Fatty Replacement Research Articles

Case Report: Methimazole-Induced Parotitis - An Unusual Presentation

A 56-year-old female with a medical history of unspecified hyperthyroidism and a recent thyroid storm presented to the ED with tachycardia, hypertension, and bilateral enlarged parotid glands. During a previous hospitalization, she was diagnosed with unspecified hyperthyroidism and started on methimazole. During hospitalization, laboratory findings suggested Graves’ disease with an acute thyroid storm. The patient also complained of enlarged parotid glands bilaterally. CT tomography of the neck revealed no calculi of the parotid glands but showed extensive fatty replacement, possibly related to methimazole use. Treatment with propranolol and IV hydrocortisone improved thyroid function. Due to the suspicion of methimazole-induced parotitis, she was transitioned to a reduced methimazole dosage for treatment of Graves’ disease, which subsequently improved her parotitis. Methimazole, the standard initial treatment for Graves’ disease, is generally well-tolerated. It can cause adverse reactions; however, parotitis is very rare and has been documented in only a few case reports. Owing to the limited number of reports, its incidence is currently unknown. Here, we present a case of methimazole-induced parotitis as an unusual presentation of thyroid storm. Drug-induced reactions can only be considered once common causes of parotitis such as viral infection, obstruction, and autoimmune diseases are ruled out. Treatment involves dosage adjustments and supportive care. Methimazole-induced parotitis is often misdiagnosed and overlooked because of the lack of reported cases. This necessitates future research into the reaction mechanisms and optimal treatment.

Clinical Applications of Cardiac Magnetic Resonance Parametric Mapping.

Cardiovascular magnetic resonance (CMR) imaging is widely regarded as the gold-standard technique for myocardial tissue characterization, allowing for the detection of structural abnormalities such as myocardial fatty replacement, myocardial edema, myocardial necrosis, and/or fibrosis. Historically, the identification of abnormal myocardial regions relied on variations in tissue signal intensity, often necessitating the use of exogenous contrast agents. However, over the past two decades, innovative parametric mapping techniques have emerged, enabling the direct quantitative assessment of tissue magnetic resonance (MR) properties on a voxel-by-voxel basis. These mapping techniques offer significant advantages by providing comprehensive and precise information that can be translated into color-coded maps, facilitating the identification of subtle or diffuse myocardial abnormalities. As unlikely conventional methods, these techniques do not require a substantial amount of structurally altered tissue to be visually identifiable as an area of abnormal signal intensity, eliminating the reliance on contrast agents. Moreover, these parametric mapping techniques, such as T1, T2, and T2* mapping, have transitioned from being primarily research tools to becoming valuable assets in the clinical diagnosis and risk stratification of various cardiac disorders. In this review, we aim to elucidate the underlying physical principles of CMR parametric mapping, explore its current clinical applications, address potential pitfalls, and outline future directions for research and development in this field.

Clinical characteristics of idiopathic inflammatory myopathies patients with anti-PM/Scl antibodies

ObjectivesTo analyze the clinical features of idiopathic inflammatory myopathies (IIMs) patients with anti-PM/Scl antibodies. MethodsIn this retrospective cohort study, we compared the clinical manifestations between patients who were solely positive for anti-PM/Scl antibodies (isolated anti-PM/Scl group) and those with a coexistence of anti-PM/Scl antibodies and myositis-specific antibodies (MSAs) (double-positive group). ResultsSixty-five IIMs patients positive for anti-PM/Scl antibodies were included, among whom 51 (78.5 %) were females, with a mean age of 49.1 years. Thirty-four (52.3 %) patients coexisted with MSAs. Compared to the double-positive group, the isolated anti-PM/Scl group demonstrated a higher proportion of women (90.3 % vs 67.6 %, p = 0.026) and a higher incidence of sclerodactyly (16.1 % vs 0, p = 0.021). Although there were no differences in the incidence of muscular weakness, dysphagia, or creatine kinase levels, thigh magnetic resonance imaging (MRI) revealed less muscle edema, atrophy, and fatty replacement in the isolated anti-PM/Scl group (p < 0.05). Interstitial lung disease (ILD) occurred in 80 % of patients, more frequently in the double-positive group (90.6 % vs 67.9 %, p = 0.028). According to HRCT, non-specific interstitial pneumonia (NSIP) was the most common pattern among anti-PM/Scl antibodies positive IIMs patients. The double-positive group exhibited higher ferritin levels, and a lower peripheral lymphocyte count (p < 0.05). The mortality rate in the double-positive group was higher than that in the isolated anti-PM/Scl group (20.6 % vs 0, p = 0.034). ConclusionAmong IIMs patients who tested positive for anti-PM/Scl antibodies, ILD emerged as the predominant clinical feature, particularly when combined with MSA. Notably, patients with isolated anti-PM/Scl antibodies exhibited a favorable prognosis following immunotherapy.

