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1.
Int J Mol Sci ; 22(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917689

RESUMO

The value of bone marrow aspirate concentrates for treatment of human knee cartilage lesions is unclear. Most of the studies were performed with intra-articular injections. However, subchondral bone plays an important role in the progression of osteoarthritis. We investigated by a literature review whether joint, subchondral bone, or/and scaffolds implantation of fresh autologous bone marrow aspirate concentrated (BMAC) containing mesenchymal stem cells (MSCs) would improve osteoarthritis (OA). There is in vivo evidence that suggests that all these different approaches (intra-articular injections, subchondral implantation, scaffolds loaded with BMAC) can improve the patient. This review analyzes the evidence for each different approach to treat OA. We found that the use of intra-articular injections resulted in a significant relief of pain symptoms in the short term and was maintained in 12 months. However, the clinical trials indicate that the application of autologous bone marrow concentrates in combination with scaffolds or in injection in the subchondral bone was superior to intra-articular injection for long-term results. The tendency of MSCs to differentiate into fibrocartilage affecting the outcome was a common issue faced by all the studies when biopsies were performed, except for scaffolds implantation in which some hyaline cartilage was found. The review suggests also that both implantation of subchondral BMAC and scaffolds loaded with BMAC could reduce the need for further surgery.


Assuntos
Transplante de Medula Óssea , Regeneração Óssea , Cartilagem Articular/patologia , Osteoartrite do Joelho/patologia , Osteoartrite do Joelho/terapia , Transplante de Medula Óssea/métodos , Gerenciamento Clínico , Humanos , Cartilagem Hialina/patologia , Injeções Intra-Articulares , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoartrite do Joelho/etiologia , Engenharia Tecidual , Resultado do Tratamento
2.
J Pharmacol Exp Ther ; 377(2): 273-283, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33658314

RESUMO

Cannabidiol (CBD) is a highly lipidic phytocannabinoid with remarkable anti-inflammatory effects. The aim of this study was to evaluate CBD's effects and mechanisms of action in the treatment of mice subjected to acute graft-versus-host disease (aGVHD). aGVHD was induced by the transplantation of bone marrow cells and splenocytes from C57BL-6j to Balb-c mice. The recipient mice were treated daily with CBD, and the treatment reduced mouse mortality by decreasing inflammation and injury and promoting immune regulation in the jejunum, ileum, and liver. Analysis of the jejunum and ileum showed that CBD treatment reduced the levels of C-C motif chemokine ligand (CCL) 2, CCL3, CCL5, tumor necrosis factor α, and interferon γ (IFNγ). CCL3 and IFNγ levels were also decreased in the liver. Mechanistically, CBD also increased the number of cannabinoid receptor type 2 (CB2) receptors on CD4+ and forkhead box P3+ cells in the intestine, which may explain the reduction in proinflammatory cytokines and chemokines. Antagonists of the CB2 receptor reduced the survival rates of CBD-treated mice, suggesting the participation of this receptor in the effects of CBD. Furthermore, treatment with CBD did not interfere with the graft-versus-leukemia response. CBD treatment appears to protect aGVHD mice by anti-inflammatory and immunomodulatory effects partially mediated by CB2 receptor interaction. Altogether, our study suggests that CBD represents an interesting approach in the treatment of aGVHD, with potential therapeutic applications in patients undergoing bone marrow transplantation. SIGNIFICANCE STATEMENT: This study provides for the first time a mechanism by which cannabidiol, a phytocannabinoid with no psychoactive effect, induces immunomodulation in the graft-versus-host disease. Enhancing intestinal cannabinoid receptor type 2 (CB2) receptor expression on CD4+ and forkhead box P3+ cells and increasing the number of these regulatory cells, cannabidiol decreases proinflammatory cytokines and increases graft-versus-host disease mice survival. This effect is dependent of CB2 receptor activation. Besides, cannabidiol did not interfere with graft-versus-leukemia response, a central response to avoid primary disease relapse.


Assuntos
Canabidiol/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Mucosa Intestinal/metabolismo , Leucemia/terapia , Receptor CB2 de Canabinoide/metabolismo , Animais , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Canabidiol/farmacologia , Células Cultivadas , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Leucemia/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/genética , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
3.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33649786

