Brain Metabolite Differences in Fetuses With Cytomegalovirus Infection: A Magnetic Resonance Spectroscopy Study.

BACKGROUND: Cytomegalovirus (CMV) is the most common intrauterine infection and may be associated with unfavorable outcomes. While some CMV-infected fetuses may show gross or subtle brain abnormalities on MRI, their clinical significance may be unclear. Conversely, normal development cannot be guaranteed in CMV-infected fetuses with normal MRI. PURPOSE: To assess brain metabolite differences in CMV-infected fetuses using magnetic resonance spectroscopy (MRS). STUDY TYPE: Retrospective. SUBJECTS: Out of a cohort of 149 cases, 44 with maternal CMV infection, amniocentesis results, and good-quality MRS were included. CMV-infected fetuses with positive polymerase chain reaction (PCR) (N = 35) were divided based on MRI results as follows: typical brain abnormalities (gross findings, N = 8), exclusive white matter hyperintense signal (WMHS) on T2-weighted images (subtle findings, N = 7), and normal MRI (N = 20). Uninfected fetuses (negative PCR) with normal MRI were included as controls (N = 9). FIELD STRENGTH: 3 T, T2-weighted half Fourier single-shot turbo spin-echo (HASTE), T2-weighted true fast imaging with steady-state free precession (TrueFISP), T1- and T2*-weighted fast low angle shot (FLASH), and 1H-MRS single-voxel point resolved spectroscopy (PRESS) sequences. ASSESSMENT: MRI findings were assessed by three radiologists, and metabolic ratios within the basal ganglia were calculated using LCModel. STATISTICAL TESTS: Analysis of covariance test with Bonferroni correction for multiple comparisons was used to compare metabolic ratios between groups while accounting for gestational age. A P-value <0.05 was deemed significant. RESULTS: MRS was successfully acquired in 63% of fetuses. Substantial agreement was observed between radiologists (Fleiss' kappa [k] = 0.8). Infected fetuses with gross MRI findings exhibited significantly reduced tNAA/tCr ratios (0.64 ± 0.08) compared with infected fetuses with subtle MRI findings (0.85 ± 0.19), infected fetuses with normal MRI (0.8 ± 0.14) and controls (0.81 ± 0.15). No other significant differences were detected (P ≥ 0.261). CONCLUSION: Reduced tNAA/tCr within the apparently normal brain tissue was detected in CMV-infected fetuses with gross brain abnormalities, suggesting extensive brain damage. In CMV-infected fetuses with isolated WMHS, no damage was detected by MRS. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Heparanase expression in periapical granulomas and radicular cysts.

Heparanase is an endo-ß-D-glucuronidase enzyme which degrades heparan sulfate glycosaminoglycan side chains of proteoglycans in the extracellular matrix and in basement membranes. The aim of this study was to evaluate the expression of heparanase in periapical granulomas (PGs) and radicular cysts (RCs). Immunohistochemistry was used to assess heparanase expression in PGs and RCs. Parameters including stain intensity, location and cell type were used to characterize heparanase expression in the periapical lesions. Ordered categories (from weak to strong) were used to compare the level of heparanase staining in the PG and RC groups. Both epithelial cells and inflammatory cells were positive for heparanase. The relative staining of the epithelial cells was strong, whereas the relative staining of the inflammatory cells was weak. Significant differences in immunohistochemical staining of epithelial cells were observed between RCs and PGs (p = 0.002). The relative expression of heparanase in epithelial cells in RCs was strong. In PGs, lesions with few or no epithelial cells, heparanase was predominantly expressed weakly by inflammatory cells. PGs and RCs have the same infectious origin. Therefore, the different cellular sources of heparanase in these periapical lesions may imply that this enzyme has specific pathogenetic functions in RCs and PGs.

[A novel miniplate model for maxillary osteotomies]. / Nouveau modèle de miniplaques pour les ostéotomies maxillaires.

