , Mutación , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Linfocitos T/inmunología , Consanguinidad , Egipto , Salud de la Familia , Femenino , Humanos , Lactante , Recién Nacido , Subunidad gamma Común de Receptores de Interleucina/genética , Janus Quinasa 3/deficiencia , Recuento de Linfocitos , Masculino , Linaje , Inmunodeficiencia Combinada Grave/patología , Linfocitos T/metabolismo
3.
Clin Exp Immunol ; 195(2): 202-212, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30307608

RESUMEN

Mutations affecting recombination activation genes RAG1 and RAG2 are associated with variable phenotypes, depending on the residual recombinase activity. The aim of this study is to describe a variety of clinical phenotypes in RAG-deficient patients from the highly consanguineous Egyptian population. Thirty-one patients with RAG mutations (from 28 families) were included from 2013 to 2017. On the basis of clinical, immunological and genetic data, patients were subdivided into three groups; classical T- B- severe combined immunodeficiency (SCID), Omenn syndrome (OS) and atypical SCID. Nineteen patients presented with typical T- B- SCID; among these, five patients carried a homozygous RAG2 mutation G35V and five others carried two homozygous RAG2 mutations (T215I and R229Q) that were detected together. Four novel mutations were reported in the T- B- SCID group; three in RAG1 (A565P, N591Pfs*14 and K621E) and one in RAG2 (F29S). Seven patients presented with OS and a novel RAG2 mutation (C419W) was documented in one patient. The atypical SCID group comprised five patients. Two had normal B cell counts; one had a previously undescribed RAG2 mutation (V327D). The other three patients presented with autoimmune cytopaenias and features of combined immunodeficiency and were diagnosed at a relatively late age and with a substantial diagnostic delay; one patient had a novel RAG1 mutation (C335R). PID disorders are frequent among Egyptian children because of the high consanguinity. RAG mutations stand behind several variable phenotypes, including classical SCID, OS, atypical SCID with autoimmunity and T- B+ CID.


Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Proteínas Nucleares/genética , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/patología , Adolescente , Adulto , Linfocitos B/inmunología , Niño , Consanguinidad , Egipto , Femenino , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Linfocitos T/inmunología , Secuenciación del Exoma , Adulto Joven
5.
Cell Death Dis ; 7: e2064, 2016 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-26794659

RESUMEN

Intravascular hemolysis can result in hemoglobinuria with acute kidney injury. In this study we systematically explored two in vivo animal models and a related cell culture system to identify hemoglobinuria-triggered damage pathways. In models of stored blood transfusion and hemoglobin (Hb) exposure in guinea pigs and beagle dogs we found that hemoglobinuria led to intrarenal conversion of ferrous Hb(Fe(2+)) to ferric Hb(Fe(3+)), accumulation of free heme and Hb-cross-linking products, enhanced 4-hydroxynonenal reactivity in renal tissue, and acute tubule injury. These changes were associated in guinea pigs with activation of a renal cortex gene expression signature indicative of oxidative stress and activation of the unfolded protein response (UPR). Tubule cells of hemolytic animals demonstrated enhanced protein expression of heme oxygenase and heat shock protein and enhanced expression of acute kidney injury-related neutrophil gelatinase-associated lipocalin. These adverse changes were completely prevented by haptoglobin treatment. The in vivo findings were extrapolated to a MS-based proteome analysis of SILAC-labeled renal epithelial cells that were exposed to free heme within a concentration range estimate of renal tubule heme exposure. These experiments confirmed that free heme is a likely trigger of tubule barrier deregulation and oxidative cell damage and reinforced the hypothesis that uncontrolled free heme could trigger the UPR as an important pathway of renal injury during hemoglobinuria.