RESUMO

Spinal cord injury (SCI) remains a global challenge due to limited treatment strategies. Transcranial magnetic stimulation (TMS), bone marrow mesenchymal stem cell (BMSC) transplantation and downregulation of Raf/MEK/ERK signaling effectively improve SCI. The combination of BMSCs and TMS displays synergistic effects on vascular dementia. However, whether TMS displays a synergistic effect when combined with BMSC transplantation or Raf inhibitor (RafI) therapy for the treatment of SCI is not completely understood. The present study aimed to compare the therapeutic effect of monotherapy and combination therapy on SCI. In the present study, 8­week­old female Sprague Dawley rats were used to establish a model of SCI using the weight­drop method followed by treatment with monotherapy (TMS, BMSCs or RafI) or combination therapy (TMS+BMSCs or TMS+RafI). The effect of monotherapy and combination therapy on locomotor function, pathological alterations, neuronal apoptosis and expression of axonal regeneration­associated factors and Raf/MEK/ERK signaling­associated proteins in the spinal cord was analyzed by Basso, Beattie and Bresnahan (BBB) scoring, hematoxylin and eosin staining, TUNEL­neuronal nuclei (NeuN) staining and immunofluorescence or western blotting, respectively. The results demonstrated that compared with untreated SCI model rats, monotherapy significantly enhanced locomotor functional recovery, as evidenced by higher BBB scores, and slightly alleviated histopathological lesions of the spinal cord in SCI model rats. Furthermore, monotherapy markedly suppressed neuronal apoptosis and promoted axonal regeneration, as well as inhibiting astroglial activation in SCI model rats. The aforementioned results were demonstrated by significantly decreased numbers of apoptotic neurons, markedly decreased expression levels of glial fibrillary acidic protein (GFAP), significantly increased numbers of NeuN+ cells, markedly increased expression levels of growth­associated protein 43 (GAP­43) and significantly upregulated nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) expression levels in monotherapy groups (excluding the RafI monotherapy group) compared with untreated SCI model rats. In addition, monotherapy markedly suppressed activation of the Raf/MEK/ERK signaling pathway, as evidenced by significantly reduced p­Raf/Raf, p­MEK/MEK and p­ERK/ERK protein expression levels in monotherapy groups (excluding the BMSC monotherapy group) compared with untreated SCI model rats. Notably, combination therapy further alleviated SCI­induced spinal cord lesions and neuronal apoptosis, increased GAP­43, NGF and BDNF expression levels, downregulated GFAP expression levels and inhibited activation of the Raf/MEK/ERK signaling pathway in SCI model rats compared with the corresponding monotherapy groups. Therefore, it was hypothesized that compared with monotherapy, combination therapy displayed an improved therapeutic effect on SCI by further suppressing Raf/MEK/ERK signaling. The results of the present study provided an important basis for the clinical application of combination therapy.


Assuntos
Transplante de Medula Óssea/métodos , Indóis/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Traumatismos da Medula Espinal/terapia , Sulfonamidas/farmacologia , Estimulação Magnética Transcraniana/métodos , Quinases raf/antagonistas & inibidores , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Terapia Combinada , Modelos Animais de Doenças , Feminino , Proteína GAP-43/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Atividade Motora/efeitos dos fármacos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Quinases raf/metabolismo
4.
FASEB J ; 35(3): e21413, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33570785

RESUMO

Successful intrauterine hematopoietic cell transplantation (IUT) for congenital hemoglobinopathies is hampered by maternal alloresponsiveness. We investigate these interactions in semi-allogenic murine IUT. E14 fetuses (B6 females × BALB/c males) were each treated with 5E+6 maternal (B6) or paternal (BALB/c) bone marrow cells and serially monitored for chimerism (>1% engraftment), trafficked maternal immune cells, and immune responsiveness to donor cells. A total of 41.0% of maternal IUT recipients (mIUT) were chimeras (mean donor chimerism 3.0 ± 1.3%) versus 75.0% of paternal IUT recipients (pIUT, 3.6 ± 1.1%). Chimeras showed higher maternal microchimerism of CD4, CD8, and CD19 than non-chimeras. These maternal cells showed minimal responsiveness to B6 or BALB/c stimulation. To interrogate tolerance, mIUT were injected postnatally with 5E+6 B6 cells/pup; pIUT received BALB/c cells. IUT-treated pups showed no changes in trafficked maternal or fetal immune cell levels compared to controls. Donor-specific IgM and IgG were expressed by 1%-3% of recipients. mIUT splenocytes showed greater proliferation of regulatory T cells (Treg) upon BALB/c stimulation, while B6 stimulation upregulated the pro-inflammatory cytokines more than BALB/c. pIUT splenocytes produced identical Treg and cytokine responses to BALB/c and B6 cells, with higher Treg activity and lower pro-inflammatory cytokine expression upon exposure to BALB/c. In contrast, naïve fetal splenocytes demonstrated greater alloresponsiveness to BALB/c compared to B6 cells. Thus pIUT, associated with increased maternal cell trafficking, modulates fetal Treg, and cytokine responsiveness to donor cells more efficiently than mIUT, resulting in improved engraftment. Paternal donor cells may be considered alternatively to maternal donor cells for intrauterine and postnatal transplantation to induce tolerance and maintain engraftment.