INTRODUCTION: The use of miniplates in orthognatic surgery, and especially for Le Fort I osteotomies, has brought great improvement in technical aspects, postoperative evolution, and long-term stability. Nevertheless, accurate modelling of theses plates remains problematic because the right balance between malleability and rigidity is hard to determine. This is why we designed an original new miniplate model. The aim of this study was to assess our new model in clinical settings. MATERIAL AND METHOD: This novel plate was made of two lateral sockets with two holes on each side, linked by a central bar, 1mm thick like the plate. Three lengths were available. A mechanical study proved that this plate was stronger than a 0.6 millimeter thick plate and that its adaptability was much superior to that of a common 1-mm thick plate. We retrospectively studied 180 patients having undergone a Le Fort I osteotomy with or without mandibular osteotomy. Follow-up ranged from 6 to 12 months. Congenital abnormalities were excluded. RESULTS: Bone healing was achieved without any complication in due time for all but two patients. In one case, a plate fracture was observed. In the other case, a slight mobility of the upper jaw appeared after removal of the device. No intolerance was observed. DISCUSSION: This novel miniplate seems to be improved when compared to other available devices. Rigid osteosynthesis of a Le Fort I osteotomy can be problematic because of the repositioning gap and the variable anatomy of the maxilla. The device must be rigid enough, inconspicuous, and well tolerated. Only three plate lengths are necessary to treat all cases, which reduces cost and storage. The only requirement is to mandatorily insert four plates every time. Removal of the plates does not seem necessary.

Protein profiling of non-malignant and malignant ascites by SELDI-TOF MS: proof of principle.

Ascites is a common clinical symptom in liver cirrhosis, inflammatory disorders of the abdomen and a major late manifestation of metastatic malignancies. Standard cytopathological techniques and immunocytochemistry have specificities and sensitivities of approximately 95 and 60%, respectively for the presence of tumor cells. Development of faster and more accurate screening methods would be of great clinical utility. In this work we examined differential analysis of the unbound proteins in the supernatant of ascites fluid by Protein-Chip SELDI mass spectrometry. There were 21 tumor cell-positive and 34 tumor cell-negative samples. We used principal component analysis coupled with linear regression applied to the mass spectra of the samples to distinguish between the sample groups. Two sample sets for statistical analysis were created after randomization, a training set with 37 samples and a validation set with 18 samples resulting in a specificity of 93% and a sensitivity of 83% on the training set. The validation set yielded a specificity and sensitivity of 75%. This study suggests that SELDI-TOF mass spectrometry appears to have great potential as a surrogate diagnostic tool to evaluate effusion specimens.

Long-term survival without graft-versus-host-disease following infusion of allogeneic myeloma-specific Vß T cell families.

BACKGROUND: Despite chemo-induction therapy and autologous stem cell transplantation (ASCT), the vast majority of patients with Multiple Myeloma (MM) relapse within 7 years and the disease remains incurable. Adoptive Allogeneic T-cell therapy (ATCT) might be curative for MM, however current ATCT protocols often lead to graft versus host disease (GvHD). Transplanting only tumor reactive donor T cells that mediate a graft-versus-myeloma (GvM) but not GvHD may overcome this problem. METHODS: We used an MHC-matched/miHA-disparate B10.D2 → Balb/c bone marrow transplantation (BMT) murine model and MOPC315.BM MM cells to develop an ATCT protocol consisting of total body irradiation, autologous-BMT and infusion of selective, myeloma-reactive lymphocytes of T cell receptor (TCR) Vß 2, 3 and 8.3 families (MM-auto BMT ATCT). RESULTS: Pre-stimulation ex vivo of allogeneic T cells by exposure to MOPC315.BM MM cells in the presence of IL-2, anti-CD3 and anti-CD28 resulted in expansion of the myeloma-reactive T cell TCRVß 2, 3 and 8.3 subfamilies. Their isolation and infusion into MM-bearing mice resulted in a vigorous GvM response without induction GvHD and long-term survival. Repeated infusion of naïve myeloma-reactive T cell TCRVß 2, 3 and 8.3 subfamilies was also effective. CONCLUSIONS: These data demonstrate that a transplantation protocol involving only selective tumor-reactive donor T cell families is an effective immunotherapy and results in long-term survival in a mouse model of human MM. The results highlight the need to develop similar ATCT strategies for MM patients that result in enhanced survival without symptoms of GvHD.

