The aim of this paper is to present a treatment for scars based on percutaneous traction. This is a structural technique in which movements are performed against the barriers detected in different ...planes. The stages of this technique are described in detail along with the results after applying it to a postarthroscopic scar on a knee. The active and passive mobility of femoro-tibial and femoro-patellar articulations improved substantially after the treatment, as verified by signs such as pain relief, greater flexibility, disappearance of inflammation and a major recovery of tissue elasticity. A sonoelastography study of the portals and patellar tendon was carried out before and after therapy, showing semiquantitatively the recovery of the viscoelastic properties of the tissue.
Since enzyme replacement therapy for Gaucher disease (MIM#230800) has become available, both awareness of and the natural history of the disease have changed. However, there remain unmet needs such ...as the identification of patients at risk of developing bone crisis during therapy and late complications such as cancer or parkinsonism. The Spanish Gaucher Disease Registry has worked since 1993 to compile demographic, clinical, genetic, analytical, imaging and follow-up data from more than 400 patients. The aims of this study were to discover correlations between patients' characteristics at diagnosis and to identify risk features for the development of late complications; for this a machine learning approach involving correlation networks and decision trees analyses was applied.
A total of 358 patients, 340 type 1 Gaucher disease and 18 type 3 cases were selected. 18% were splenectomyzed and 39% had advanced bone disease. 81% of cases carried heterozygous genotype. 47% of them were diagnosed before the year 2000. Mean age at diagnosis and therapy were 28 and 31.5 years old (y.o.) respectively. 4% developed monoclonal gammopathy undetermined significance or Parkinson Disease, 6% cancer, and 10% died before this study. Previous splenectomy correlates with the development of skeletal complications and severe bone disease (p = 0.005); serum levels of IgA, delayed age at start therapy (> 9.5 y.o. since diagnosis) also correlates with severe bone disease at diagnosis and with the incidence of bone crisis during therapy. High IgG (> 1750 mg/dL) levels and age over 60 y.o. at diagnosis were found to be related with the development of cancer. When modelling the decision tree, patients with a delayed diagnosis and therapy were the most severe and with higher risk of complications.
Our work confirms previous observations, highlights the importance of early diagnosis and therapy and identifies new risk features such as high IgA and IgG levels for long-term complications.
Gaucher disease (GD) is a genetic lysosomal disorder characterized by high bone marrow (BM) involvement and skeletal complications. The pathophysiology of these complications is not fully elucidated. ...Magnetic resonance imaging (MRI) is the gold standard to evaluate BM. This study aimed to apply machine-learning techniques in a cohort of Spanish GD patients by a structured bone marrow MRI reporting model at diagnosis and follow-up to predict the evolution of the bone disease. In total, 441 digitalized MRI studies from 131 patients (M: 69, F:62) were reevaluated by a blinded expert radiologist who applied a structured report template. The studies were classified into categories carried out at different stages as follows: A: baseline; B: between 1 and 4 y of follow-up; C: between 5 and 9 y; and D: after 10 years of follow-up. Demographics, genetics, biomarkers, clinical data, and cumulative years of therapy were included in the model. At the baseline study, the mean age was 37.3 years (1-80), and the median Spanish MRI score (S-MRI) was 8.40 (male patients: 9.10 vs. female patients: 7.71) (
< 0.001). BM clearance was faster and deeper in women during follow-up. Genotypes that do not include the c.1226A>G variant have a higher degree of infiltration and complications (
= 0.017). A random forest machine-learning model identified that BM infiltration degree, age at the start of therapy, and femur infiltration were the most important factors to predict the risk and severity of the bone disease. In conclusion, a structured bone marrow MRI reporting in GD is useful to standardize the collected data and facilitate clinical management and academic collaboration. Artificial intelligence methods applied to these studies can help to predict bone disease complications.
Chronic fatigue (CFg) is a prevalent symptom in Gaucher disease (GD) at diagnosis (79%) and remains in a quarter of patients after years of therapy. Bone abnormalities are present in over 70% and ...peripheral neuropathy in about 11% of the patients, which contributes to the disabling and debilitating complications. Our hypothesis is that other factors such as muscle-tendinous weakness could have influence in the development of CFg.
We have evaluated the fiber structure and elasticity of muscle-tendinous unit by strain-elastography (S-ELA) and analyzed their influence in the CFg. S-ELA study was performed in Achilles tendon in 25 type 1 and two type 3 GD patients, all of them with fatigue and were on enzymatic replacement therapy for mean 13 years; simultaneously, bone marrow burden by MRI and calcaneus ultrasound densitometry were evaluated. Blood cell counts, plasma biomarkers, GBA1 genotyping, and SF36 quality of life scale (QoL) were also performed.
descriptive and comparative test.