Assuntos
Transplante de Medula Óssea , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica/imunologia , Transplante Homólogo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Transplante de Medula Óssea/métodos , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/métodos , Camundongos , Camundongos Endogâmicos BALB C , Quimeras de Transplante/imunologia , Transplante Homólogo/métodos
5.
Transfusion ; 61(4): 1041-1046, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33528026

RESUMO

BACKGROUND: Recent case reports have described the efficacy of daratumumab to treat refractory pure red cell aplasia (PRCA) following major ABO mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In this report, we describe the use of daratumumab as a first-line agent for treatment of delayed red blood cell (RBC) engraftment following a major ABO mismatched pediatric HSCT and provide a review of the literature. STUDY DESIGN AND MATERIALS: We report on a 14-year-old with DOCK8 deficiency who underwent a myeloablative, haploidentical bone marrow transplant from her major ABO mismatched sister (recipient O+, donor A+) for treatment of her primary immunodeficiency. Despite achieving full donor chimerism, she had delayed RBC engraftment requiring ongoing transfusions. Due to iron deposition, symptomatic anemia, and persistence of anti-A iso-hemagglutinins despite discontinuation of immunosuppression, treatment for delayed RBC engraftment with the CD38-targeted monoclonal antibody daratumumab was selected as a less immunosuppressive agent that could more selectively target iso-hemagglutinin producing plasma cells without causing broad B-cell aplasia. RESULTS: Clinical effect with daratumumab was demonstrated by reduced iso-hemagglutinin titer, increased reticulocytosis, normalization of her hemoglobin, and transfusion independence. In the 11-month follow-up period to date, no additional transfusions or immunosuppression have been necessary, despite persistence of low-level anti-A iso-hemagglutinin. CONCLUSION: Our experience suggests that daratumumab was an effective first-line therapy for delayed RBC engraftment and that earlier consideration for daratumumab in treatment of delayed RBC engraftment may be warranted.


Assuntos
Sistema ABO de Grupos Sanguíneos/imunologia , Anticorpos Monoclonais/farmacologia , Transplante de Medula Óssea/métodos , Função Retardada do Enxerto/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/deficiência , Doenças da Imunodeficiência Primária/terapia , Adolescente , Assistência ao Convalescente , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Quimerismo , Eritrócitos/imunologia , Feminino , Hemaglutininas/sangue , Hemaglutininas/efeitos dos fármacos , Humanos , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Aplasia Pura de Série Vermelha/tratamento farmacológico , Transplante Haploidêntico/efeitos adversos , Resultado do Tratamento
6.
Exp Cell Res ; 399(2): 112473, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33428902

RESUMO

Sepsis is a complicated multi-system disorder characterized by a dysregulated host response to infection. Despite substantial progress in the understanding of mechanisms of sepsis, translation of these advances into clinically effective therapies remains challenging. Mesenchymal Stromal Cells (MSCs) possess immunomodulatory properties that have shown therapeutic promise in preclinical models of sepsis. The therapeutic effects of MSCs may vary depending on the source and type of these cells. In this comparative study, the gene expression pattern and surface markers of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) as well as their therapeutic effects in a clinically relevant mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP), were investigated. The results showed remarkable differences in gene expression profile, surface markers and therapeutic potency in terms of enhancing survival and pro/anti-inflammatory responses between the two MSC types. BM-MSCs improved survival concomitant with an enhanced systemic bacterial clearance and improved inflammatory profile post CLP surgery. Despite some improvement in the inflammatory profile of the septic animals, treatment with UC-MSCs did not enhance survival or bacterial clearance. Overall, the beneficial therapeutic effects of BM-MSCs over UC-MSCs may likely be attributed to their pro-inflammatory function, and to some extent anti-inflammatory features, reflected in their gene expression pattern enhancing macrophage polarization to M1/M2 phenotypes resulting in a balanced pro- and anti-inflammatory response against polymicrobial sepsis.


Assuntos
Células da Medula Óssea/citologia , Transplante de Medula Óssea , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Sepse/terapia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Imunofenotipagem , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Sepse/genética , Sepse/imunologia , Sepse/patologia
7.
Int J Hematol ; 113(2): 302-307, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33000368

RESUMO

Human C1q deficiency is frequently associated with systemic lupus erythematosus (SLE), which requires long-term systemic corticosteroid administration. We report the case of a 12-year-old female patient with C1q deficiency presenting with intractable SLE who successfully underwent bone marrow transplantation from a human leukocyte antigen (HLA)-mismatched unrelated donor with an immunosuppressive conditioning regimen based on fludarabine, melphalan, and anti-thymocyte globulin. She developed Grade I graft-versus-host disease, but did not have any transplantation-related morbidity. Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells. Hematopoietic stem cell transplantation from an HLA-mismatched donor is a feasible treatment for patients with C1q deficiency with refractory SLE that is dependent on systemic corticosteroid treatment who do not have an HLA-matched donor.