Time to engraftment following allogeneic stem cell transplantation is significantly longer in patients with myelodysplastic syndrome than with acute myeloid leukemia.

Patients with myelodysplastic syndrome (MDS) commonly present with pancytopenia, suggesting that the marrow stroma fails to support the growth of both malignant and normal stem cells. We therefore retrospectively analyzed the duration to engraftment of neutrophils (> or =0.5 x 10(9)/l and > or =1.0 x 10(9)/l) and platelets (> or =20 and > or =50 x 10(9)/l) in 37 MDS patients and 42 patients suffering from primary AML, following allogeneic SCT. A significantly shorter time to engraftment was documented in AML as compared to MDS patients in all four parameters. These results held true even when we subgrouped the patients according to gender, age (50 years being the cutoff age between young and elderly patients), patient-donor relationship, donor match and intensity of conditioning. To the best of our knowledge, this is the first time that such a comparison has been made. We suggest that the longer duration of post transplant pancytopenia that is frequently observed in MDS patients may also influence post transplant outcome.

Patient-specific medial unicompartmental knee arthroplasty has a greater protective effect on articular cartilage in the lateral compartment: A Finite Element Analysis.

OBJECTIVES: Patient-specific (PS) implantation surgical technology has been introduced in recent years and a gradual increase in the associated number of surgical cases has been observed. PS technology uses a patient's own geometry in designing a medical device to provide minimal bone resection with improvement in the prosthetic bone coverage. However, whether PS unicompartmental knee arthroplasty (UKA) provides a better biomechanical effect than standard off-the-shelf prostheses for UKA has not yet been determined, and still remains controversial in both biomechanical and clinical fields. Therefore, the aim of this study was to compare the biomechanical effect between PS and standard off-the-shelf prostheses for UKA. METHODS: The contact stresses on the polyethylene (PE) insert, articular cartilage and lateral meniscus were evaluated in PS and standard off-the-shelf prostheses for UKA using a validated finite element model. Gait cycle loading was applied to evaluate the biomechanical effect in the PS and standard UKAs. RESULTS: The contact stresses on the PE insert were similar for both the PS and standard UKAs. Compared with the standard UKA, the PS UKA did not show any biomechanical effect on the medial PE insert. However, the contact stresses on the articular cartilage and the meniscus in the lateral compartment following the PS UKA exhibited closer values to the healthy knee joint compared with the standard UKA. CONCLUSION: The PS UKA provided mechanics closer to those of the normal knee joint. The decreased contact stress on the opposite compartment may reduce the overall risk of progressive osteoarthritis.Cite this article: K-T. Kang, J. Son, D-S. Suh, S. K. Kwon, O-R. Kwon, Y-G. Koh. Patient-specific medial unicompartmental knee arthroplasty has a greater protective effect on articular cartilage in the lateral compartment: A Finite Element Analysis. Bone Joint Res 2018;7:20-27. DOI: 10.1302/2046-3758.71.BJR-2017-0115.R2.

A computational simulation study to determine the biomechanical influence of posterior condylar offset and tibial slope in cruciate retaining total knee arthroplasty.

OBJECTIVES: Posterior condylar offset (PCO) and posterior tibial slope (PTS) are critical factors in total knee arthroplasty (TKA). A computational simulation was performed to evaluate the biomechanical effect of PCO and PTS on cruciate retaining TKA. METHODS: We generated a subject-specific computational model followed by the development of ± 1 mm, ± 2 mm and ± 3 mm PCO models in the posterior direction, and -3°, 0°, 3° and 6° PTS models with each of the PCO models. Using a validated finite element (FE) model, we investigated the influence of the changes in PCO and PTS on the contact stress in the patellar button and the forces on the posterior cruciate ligament (PCL), patellar tendon and quadriceps muscles under the deep knee-bend loading conditions. RESULTS: Contact stress on the patellar button increased and decreased as PCO translated to the anterior and posterior directions, respectively. In addition, contact stress on the patellar button decreased as PTS increased. These trends were consistent in the FE models with altered PCO. Higher quadriceps muscle and patellar tendon force are required as PCO translated in the anterior direction with an equivalent flexion angle. However, as PTS increased, quadriceps muscle and patellar tendon force reduced in each PCO condition. The forces exerted on the PCL increased as PCO translated to the posterior direction and decreased as PTS increased. CONCLUSION: The change in PCO alternatively provided positive and negative biomechanical effects, but it led to a reduction in a negative biomechanical effect as PTS increased.Cite this article: K-T. Kang, Y-G. Koh, J. Son, O-R. Kwon, J-S. Lee, S. K. Kwon. A computational simulation study to determine the biomechanical influence of posterior condylar offset and tibial slope in cruciate retaining total knee arthroplasty. Bone Joint Res 2018;7:69-78. DOI: 10.1302/2046-3758.71.BJR-2017-0143.R1.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis.