All patients showed a normal Achilles tendinous structure. Abnormal stiff grade 2-3 was found in 17/27 (62.9%); in 11/27 (40.7%) of patients, the alteration was bilateral. There were no correlations between the S-ELA results to other variables; nevertheless, a significant correlation between the degree of tendon hardness and the low score on the QoL scales (p = 0.0035) was found. The S-ELA is a sensitive painless, fast, and low cost method to detect muscle-tendinous subclinical dysfunction that could contribute to CFg in GD. The identification of subclinical tendon alteration would be a sign of alarm, focused on the risk of development of bone complications.
Intratendinous alteration in strain-elastography is an independent variable in GD patients with persistent fatigue.
Bone involvement is the most common cause of functional limitation, disability and poor quality of life in patients with lysosomal storage disease (LSD). In type 1 Gaucher disease (GD1) intraosseous ...lesions have a vascular involvement with obstruction and / or local hemorrhage, once established it, secondary irreversible sequels with structure changes are developed. The intimate mechanisms that induce these feared complications are only partially known and the risk factors are not well established. There has been speculation about the relationship between the type of genetic defect and the severity of the disease. The most frequent mutations found in the Spanish population are point direction changes in the GBA gene (c.1226A> G (N370S) and c.1448T> C (L444P). However, other types of mutations (nonsense, splicing, frameshift stop codon, deletions, insertions, recombination) that induce a lower residual enzyme activity and, consequently, a higher storage rate and therefore more intensity of symptoms are found.
Objective: To analyze the relationship between different missense mutation and the presence and developing of vascular bone lesions in GD 1 patients.
Patients and Methods: We have analyzed the data obtained in our LSD Unit over the last 20 years in the evaluation of bone disease by magnetic resonance imaging with semi-quantitative estimation of the involvement by S-MRI and BMB scores and determination of bone mineral density by ultrasound in 131 GD patients (Andrade-Campos et al 2016). Here we present a sub-study in 85 patients heterozygous for c.1226A> G comparing the data obtained related to their genetic characteristics. According to the genotype were classified the patients in three groups, A: c.1226A> G / c.1448T> C (34), B: c.1226A> G in heterozygosity with other missense mutation (34) and C: c.1226A> G mutation with other types (17). In addition to search for plasma biomarkers associated to bone disease and verify them we have applied a targeted proteomics strategy. We have transformed monocytes to osteoclasts from these groups of patients and by proteomics profiles we have compared with osteoclasts of healthy controls by isobaric tag for relative and absolute quantification (iTRAQ). Labelling with iTRAQ in combination with sample pre-fractionation and nano liquid chromatography-tandem MS was used for identification and quantification of the basal proteome. More than 700 proteins were identified with this strategy. To verify the quantification of the proteins identified we have selected the MRM (multiple reaction monitoring) strategy for differential quantification according their highly sensitive, reproducible and accurate.
Results: The mean age at diagnosis for each of the groups was similar. A: 30.85 (6-68)> 30 years: 19 (55.88%), C: 28.52 (4-56)> 30 years: 8 (47%) And significantly lower in B: 18.32 (3-60;> 30years: 10 (29.41%) (p = 0.01). The M/F ratio was balanced in group A (F: 52.9%) while there was predominance of females in group C (64.72%) and males in group B (64.70%). The proportion of splenectomized patients in groups A and B was similar (32.3%), whereas in group C was significantly higher (52.9%) (p = 0.01). Patients in groups A and B presented similar scores S-MRI and BMB 11,2 / 7,32 while group C showed a significant higher score 14.3 / 8.23 (p: 0.01) and higher incidence of osteopenia and osteoporosis. Only 17% of patients in group C and 20% in group B showed uncomplicated bone marrow infiltration compared to 50% in group A. The mean concentration of the biomarkers (chitotriosidase activity and CCL18/PARC) was similar between the three groups. The results of iTRAQ study has identified some target proteins with potential use as biomarkers that will be present in the meeting if the work is selected to be presented.
In conclusion, patients with genotype that include an allele with complex mutations, present greater risk of suffering vascular bone complications (osteonecrosis, infarctions, bone demineralization). It is important to consider these genetic characteristics to establish recommendations about the importance of diagnosis and early treatment as well as to avoid splenectomy and to follow up by annual MRI and DEXA. The standard biomarkers of the disease do not establish differences between risk groups. The protein expression analyzed has show differential expression of some proteins that need to be addressed by target proteomic strategy.
No relevant conflicts of interest to declare.