Assuntos
Transplante de Medula Óssea , Complemento C1q/deficiência , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/terapia , Doadores não Relacionados , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Criança , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/genética , Antígenos HLA/imunologia , Teste de Histocompatibilidade , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento
8.
Spine (Phila Pa 1976) ; 46(10): 631-637, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32991510

RESUMO

STUDY DESIGN: Rat posterolateral lumbar fusion model. OBJECTIVE: The aim of this study was to compare the efficacy of freshly isolated adipose tissue-derived stromal vascular fraction (A-SVF) and bone marrow cells (BMCs) cells in achieving spinal fusion in a rat model. SUMMARY OF BACKGROUND DATA: Adipose tissue-derived stromal cells (ASCs) offer advantages as a clinical cell source compared to bone marrow-derived stromal cells (BMSCs), including larger available tissue volumes and reduced donor site morbidity. While pre-clinical studies have shown that ex vivo expanded ASCs can be successfully used in spinal fusion, the use of A-SVF cells better allows for clinical translation. METHODS: A-SVF cells were isolated from the inguinal fat pads, whereas BMCs were isolated from the long bones of syngeneic 6- to 8-week-old Lewis rats and combined with Vitoss (Stryker) bone graft substitute for subsequent transplantation. Posterolateral spinal fusion surgery at L4-L5 was performed on 36 female Lewis rats divided into three experimental groups: Vitoss bone graft substitute only (VO group); Vitoss + 2.5 × 106 A-SVF cells/side; and, Vitoss + 2.5 × 106 BMCs/side. Fusion was assessed 8 weeks post-surgery via manual palpation, micro-computed tomography (µCT) imaging, and histology. RESULTS: µCT imaging analyses revealed that fusion volumes and µCT fusion scores in the A-SVF group were significantly higher than in the VO group; however, they were not significantly different between the A-SVF group and the BMC group. The average manual palpation score was highest in the A-SVF group compared with the BMC and VO groups. Fusion masses arising from cell-seeded implants yielded better bone quality than nonseeded bone graft substitute. CONCLUSION: In a rat model, A-SVF cells yielded a comparable fusion mass volume and radiographic rate of fusion to BMCs when combined with a clinical-grade bone graft substitute. These results suggest the feasibility of using freshly isolated A-SVF cells in spinal fusion procedures.Level of Evidence: N/A.


Assuntos
Tecido Adiposo/transplante , Células da Medula Óssea , Transplante de Medula Óssea/métodos , Vértebras Lombares/cirurgia , Células-Tronco Mesenquimais , Fusão Vertebral/métodos , Animais , Substitutos Ósseos/administração & dosagem , Fosfatos de Cálcio/administração & dosagem , Feminino , Vértebras Lombares/diagnóstico por imagem , Ratos , Ratos Endogâmicos Lew , Silicatos/administração & dosagem , Microtomografia por Raio-X/métodos
9.
Bone Marrow Transplant ; 56(2): 305-313, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32980860

RESUMO

On January 20, 2020, the first patient with coronavirus disease 2019 (COVID-19) in the United States of America was diagnosed in Washington state, which subsequently experienced rapidly increasing numbers of COVID-19 cases, hospitalizations, and deaths. This placed the Seattle Blood and Marrow Transplant Program at Fred Hutchinson Cancer Research Center (Fred Hutch) in the national epicenter of this pandemic. Here, we summarize the experience gained during our rapid response to the COVID-19 pandemic. Our efforts were aimed at safely performing urgent and potentially life-saving stem cell transplants in the setting of pandemic-related stresses on healthcare resources and shelter-in-place public health measures. We describe the unique circumstances and challenges encountered, the current state of the program amidst evolving COVID-19 cases in our community, and the guiding principles for recovery. We also estimate the collateral impact of directing clinical resources toward COVID-19-related care on cancer patients in need of stem cell transplantation. Although our experience was influenced by specific regional and institutional factors, it may help inform how transplant programs respond to COVID-19 and future pandemics.


Assuntos
Transfusão de Sangue/métodos , Transplante de Medula Óssea/métodos , COVID-19/epidemiologia , Condicionamento Pré-Transplante/métodos , Humanos , Pandemias , Estados Unidos/epidemiologia
10.
Knee Surg Sports Traumatol Arthrosc ; 29(4): 1090-1097, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32556433

RESUMO

PURPOSE: To determine whether microfracture with bone marrow aspirate concentrate (BMAC) improves functional outcome and cartilage regeneration better than microfracture alone in patients undergoing high tibial osteotomy (HTO) for medial unicompartmental osteoarthritis (OA). METHODS: Among 436 patients treated with HTO for medial unicompartmental OA with varus deformity between 2010 and 2016, clinical outcomes were retrospectively compared between the microfracture alone group (group I, 43 cases) and microfracture with BMAC augmentation group (group II, 48 cases). Of these, 64 patients underwent a second-look arthroscopic assessment. Clinical outcomes were compared based on the Knee Society Score (KSS), International Knee Documentation Committee (IKDC) subjective score, and Western Ontario and McMaster Universities Arthritis Index (WOMAC). Cartilage regeneration was assessed according to Koshino's staging system and the International Cartilage Repair Society (ICRS) Cartilage Repair Assessment (CRA) grading system. RESULTS: At the last follow-up, there were no significant intergroup differences in terms of KSS for pain and function (p > 0.05). Moreover, WOMAC scores were similar between the two groups (p > 0.05). Regarding second-look arthroscopy findings, according to Koshino's staging system, there was no significant intergroup difference in terms of defect coverage (p = 0.187). However, group II showed a significantly better mean CRA score than group I (p = 0.035). CONCLUSION: There were no significant differences in clinical outcomes and cartilage regeneration between the groups. However, the CRA score was significantly higher with BMAC augmentation and microfracture than microfracture alone. Therefore, BMAC augmentation had a synergistic effect for a better cartilage regeneration, although studies with a longer follow-up might help to confirm whether microfracture with BMAC augmentation would ensure better clinical outcomes than microfracture alone for the treatment of knee OA.