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Allogeneic hematopoietic stem cell transplantation in the elderly.

The development of reduced intensity or non-myeloablative conditioning (NST) in preparation for allogeneic stem cell transplantation (SCT) revolutionized the field and led to reconsideration of the dogma of upper age limit that was set up by the transplant centers as an eligibility parameter. Analysis of the literature data showed that NST regimens are associated with decreased transplant related mortality, and graft-versus-host disease, in comparison with standard myeloablative conditioning, in patients above the age of 50-55 years, or in younger patients with significant comorbidities. However we have to mention, that our considerations are based on the retrospective analysis of the literature data, and that well controlled prospective randomized studies are needed in order to definitely assess the role of NST. Comorbidity indices might be proved as the most important parameters for the choice of the most proper regimen for each patient in need and should be included in future trials.

Peliosis hepatis following treatment with androgen-steroids in patients with bone marrow failure syndromes.

Androgens widely used in the treatment of bone marrow failure syndromes can in rare cases cause hepatic peliosis, a pathological entity characterized by multiple blood-filled cavities in the liver parenchyma. Bone marrow failure syndromes per se are associated with a low coagulation status, which is further magnified by bone marrow transplantation for aplastic anaemia due to deep thrombocytopenia. Both these conditions can cause bleeding; their combination is especially dangerous. We describe two cases of aplastic anaemia due to paroxysmal nocturnal hemoglobinuria and Fanconi syndrome, in which patients developed peliosis hepatis after prolonged treatment with androgens. One patient developed severe subcapsular bleeding, successfully treated with catheterization of the right hepatic artery and embolization of the bleeding site. The second patient bridged over deep post-transplant aplasia with high frequency platelet transfusions, and demonstrated an uncomplicated post-BMT course. We suggest avoiding or interrupting treatment with androgens in patients preparing for BMT.

Allogeneic stem cell transplantation from matched related and unrelated donors in thalassemia major patients using a reduced toxicity fludarabine-based regimen.

The only radical cure for thalassemia major patients today is the replacement of the defective hematopoietic system by allogeneic stem cell transplantation (allo-SCT). The major obstacles for the application of allo-SCT even from matched family members have been the transplant-related morbidity and mortality and graft failure that is usually associated with the recurrence of the thalassemia hematopoiesis. The outcome of allo-SCT from HLA-identical family donors is largely dependent on the age of the recipient as well as on pretransplant parameters reflecting the degree of organ damage from iron overload. In this study we report our experience of allo-SCT from matched related and unrelated donors, using a reduced toxicity conditioning consisting of fludarabine, busulfan or more recently busulfex and antithymocyte globulin, in a cohort of 20 patients with thalassemia major. The regimen-related toxicity was minimal, while the incidence of acute grade II-IV and chronic GVHD was 25 and 25%, respectively. With a median follow-up period of 39 months (range: 5-112 months) the overall survival was 100%, while thalassemia-free survival was 80%. Although the results of our study look promising, larger cohorts of patients and prospective clinical trials are required to confirm the benefits of our approach as a possible better alternative to the existing protocols.

Haematopoietic stem cell transplantation trends in children over the last three decades: a survey by the paediatric diseases working party of the European Group for Blood and Marrow Transplantation.