Parameter optimization for proton density fat fraction quantification in skeletal muscle tissue at 7 T

ObjectiveTo establish an image acquisition and post-processing workflow for the determination of the proton density fat fraction (PDFF) in calf muscle tissue at 7 T.Materials and methodsEcho times (TEs) of the applied vendor-provided multi-echo gradient echo sequence were optimized based on simulations of the effective number of signal averages (NSA*). The resulting parameters were validated by measurements in phantom and in healthy calf muscle tissue (n = 12). Additionally, methods to reduce phase errors arising at 7 T were evaluated. Finally, PDFF values measured at 7 T in calf muscle tissue of healthy subjects (n = 9) and patients with fatty replacement of muscle tissue (n = 3) were compared to 3 T results.ResultsSimulations, phantom and in vivo measurements showed the importance of using optimized TEs for the fat–water separation at 7 T. Fat–water swaps could be mitigated using a phase demodulation with an additional B0 map, or by shifting the TEs to longer values. Muscular PDFF values measured at 7 T were comparable to measurements at 3 T in both healthy subjects and patients with increased fatty replacement.ConclusionPDFF determination in calf muscle tissue is feasible at 7 T using a chemical shift-based approach with optimized acquisition and post-processing parameters.

DIAGNOSTIC CRITERIA FOR NON–DILATED LEFT VENTRICULAR CARDIOMYOPATHY WITH PROGNOSTIC SIGNIFICANCE

Abstract Background Non–dilated left ventricular cardiomyopathy (NDLVC) is a novel diagnostic entity defined as non–ischemic LV scarring or fatty replacement regardless of the presence of global or regional wall motion abnormalities, or isolated global LV hypokinesia without scarring. While the absence of LV dilation and systolic dysfunction are implicit, no cut–offs were proposed. Methods All patients undergoing cardiac magnetic resonance (CMR) examination at a tertiary referral center from 2012 to 2022 and meeting the definition of NDLVC were evaluated. The primary endpoint was a composite of cardiac death, sustained ventricular tachycardia (VT) or ventricular fibrillation, appropriate defibrillator intervention; the secondary endpoint included also non–sustained VT. Results The cohort included 262 patients, with 176 men (67%) and a median age of 55 years (interquartile range 44–64 years). Patients without moderate (n=243, 93%) or severe LV dilation (n=249, 95%) had a longer survival free from both endpoints. The 50% LVEF threshold identified patients with different outcomes, whereas the 55% and 60% cut–offs did not. LVEF ≥50% and no severe LV dilation predicted a better outcome independent of percent LGE in the LV, the number of LV segments with LGE, LV fibro–fatty replacement, or right ventricular involvement. LVEF ≥50% and no severe LV dilation retained an independent prognostic value even in patients with LV LGE (80% of the whole cohort). Conclusions Excluding severe LV dilation (LVEDVi &amp;gt;129 mL/m2 in men and &amp;gt;116 mL/m2 in women) and LV dysfunction (LVEF &amp;lt;50%) could enhance the prognostic utility of the NDLVC definition.