Assuntos
Transplante de Medula Óssea/métodos , Cartilagem Articular/cirurgia , Fraturas de Estresse/cirurgia , Osteoartrite do Joelho/cirurgia , Osteotomia/métodos , Adulto , Idoso , Artroscopia/métodos , Células da Medula Óssea , Feminino , Humanos , Traumatismos do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Regeneração , Estudos Retrospectivos , Cirurgia de Second-Look/métodos , Resultado do Tratamento
11.
Foot Ankle Surg ; 27(1): 87-92, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32165094

RESUMO

INTRODUCTION: Isolated subtalar osteoarthritis (OA) is a debilitating condition usually occurring after trauma and particularly in the setting of an intraarticular calcaneal fracture. Currently, subtalar (talo-calcaneal joint) fusion surgery is the treatment of choice in managing subtalar OA after failure of conservative treatment. Unfortunately, subtalar fusion eliminates joint motion and increases the load over the adjacent midfoot and ankle joints, which affects the outcome of the surgery over time. Popular in the ankle, distraction arthroplasty offers another joint-preserving option, particularly important for active patients. In contrast to fusion as a salvage procedure, subtalar distraction arthroplasty allows the possibility of maintaining the function of the arthritic subtalar joint while reducing pain and improving the overall function of the foot and ankle. METHODS: We performed subtalar distraction arthroplasty using a circular external fixator combined with BMAC on seven patients with symptomatic and refractory subtalar OA. All these patients were interested in an alternative to fusion. We obtained clinical and radiographic data before and after surgery. Ankle Osteoarthritis Score (AOS) and the Marijnissen Distraction Clinical Score (MDCS) were obtained before surgery, after one year, and at latest follow-up. RESULTS: The average age was 56 years (range 45-69). The mean duration of post-operative follow-up was 35.4 months (range 15.2-53.5). The inversion of the ankle joint changed from 16.9° (10°-25°) pre-operatively to 14.3° (10°-20°) post-operatively (P = 0.28), and the eversion from 5.6° (0°-10°) to 10.0° (0°-20°) (P = 0.17). We found an increase in subtalar joint space from 1.4 mm (0-3) to 2.6 mm (2-4) before and after surgery (P = 0.01), respectively. Finally, Pixel Density Ratio (PDR) increased from 0.87 (0.66-1.30) to 1.01 (0.89-1.18) (P = 0.19). Compared to pre-operative conditions, we observed a decrease in subchondral sclerosis on X-ray in all cases post-operatively. The AOS score for ankle pain improved from 58.8 (47-74) to 15.1 (0-31) (p < 0.01). The AOS score for ankle disability improved from 68.2 (57-81) to 16.1 (0-43.5) (p < 0.001). We found improvement in the MDCS over time for all measured parameters. The clinical condition improved from 1.4 (0-2) to 0.8 (0-2) after one year and to 0.3 (0-2) at the latest follow-up (p < 0.001). Mobility was measured as ROM in the treated ankle relative to each patient's contralateral ankle. This increased from 35% (0-100) to 66% (15-120) to 76% (15-100) (p = 0.059). Function improved from 2.3 (0-3) to 1.3 (0-3) to 0.6 (0-3) (p < 0.001). Pain decreased from 7.4 (2-10) to 4.4 (2-8) to 2.1 (0-7) (p < 0.01). Complications include one patient with sensory neuralgia. CONCLUSIONS: Preliminarily, results of subtalar distraction arthroplasty as a new joint preservation technique are encouraging. Our research suggests the possibility of subtalar distraction arthroplasty as an effective treatment for symptomatic subtalar OA. Furthermore, this new operation does not eliminate the possibility of a future surgery like fusion. Subtalar distraction arthroplasty can be helpful in the management of subtalar OA in active patients who desire preservation of foot and ankle motion.