This paper describes the trends in haematopoietic stem cell transplantation (HSCT) activity for children in Europe over the last three decades. We analysed 31,713 consecutive paediatric HSCTs reported by the European Group for Blood and Marrow Transplantation (EBMT) centres between 1970 and 2002. Data were taken from the EBMT registry and were compared according to period and centre category (paediatric or combined). Since 1996, there has been a significant increase in the number of HSCTs performed exclusively by paediatric centres, as well as in the number of alternative donor HSCTs, and in the use of peripheral blood stem cells (P<0.0001). The number of allogeneic HSCTs (allo-HSCTs) for acute lymphoblastic leukaemia, acute myeloblastic leukaemia and chronic myeloid leukaemia remained stable, whereas it increased for myelodysplastic syndromes and lymphomas, and decreased significantly for non-malignant diseases (P<0.0001). Multivariate analysis showed that younger age, human leukocyte antigen genoidentical donors, HSCT performed after 1996 and transplant centres performing more than 10 allo-HSCT/year were all associated with decreased transplant-related mortality (TRM) (P<0.0001). The number of autologus HSCTs (auto-HSCTs) for acute leukaemia decreased significantly, whereas it increased for solid tumours (P<0.0001). Multivariate analysis showed that both auto-HSCT performed before 1996 and paediatric solid tumours (P<0.0001) had higher TRM. Indications for paediatric HSCT have changed considerably during the last seven years. These changes provide tools for decision making in health-care planning and counselling.

A patient with progressive multiple myeloma treated successfully with arsenic trioxide after allogeneic bone marrow transplantation.

Multiple myeloma (MM) is an incurable progressive disease. Many therapeutic options are available to delay progression, including autologous and allogeneic bone marrow transplantation. At advanced stages, MM is often refractory to treatment. We report a heavily pretreated patient with graft-versus-host disease after bone marrow transplantations, treated at a terminal stage with a modified protocol for arsenic trioxide (ATO). This patient with poor clinical status tolerated the treatment very well. He had a remarkable clinical response and achieved complete remission. The mechanisms of ATO are presented and the potential role of ATO for MM is discussed.

Regional intra-arterial steroid treatment in 120 patients with steroid-resistant or -dependent GvHD.

GvHD results in death in the majority of steroid-resistant patients. This report assesses the safety and efficacy of two regional intra-arterial steroid (IAS) treatment protocols in the largest published cohort of patients with resistant/dependent hepatic and/or gastrointestinal GvHD, as well as identification of predictors of response to IAS and survival. One hundred and twenty patients with hepatic, gastrointestinal GvHD or both were given IAS. Gastrointestinal initial response (IR) and complete response (CR) were documented in 67.9% and 47.6%, respectively, whereas hepatic IR/CR in 54.9% and 33.3%, respectively. The predictors of gastrointestinal CR were lower peak GvHD and steroid-dependent (SD) GvHD. The predictors for hepatic CR were male patient, reduced intensity conditioning and SD GvHD. Twenty-six of the 120 patients (21.6%) are currently alive (median follow-up for the survivors 91.5 months). The 12 months' overall survival is 30% with no treatment-associated deaths. Predictors of 12 months' survival were as follows: first transplant, age<20 years, non-TBI regimen and GvHD CR. Shorter time to gastrointestinal IR but not time to hepatic IR was associated with improved 12 months' survival. IAS appears to be safe and effective. Gastrointestinal treatment is more effective than hepatic treatment. In our study, we conclude our current recommendations for IAS treatment.

Computational study on the effect of malalignment of the tibial component on the biomechanics of total knee arthroplasty: A Finite Element Analysis.