A WELL KNOWN CARDIOMYOPATHY BEHIND A FAMILY DRAMA: A CASE REPORT

Abstract We report a case of a 55–year–old woman who came to our regional reference center for cardiomyopathies. Her cardiovascular risk factors were systemic arterial hypertension, dyslipidemia, family history of sudden cardiac death. Her first son –20 years old– had died of sudden cardiac death during a football match, at the peak of the exertion, one year before. The autopsy had showed biventricular, diffuse fibro–fatty replacement areas diagnostic for arrhythmogenic cardiomyopathy. DNA extraction in tissue was evaluated for genetic testing. According to 2022 ESC Guidelines, familial evaluation of descendents of patients died of sudden cardiac death should include: genetic testing, gathering of medical history and performing physical examination, standard and high precordial leads ECG, echocardiography and exercise testing, CMR and ambulatory cardiac rhythm monitoring. All of these were normal, except for cardio RM which revealed: aneurysmatic bulging of the right ventricular wall, most prominent at the apex and free wall with normal contractility. Absence of both left and right ventricular dilatation. Left ventricular and right ventricular ejection fraction measured 58% and 55% respectively. According to Padua’s criteria the woman had borderline arrhythmogenic cardiomyopathy. Instead, her 18 years old little son used to practice sports and used anabolics. His cardio–RMN demonstrated: reduced function of the right ventricle with mild dilation and biventricular bulging areas. The patient met the criteria for definite Arrhythmogenic Cardiomyopathy since he had two major criteria. In the meantime of the results of genetic testing, suspension of the smoking habit and reduction of strenuous physical activity were advised. Conclusions Arrhythmogenic displasia of right ventricle is characterized histopathologically by the extensive replacement of right ventricular myocardium with fibro–fatty tissue (dysplasia triangle). Involvement of the left ventricle has been documented on a lesser frequency and has a higher mortality. Different from other conditions, in arrhythmogenic cardiomyopathy, sports practice not only conveys arrhythmic risk to that specific moment (as it happens to the little patient) but also accelerates disease progression.

Case Report: Methimazole-Induced Parotitis - An Unusual and Rare Presentation of Thyroid Storm

A 56-year-old female with a medical history of unspecified hyperthyroidism and a recent thyroid storm presented to the ED with tachycardia, hypertension, and bilateral enlarged parotid glands. During a previous hospitalization, she was diagnosed with unspecified hyperthyroidism and started on methimazole. During hospitalization, laboratory findings suggested Graves’ disease with an acute thyroid storm. The patient also complained of enlarged parotid glands bilaterally. CT tomography of the neck revealed no calculi of the parotid glands but showed extensive fatty replacement, possibly related to methimazole use. Treatment with propranolol and IV hydrocortisone improved thyroid function. Due to the suspicion of methimazole-induced parotitis, she was transitioned to a reduced methimazole dosage for treatment of Graves’ disease, which subsequently improved her parotitis. Methimazole, the standard initial treatment for Graves’ disease, is generally well-tolerated. It can cause adverse reactions; however, parotitis is very rare and has been documented in only a few case reports. Owing to the limited number of reports, its incidence is currently unknown. Here, we present a case of methimazole-induced parotitis as an unusual presentation of thyroid storm. Drug-induced reactions can only be considered once common causes of parotitis such as viral infection, obstruction, and autoimmune diseases are ruled out. Treatment involves dosage adjustments and supportive care. Methimazole-induced parotitis is often misdiagnosed and overlooked because of the lack of reported cases. This necessitates future research into the reaction mechanisms and optimal treatment.

Fatty infiltration of gastrocnemius-soleus muscle complex: Considerations for myosteatosis rehabilitation.