Asunto(s)
Lesión Renal Aguda/etiología , Hemoglobinuria/etiología , Lesión Renal Aguda/genética , Animales , Perros , Cobayas , Hemo , Hemólisis , Oxidación-Reducción , Estrés Oxidativo
6.
Cell Death Differ ; 22(4): 597-611, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25301065

RESUMEN

Dual control of cellular heme levels by extracellular scavenger proteins and degradation by heme oxygenases is essential in diseases associated with increased heme release. During severe hemolysis or rhabdomyolysis, uncontrolled heme exposure can cause acute kidney injury and endothelial cell damage. The toxicity of heme was primarily attributed to its pro-oxidant effects; however additional mechanisms of heme toxicity have not been studied systematically. In addition to redox reactivity, heme may adversely alter cellular functions by binding to essential proteins and impairing their function. We studied inducible heme oxygenase (Hmox1)-deficient mouse embryo fibroblast cell lines as a model to systematically explore adaptive and disruptive responses that were triggered by intracellular heme levels exceeding the homeostatic range. We extensively characterized the proteome phenotype of the cellular heme stress responses by quantitative mass spectrometry of stable isotope-labeled cells that covered more than 2000 individual proteins. The most significant signals specific to heme toxicity were consistent with oxidative stress and impaired protein degradation by the proteasome. This ultimately led to an activation of the response to unfolded proteins. These observations were explained mechanistically by demonstrating binding of heme to the proteasome that was linked to impaired proteasome function. Oxidative heme reactions and proteasome inhibition could be differentiated as synergistic activities of the porphyrin. Based on the present data a novel model of cellular heme toxicity is proposed, whereby proteasome inhibition by heme sustains a cycle of oxidative stress, protein modification, accumulation of damaged proteins and cell death.


Asunto(s)
Hemo/farmacología , Estrés Oxidativo/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Bortezomib/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Dicroismo Circular , Células HEK293 , Proteínas de Choque Térmico/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Complejo de la Endopetidasa Proteasomal/química , Inhibidores de Proteasoma/farmacología , Unión Proteica , Proteína Sequestosoma-1 , Espectrofotometría Ultravioleta , Ubiquitina/metabolismo
7.
Mol Hum Reprod ; 16(11): 846-55, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20624824

RESUMEN

DNA microarray analysis was performed with mouse multipotent adult germline stem cells (maGSCs) and embryonic stem cells (ESCs) from different genetic backgrounds cultured under standard ESC-culture conditions and under differentiation-promoting conditions by the withdrawal of the leukemia inhibitory factor (LIF) and treatment with retinoic acid (RA). The analyzed undifferentiated cell lines are very similar based on their global gene expression pattern and show 97-99% identity dependent on the analyzed background. Only 621 genes are differentially expressed in cells derived from mouse 129SV-background and 72 genes show differences in expression in cells generated from transgenic Stra8-EGFP/Rosa26-LacZ-background. Both maGSCs and ESCs express the same genes involved in the regulation of pluripotency and even show no differences in the expression level of these genes. When comparing maGSCs with previously published signature genes of other pluripotent cell lines, we found that maGSCs shared a very similar gene expression pattern with embryonic germ cells (EGCs). Also after differentiation of maGSCs and ESCs the transcriptomes of the cell lines are nearly identical which suggests that both cell types differentiate spontaneously in a very similar way. This is the first study, at transcriptome level, to compare ESCs and a pluripotent cell line derived from an adult organism (maGSCs).


Asunto(s)
Células Madre Adultas/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Células Madre Multipotentes/metabolismo , Células Madre Pluripotentes/metabolismo , Animales , Diferenciación Celular , Línea Celular , Ratones , Regulación hacia Arriba
9.
Acta Cytol ; 36(3): 440-4, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-1580133