OBJECTIVES: Malalignment of the tibial component could influence the long-term survival of a total knee arthroplasty (TKA). The object of this study was to investigate the biomechanical effect of varus and valgus malalignment on the tibial component under stance-phase gait cycle loading conditions. METHODS: Validated finite element models for varus and valgus malalignment by 3° and 5° were developed to evaluate the effect of malalignment on the tibial component in TKA. Maximum contact stress and contact area on a polyethylene insert, maximum contact stress on patellar button and the collateral ligament force were investigated. RESULTS: There was greater total contact stress in the varus alignment than in the valgus, with more marked difference on the medial side. An increase in ligament force was clearly demonstrated, especially in the valgus alignment and force exerted on the medial collateral ligament also increased. CONCLUSION: These results highlight the importance of accurate surgical reconstruction of the coronal tibial alignment of the knee joint. Varus and valgus alignments will influence wear and ligament stability, respectively in TKA.Cite this article: D-S. Suh, K-T. Kang, J. Son, O-R. Kwon, C. Baek, Y-G. Koh. Computational study on the effect of malalignment of the tibial component on the biomechanics of total knee arthroplasty: A Finite Element Analysis. Bone Joint Res 2017;6:623-630. DOI: 10.1302/2046-3758.611.BJR-2016-0088.R2.

Preservation of kinematics with posterior cruciate-, bicruciate- and patient-specific bicruciate-retaining prostheses in total knee arthroplasty by using computational simulation with normal knee model.

OBJECTIVES: Preservation of both anterior and posterior cruciate ligaments in total knee arthroplasty (TKA) can lead to near-normal post-operative joint mechanics and improved knee function. We hypothesised that a patient-specific bicruciate-retaining prosthesis preserves near-normal kinematics better than standard off-the-shelf posterior cruciate-retaining and bicruciate-retaining prostheses in TKA. METHODS: We developed the validated models to evaluate the post-operative kinematics in patient-specific bicruciate-retaining, standard off-the-shelf bicruciate-retaining and posterior cruciate-retaining TKA under gait and deep knee bend loading conditions using numerical simulation. RESULTS: Tibial posterior translation and internal rotation in patient-specific bicruciate-retaining prostheses preserved near-normal kinematics better than other standard off-the-shelf prostheses under gait loading conditions. Differences from normal kinematics were minimised for femoral rollback and internal-external rotation in patient-specific bicruciate-retaining, followed by standard off-the-shelf bicruciate-retaining and posterior cruciate-retaining TKA under deep knee bend loading conditions. Moreover, the standard off-the-shelf posterior cruciate-retaining TKA in this study showed the most abnormal performance in kinematics under gait and deep knee bend loading conditions, whereas patient-specific bicruciate-retaining TKA led to near-normal kinematics. CONCLUSION: This study showed that restoration of the normal geometry of the knee joint in patient-specific bicruciate-retaining TKA and preservation of the anterior cruciate ligament can lead to improvement in kinematics compared with the standard off-the-shelf posterior cruciate-retaining and bicruciate-retaining TKA.Cite this article: Y-G. Koh, J. Son, S-K. Kwon, H-J. Kim, O-R. Kwon, K-T. Kang. Preservation of kinematics with posterior cruciate-, bicruciate- and patient-specific bicruciate-retaining prostheses in total knee arthroplasty by using computational simulation with normal knee model. Bone Joint Res 2017;6:557-565. DOI: 10.1302/2046-3758.69.BJR-2016-0250.R1.

Long-term follow-up of a retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic transplantation from matched related donors in myelodysplastic syndromes.

This study shows the long-term updated outcomes of a multicenter retrospective study which analyzed 843 patients with myelodysplastic syndrome (MDS) who underwent transplantation with an HLA-identical sibling donor with either reduced-intensity conditioning (RIC) in 213 patients, or standard myeloablative conditioning (MAC) in 630 patients. In multivariate analysis, the 13-year relapse rate was significantly increased after RIC (31% after MAC vs 48% in RIC; HR, 1.5; 95% CI, 1.1-1.9; P=0.04), but with no differences in overall survival (OS) (30% after MAC vs 27% in RIC; P=0.4) and PFS (29 vs 21%, respectively, P=0.3). Non-relapse mortality was higher in MAC (40 vs 31%; P=0.1), especially in patients older than 50 years (50 vs 33%, P<0.01). In addition, long-term follow-up confirms the importance of other variables on 13-year OS, mainly MDS risk category, disease phase, cytogenetics and receiving a high donor cell dose, irrespective of the conditioning regimen used.