Assuntos
Articulação do Tornozelo/cirurgia , Artrodese/métodos , Artroplastia/métodos , Transplante de Medula Óssea/métodos , Fixadores Externos , Osteoartrite/cirurgia , Articulação Talocalcânea/cirurgia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
12.
Clin Podiatr Med Surg ; 38(1): 1-16, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33220739

RESUMO

Bone marrow aspirate (BMA) is an emerging therapy that is gaining popularity for orthoplastic reconstruction. The stem cells collected are multipotent and regenerative in nature. In addition to stem cells, other biological components collected augment the mitogen of local cells, proliferation, and angiogenesis, and inhibit proinflammatory cytokine and bacteria to optimize an environment to heal. The most common site for harvest is the iliac crest. Techniques for harvesting BMA are simple to perform, financially modest, and associated with low morbidity. Additional research is needed to evolve and standardize the technology; however, BMA is proven to be advantageous for tissue repair.


Assuntos
Transplante de Medula Óssea/métodos , Fraturas Ósseas/terapia , Ligamentos Articulares/cirurgia , Traumatismos dos Nervos Periféricos/terapia , Traumatismos dos Tendões/terapia , Calcâneo , Contraindicações de Procedimentos , Consolidação da Fratura , Humanos , Ílio , Ligamentos Articulares/lesões , Plasma Rico em Plaquetas , Tíbia , Cicatrização
13.
Ann Clin Lab Sci ; 50(6): 781-789, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33334794

RESUMO

OBJECTIVE: Major ABO incompatible hematopoietic progenitors from bone marrow (HPC(M)) donor collections that are destined for clinical transplantation are typically processed to deplete products of red blood cells (RBCs). The purpose of this study was to compare RBC depletion when using the Spectra Optia® relative to a 2-step method involving a COBE2991 instrument to obtain a buffy coat followed by a hydroxyethyl starch (HES) density gradient (COBE+HES) of the buffy coat. METHODS: Post-processing recoveries of products undergoing 4, 8, and 10 bone marrow processing (BMP) cycles (i.e. 1 cycle=1 volume of HPC(M)) with the Spectra Optia® were determined for volume, RBC content, viable total nucleated cells (vTNC), viable CD34+ cells (vCD34), viable CD3+ cells (vCD3) and colony-forming-cells (CFC). Subsequent RBC depletions with Spectra Optia® were then performed with 10 BMP cycles on additional HPC(M) collections and were compared against a retrospective analysis of historical COBE+HES post-processing data. RESULTS: Ten BMP cycles of HPC(M) (n=6) products were identified as optimal with volume reductions of 81.3±1.6 % and RBC reductions of 97.0±0.6 % with the Spectra Optia®. This also resulted in an average of 0.28 ±0.14 mL of RBC/kg (mean±SD; n=6) with vTNC yields of 65.0±10.9%, vCD34+ yields of 98.5±12.7%, and vCD3+ yields of 90.6±10.0%. Recoveries with the COBE+HES methodology resulted in vTNC recoveries of 62.9±20.5% (mean±SD; n=30) and 0.63±0.71 mL of RBC/kg (mean±SD; n=30). CONCLUSIONS: The Spectra Optia® is a viable option for depleting HPC(M) harvests of contaminating RBC in situations of ABO incompatibility. Target cells from a MNC rich fractionation were preserved through processing while eliminating RBC contaminants.


Assuntos
Remoção de Componentes Sanguíneos/métodos , Eritrócitos/imunologia , Células-Tronco Hematopoéticas/metabolismo , Sistema ABO de Grupos Sanguíneos/metabolismo , Medula Óssea/imunologia , Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Separação Celular/métodos , Voluntários Saudáveis , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/patologia , Humanos , Estudos Retrospectivos , Doadores de Tecidos
14.
N Z Med J ; 133(1527): 104-110, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33332332

RESUMO

Multiple myeloma is the second most common blood cancer in New Zealand with higher incidence in Maori and Pacific Island populations. It remains an incurable disease but the rapidly changing treatment landscape has led to improved outcome. In response to recent changes in funding of anti-myeloma therapy in New Zealand, the New Zealand Myeloma Interest Group has reviewed the latest literature and updated the treatment pathway of transplant-eligible patients with newly diagnosed multiple myeloma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Quimioterapia de Consolidação , Quimioterapia de Indução , Quimioterapia de Manutenção , Mieloma Múltiplo/terapia , Transplante de Medula Óssea/métodos , Bortezomib/administração & dosagem , Consenso , Quimioterapia de Consolidação/métodos , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Quimioterapia de Indução/métodos , Lenalidomida , Nova Zelândia , Guias de Prática Clínica como Assunto , Talidomida/administração & dosagem
15.
Sci Rep ; 10(1): 19891, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199760

RESUMO

Cell therapy using intramuscular injections of autologous bone-marrow mononuclear cells (BM-MNCs) improves clinical symptoms and can prevent limb amputation in atherosclerotic peripheral arterial disease (PAD) patients with critical limb ischemia (CLI). The purpose of this study was to evaluate the effects of the number of implanted BM-MNCs on clinical outcomes in atherosclerotic PAD patients with CLI who underwent cell therapy. This study was a retrospective observational study with median follow-up period of 13.5 years (range, 6.8-15.5 years) from BM-MNC implantation procedure. The mean number of implanted cells was 1.2 ± 0.7 × 109 per limb. There was no significant difference in number of BM-MNCs implanted between the no major amputation group and major amputation group (1.1 ± 0.7 × 109 vs. 1.5 ± 0.8 × 109 per limb, P = 0.138). There was also no significant difference in number of BM-MNCs implanted between the no death group and death group (1.5 ± 0.9 × 109 vs. 1.8 ± 0.8 × 109 per patient, P = 0.404). Differences in the number of BM-MNCs (mean number, 1.2 ± 0.7 × 109 per limb) for cell therapy did not alter the major amputation-free survival rate or mortality rate in atherosclerotic PAD patients with CLI. A large number of BM-MNCs will not improve limb salvage outcome or mortality.