RESUMEN

Rare cases of extrapulmonary Pneumocystis carinii (EPPC) have been seen in patients with acquired immunodeficiency syndrome (AIDS). We report seven such diagnoses of nonpulmonary P carinii (PC) from four AIDS patients between 1986 and 1989. The specimens included fine needle aspirate of liver, spleen, periarticular tissue and pleura as well as ankle fluid, pleural fluid and ascites. In some, but not all, cases the patients had concurrent or previous episodes of PC pneumonia. In all cases the typical granular, eosinophilic aggregates of PC cysts were noted on routine Papanicolaou staining, leading to the definitive detection of PC cysts with Grocott silver stain. In most cases, evidence for granulomalike and neovascularized tissue reaction was present in cytologic material. One specimen demonstrated concurrent acid fast bacilli. In the setting of AIDS, cytology of effusions and masses should include an evaluation for EPPC.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Exudados y Transudados/microbiología , Infecciones Oportunistas/complicaciones , Infecciones por Pneumocystis/patología , Adulto , Líquido Ascítico/microbiología , Citodiagnóstico , Humanos , Hepatopatías/microbiología , Masculino , Persona de Mediana Edad , Derrame Pleural/microbiología , Infecciones por Pneumocystis/complicaciones , Enfermedades del Bazo/microbiología
10.
Mod Pathol ; 4(2): 196-200, 1991 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-2047382

RESUMEN

A total of 203 primary invasive breast cancers were sampled by ex vivo fine-needle aspiration (FNA), directly yielding adequate single cell suspensions for flow cytometric DNA analysis in 194 (96%). Labor-intensive and time-consuming steps of mechanical and enzymatic cellular disaggregation required by the use of fresh, frozen, or paraffin-embedded tissue were avoided, thereby minimizing preparation time. Conservation of tumor tissue allowed for the sampling of very small breast cancers. DNA ploidy and S-phase fraction data were comparable to flow cytometric data reported in other breast cancer studies using various sampling methods. Ex vivo FNA is the easiest and fastest method for sampling breast cancers for flow cytometric DNA analysis.


Asunto(s)
Neoplasias de la Mama/patología , ADN de Neoplasias/genética , Ploidias , Biopsia con Aguja , Neoplasias de la Mama/química , Neoplasias de la Mama/genética , División Celular , Fraccionamiento Celular/métodos , ADN de Neoplasias/análisis , Femenino , Citometría de Flujo/métodos , Humanos , Fase S , Manejo de Especímenes
11.
Am Heart J ; 120(6 Pt 1): 1320-5, 1990 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-2248178

RESUMEN

Repair of aortic valve stenosis due to calcific degeneration may lead to hemodynamic and clinical improvement without the problems inherent with prosthetic valves. We have evaluated the use of a device capable of débriding calcium, the Cavitron ultrasonic aspirator (CUSA), as an adjunct to mechanical débridement in the repair of calcific aortic stenosis. Ten patients (five women), ages 63 to 83 years, were studied by M-mode, two-dimensional, and Doppler echocardiography before and an average of 26 (range 3 to 124) days after this procedure. The degree of calcification of the valve cusps was clearly reduced. The maximal cusp excursion increased from 0.7 +/- 0.1 cm preoperatively to 1.5 +/- 0.4 cm postoperatively (p = 0.006). The peak aortic gradient fell from 80 +/- 36 mm Hg to 28 +/- 10 mm Hg (p = 0.0007). The mean aortic gradient fell from 53 +/- 20 mm Hg to 16 +/- 5 mm Hg (p less than 0.0001). Aortic valve area calculated by the continuity equation increased from 0.6 + 0.2 cm2 to 1.6 +/- 0.6 cm2 (p = 0.0009). No patient had more than mild aortic insufficiency preoperatively. Postoperatively, color Doppler flow mapping revealed severe aortic insufficiency in two patients. Seven patients had further echocardiographic evaluation 99 (range 33 to 196) days after the procedure. These studies revealed the development of severe aortic insufficiency in an additional four patients. Four patients with severe symptomatic aortic insufficiency eventually underwent aortic valve replacement. Pathology revealed scarring and retraction of the aortic cusps. Widening of the commissures was responsible for the severe aortic insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Estenosis de la Válvula Aórtica/terapia , Calcinosis/terapia , Desbridamiento/métodos , Terapia por Ultrasonido/métodos , Anciano , Anciano de 80 o más Años , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/patología , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Puente Cardiopulmonar , Desbridamiento/instrumentación , Ecocardiografía , Ecocardiografía Doppler , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Terapia por Ultrasonido/instrumentación
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