Introduction
Type 1 Gaucher disease (GD)(OMIM # 230800), has a pan-ethnic distribution, in Spain its prevalence is about 1/100,000. Since more than twenty years the impact of therapies in the ...awareness of the disease is changing the characteristics and expectations of patients. The Spanish Gaucher disease Registry (SGDR) is working since 1993 and compiled demographic, clinical, genetic, analytical and imaging data about 360 type 1 GD Spanish patients. The application of new high computing capacity and powerful network analysis to analyze the registered data could provide a visualization tool and allows to extract knowledge from complex and very numerous relationships. The objective of this analysis is to discover useful ideas and new correlations to predict the risk of developing late complications and to extract knowledge of complex and very numerous relationships.
Patients & Methods
From 416 patients included in the SGDR we have selected 358 with more than 70% of data and follow-up. GD type 2 patients have been excluded. The variables included in the database at diagnosis: demographic data and the clinical, analytical and imaging information at diagnostic and during the treatment follow-up as well as comorbidities. With Kampal Data Solutions, a spin-off company of the University of Zaragoza dedicated to the development of computer applications and advanced data analytics, this company has experience in the homogenization of information and in the elaboration of classic and advanced statistics projects, as well as in the visualization of said information complex network techniques and the relationship between variables and model designs.Variables:Birthdate, age at diagnosis, gender, death date, severity category of disease (mild, moderate, severe), concomitant diseases, Parkinson disease in relatives, liver volume, spleen volume, spleen removal, bone disease, S-MRI, DEXA, chitotriosidase, CCL18/PARC, lyso Gb1, B12 vitamin level, iron concentration, ferritin, cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, AST, ALT, GGT, acid phosphatase, bilirubin, hemoglobin concentration, Hsc, WBC count, platelets count, serum gammaglobulin fraction, IgG, IgA, IgM, GBA activity, GBAgenotype, CHIT1genotype, age to start therapy, type of therapy (ERT, SRT), new bone crisis or joint replacement, development of malignancies or Parkinson disease.
Results: The 358 subjects were mostly GD1 (340 vs 18 GD3), 18% were splenectomized and 39% have advanced bone disease and bone complications. Most of the patients have a complex heterozygous genotype (81% vs 19% homozygous). 47% of patients were diagnosed before 2,000 and 10% die before this study. Most of them are receiving ERT (54%). About comorbidities, 4% of patients developed MGUS or Parkinson disease and 6% malignant neoplasias. The main results have founded a significant correlation between skeletal complications and impaired and spleen removal (p=0.0005); this fact confirm previous reports. In this study a low IgA serum level shows a significant correlation with severe bone disease(p=0.0000), and with the incidence of new bone crisis during long term ERT. A IgG increase was related to the development of neoplasia. There were two more important factors that we have found; the age at diagnosis and the age to start therapy.
Comments:
Registries are key resources to help increasing timely and accurate diagnosis, improving patient's management, tailoring treatments, facilitating clinical trials, supporting healthcare planning and speeding up research. This is the very first attempt to establish a correlation network among different biomarkers and clinical characteristics in a national base cohort. As has been hypothesized seems that the impairment of immune system has a strong impact in long term complications, in our study the humoral immunity dysfunction pops up as an important factor. Despite of our short cohort, the quality of data is accurate and can reflect the own Spanish Gaucher disease characteristics. Currently we are working in the design of algorithms to help to predict patient outcomes.
No relevant conflicts of interest to declare.
BackgroundThere are multiple hematological and other entities (metastases, infections) that can affect the bone marrow (BM). The gold standard imaging technique for BM examination is magnetic ...resonance imaging (MRI). Technological advances have made it possible to digitalize image files and create applications that help to produce higher quality structured reports, facilitating the analysis of data and unifying the criteria collected, making it possible to fill an existing gap. The aim of this study is to present a structured report model applicable to BM studies by MRI. MethodsWe have carried out a systematic review following the recommendations of the PRISMA checklist report to explore previous publications applying structured BM MRI reporting. Eligibility criteria: the selection of articles carried out by MeSH thesaurus. Original or review articles of BM pathology assessed by MRI. Our group with a wide experience in the evaluation of BM by MRI have designed a model for BM report using eight items: demographic data, diagnostic suspicion, technical data, type of exam initial or control, distribution and patterns involvement, complications and location, total assessment comments. ResultsWe have not found articles that reflect the existence of a structured report of BM examination by MRI. Only one descriptive article has been identified on guidelines for acquisition, interpretation and reporting which refers to a single entity. With the selected parameters, a software has been developed that allows to fill in the sections of the structured report with ease and immediacy and to send the result directly to the clinician. DiscussionStructured reports are the result of applying a logical structure to the radiological report, and the rules of elaboration comprise several criteria: (I) using a uniform language. The standardization of terminology avoids ambiguity in reporting and makes it easier to compare reports. (II) Accurately describe the radiological findings, following a prescribed order with review questions and answers. (III) Drafting using diagnostic screening tables. (IV) Respect the radiologists' workflow by facilitating the work and not hindering it. The final report of this work has been the product of the clinical-radiological collaboration in our working group.
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