Assuntos
Células da Medula Óssea/citologia , Transplante de Medula Óssea/métodos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Extremidades/fisiopatologia , Isquemia/terapia , Salvamento de Membro , Idoso , Feminino , Seguimentos , Humanos , Isquemia/patologia , Masculino , Prognóstico , Estudos Retrospectivos , Transplante Autólogo
16.
Br J Haematol ; 191(4): 612-616, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33190255

RESUMO

Bone marrow transplantation (BMT) has evolved over the last 60 years from a pioneering treatment fraught with unknown factors and complications to a widely practiced standard of care that has saved the lives of countless individuals with malignant and non-malignant conditions. Over this period, transplanters in the UK have made a significant international contribution to the field through cutting edge clinical and laboratory research. Today, stem cell transplantation in the UK continues to advance through rigorous and innovative clinical trials which focus on improving outcome by reducing transplant toxicity and the risk of disease relapse. In this review, we start with a personal view of the early years of BMT in the UK, document the many seminal accomplishments in the field of BMT which took place in the UK, and end with a look towards the future of BMT, in the UK and worldwide.


Assuntos
Transplante de Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/história , Transplante de Medula Óssea/métodos , Ensaios Clínicos como Assunto , Transplante de Células-Tronco Hematopoéticas/história , Transplante de Células-Tronco Hematopoéticas/métodos , História do Século XX , História do Século XXI , Humanos , Avaliação de Resultados em Cuidados de Saúde , Transplante Autólogo , Transplante Homólogo , Reino Unido
17.
Front Immunol ; 11: 584950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240273

RESUMO

A match of HLA loci between patients and donors is critical for successful hematopoietic stem cell transplantation. However, the extreme polymorphism of HLA loci - an outcome of millions of years of natural selection - reduces the chances that two individuals will carry identical combinations of multilocus HLA genotypes. Further, HLA variability is not homogeneously distributed throughout the world: African populations on average have greater variability than non-Africans, reducing the chances that two unrelated African individuals are HLA identical. Here, we explore how self-identification (often equated with "ethnicity" or "race") and genetic ancestry are related to the chances of finding HLA compatible donors in a large sample from Brazil, a highly admixed country. We query REDOME, Brazil's Bone Marrow Registry, and investigate how different criteria for identifying ancestry influence the chances of finding a match. We find that individuals who self-identify as "Black" and "Mixed" on average have lower chances of finding matches than those who self-identify as "White" (up to 57% reduction). We next show that an individual's African genetic ancestry, estimated using molecular markers and quantified as the proportion of an individual's genome that traces its ancestry to Africa, is strongly associated with reduced chances of finding a match (up to 60% reduction). Finally, we document that the strongest reduction in chances of finding a match is associated with having an MHC region of exclusively African ancestry (up to 75% reduction). We apply our findings to a specific condition, for which there is a clinical indication for transplantation: sickle-cell disease. We show that the increased African ancestry in patients with this disease leads to reduced chances of finding a match, when compared to the remainder of the sample, without the condition. Our results underscore the influence of ancestry on chances of finding compatible HLA matches, and indicate that efforts guided to increasing the African component of registries are necessary.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Anemia Falciforme/genética , Medula Óssea/cirurgia , Transplante de Medula Óssea/métodos , Brasil , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene/genética , Genótipo , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Humanos , Polimorfismo Genético/genética , Sistema de Registros , Doadores não Relacionados
18.
Sci Rep ; 10(1): 16514, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020528

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency leads to lower cholesterol and is associated with reduced vascular complications in the general population. Cholesterol lowering may also have beneficial effects in sickle cell disease (SCD). The objective of this study was to determine effects of PCSK9 deficiency in a mouse model of SCD. Bone marrow transplantation (BMT) was performed from donor SCD mice to wild-type, PCSK9-deficient, and LDLR-deficient recipients to generate SCD controls (Pcsk9+/+, SCDbmt) with preserved PCSK9 status, SCD mice with deficiency of PCSK9 (Pcsk9-/-, SCDbmt), and SCD mice with deficiency of LDLR (Ldlr-/-, SCDbmt). Although cholesterol levels were lower in Pcsk9-/-, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice, anemia was more severe in Pcsk9-/-, SCDbmt mice. Increased reticulocytosis, enhanced ex vivo erythrocyte sickling, and increased erythrocyte phosphatidylserine exposure was also observed. Livers, spleens, and kidneys contained increased iron in Pcsk9-/-, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice consistent with greater hemolysis. SCD mice with deficiency of LDLR (Ldlr-/-, SCDbmt mice) had similar anemia as Ldlr+/+, SCDbmt mice despite higher serum cholesterol. In conclusion, deficiency of PCSK9 is associated with worsened anemia in SCD mice due to increased hemolysis. These findings may have implications for lipid-lowering strategies in patients with SCD, as well as for potential novel modifiers of anemia severity.


Assuntos
Anemia Falciforme/fisiopatologia , Anemia/metabolismo , Pró-Proteína Convertase 9/metabolismo , Anemia/fisiopatologia , Anemia Falciforme/metabolismo , Animais , Transplante de Medula Óssea/métodos , Colesterol/metabolismo , LDL-Colesterol/sangue , Modelos Animais de Doenças , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/fisiologia , Pró-Proteína Convertases/metabolismo , Receptores de LDL/metabolismo , Receptores de LDL/fisiologia , Serina Endopeptidases/metabolismo , Subtilisinas/metabolismo
19.
Ann Hematol ; 99(12): 2723-2729, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32935189

RESUMO

Despite the increasing role of molecular markers, differential counts and morphology of hematopoietic cells in the bone marrow (BM) remain essential diagnostic criteria in hematological diseases. However, the respective reference values for BM myelogram commonly used came from small series with limited numbers of healthy individuals. We evaluated the myelograms of 236 healthy individuals who underwent unrelated bone marrow donation. Health check-ups were performed 4 weeks prior to harvest. Samples for this study, taken from the first aspiration, were stained according to the standard Pappenheim method. Three experienced investigators assessed cellularity, megakaryopoiesis, and differential counts independently. The median donor age was 31 (range 18-51) years. Predonation tests did not reveal any relevant morbidity. Thirty-seven out of 42 hypocellular marrow samples were from younger donors up to 39 years. Content of megakaryocytes was normal in 210 specimens (89%). Gender and body mass index had significant impact on hematopoiesis, whereas age had not. The number of erythroblasts was higher (about 32%) and the proportion granulopoiesis slightly lower (about 50%) compared with previous studies. Differential counts showed also some differences with respect to individual maturation stages in these lines. Interrater comparisons showed greater reliability for the assignment of cells to the different hematopoietic cell lines than for single-cell diagnoses. This study largely confirms the results for cell counts in normal human bone marrow available from previous reports and provides some insights into factors that affect individual cell populations. It also reveals substantial variability among even experienced investigators in cytological diagnoses.


Assuntos
Contagem de Células Sanguíneas/normas , Células da Medula Óssea/fisiologia , Transplante de Medula Óssea/normas , Doadores Vivos , Adolescente , Adulto , Contagem de Células Sanguíneas/métodos , Transplante de Medula Óssea/métodos , Contagem de Células/métodos , Contagem de Células/normas , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
20.
Pediatr Blood Cancer ; 67(10): e28444, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32776425

RESUMO

BACKGROUND: Recent data show survival after matched unrelated donor (MUD) bone marrow transplantation (BMT) is similar to matched sibling procedures for young patients with severe aplastic anemia (SAA). Donor delays, risk of transplant-related mortality (TRM), and concern about chronic graft versus host disease raise questions about whether MUD BMT or immune suppression therapy (IST) should be preferred initial therapy for young patients lacking matched sibling donors. PROCEDURE: We performed a pilot trial to assess the feasibility of randomizing patients under age 26 with newly diagnosed SAA to receive IST versus MUD BMT. Primary aims assessed the acceptability of randomization and timing of BMT. Secondary aims measured toxicities, response, and survival. RESULTS: Sixty-seven patients with possible SAA were screened at nine centers. Of 57 with confirmed SAA, 23 underwent randomization and received therapy with a median follow-up of 18 months. Of 12 randomized to BMT, 10 started BMT as initial therapy at a median of 36 days after randomization. One BMT recipient experienced secondary graft failure, requiring a second procedure. Six of 11 randomized to IST responded, whereas five with refractory disease underwent successful salvage BMT. One patient achieving complete response relapsed after discontinuation of immune suppression and died of infection after salvage BMT. CONCLUSIONS: This feasibility study showed that a high percentage of patients underwent randomization and received up-front MUD BMT. Our study lays the groundwork for a larger randomized trial that will define best initial therapy for young patients with SAA who have an available MUD.


Assuntos
Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Transplante de Medula Óssea/métodos , Imunossupressores/uso terapêutico , Seleção de Pacientes , Tempo para o Tratamento/normas , Adolescente , Adulto , Criança , Pré-Escolar , Terapia Combinada , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Lactente , Masculino , Projetos Piloto , Prognóstico , Doadores não Relacionados , Adulto Jovem
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