Although previous studies have reported fatty infiltration of the gastrocnemius-soleus complex, little is known about the volumetric distribution and patterns of fatty infiltration. The purpose of this anatomical study was to document and quantify the frequency, distribution, and pattern of fatty infiltration of the gastrocnemius-soleus complex. One hundred formalin-embalmed specimens (mean age 78.1 ± 12.3 years; 48F/52M) were serially dissected to document the frequency, distribution, and pattern of fatty infiltration in the medial and lateral heads of gastrocnemius and soleus muscles. Fatty infiltration was found in 23% of specimens, 13 unilaterally (8F/5M) and 10 (5M/5F) bilaterally. The fatty infiltration process was observed to begin medially from the medial aspect of the medial head of gastrocnemius and medial margin of soleus and then progressed laterally throughout the medial head of gastrocnemius and the marginal, anterior, and posterior soleus. The lateral head of gastrocnemius remained primarily muscular in all specimens. Microscopically, the pattern of infiltration was demonstrated as intramuscular with intact aponeuroses, and septa. The remaining endo-, peri-, and epimysium preserved the overall contour of the gastrocnemius-soleus complex, even in cases of significant fatty replacement. Since the external contour of the calf is preserved, the presence of fatty infiltration may be underdiagnosed in the clinic without imaging. Myosteatosis is associated with gait and balance challenges in the elderly, which can impact quality of life and result in increased risk of falling. The findings of the study have implications in the rehabilitation management of elderly patients with sarcopenia and myosteatosis.

Miyoshi myopathy associated with spine rigidity and multiple contractures: a case report

BackgroundDysferlinopathy is a phenotypically heterogeneous group of hereditary diseases caused by mutations in the DYSF gene. Early contractures are considered rare, and rigid spine syndrome in dysferlinopathy has been previously reported only once.Case presentationWe describe a 23-year-old patient with Miyoshi myopathy with a rigid spine and multiple contractures, a rare phenotypic variant. The disease first manifested when the patient was 13 years old, with fatigue of the gastrocnemius muscles and the development of pronounced contractures of the Achilles tendons, flexors of the fingers, and extensors of the toes, followed by the involvement of large joints and the spine. Magnetic resonance imaging revealed signs of connective tissue and fatty replacement of the posterior muscles of the thighs and lower legs. Edema was noted in the anterior and medial muscle groups of the thighs, lower legs, and the multifidus muscle of the back. Whole genome sequencing revealed previously described mutations in the DYSF gene in exon 39 (c.4282 C > T) and intron 51 (c.5785-824 C > T). An immunohistochemical analysis and Western blot showed the complete absence of dysferlin protein expression in the muscle fibers.ConclusionsThis case expands the range of clinical and phenotypic correlations of dysferlinopathy and complements the diagnostic search for spine rigidity.

Magnetic resonance imaging-based criteria to differentiate dysferlinopathy from other genetic muscle diseases

The identification of disease-characteristic patterns of muscle fatty replacement in magnetic resonance imaging (MRI) is helpful for diagnosing neuromuscular diseases. In the Clinical Outcome Study of Dysferlinopathy, eight diagnostic rules were described based on MRI findings. Our aim is to confirm that they are useful to differentiate dysferlinopathy (DYSF) from other genetic muscle diseases (GMD). The rules were applied to 182 MRIs of dysferlinopathy patients and 1000 MRIs of patients with 10 other GMD. We calculated sensitivity (S), specificity (Sp), positive and negative predictive values (PPV/NPV) and accuracy (Ac) for each rule. Five of the rules were more frequently met by the DYSF group. Patterns observed in patients with FKRP, ANO5 and CAPN3 myopathies were similar to the DYSF pattern, whereas patterns observed in patients with OPMD, laminopathy and dystrophinopathy were clearly different. We built a model using the five criteria more frequently met by DYSF patients that obtained a S 95.9%, Sp 46.1%, Ac 66.8%, PPV 56% and NPV 94% to distinguish dysferlinopathies from other diseases. Our findings support the use of MRI in the diagnosis of dysferlinopathy, but also identify the need to externally validate “disease-specific” MRI-based diagnostic criteria using MRIs of other GMD patients.

Distal myopathy due to digenic inheritance of TIA1 and SQSTM1 variants in two unrelated Spanish patients

Welander distal myopathy typically manifests in late adulthood and is caused by the founder TIA1 c.1150G>A (p.Glu384Lys) variant in families of Swedish and Finnish descent. Recently, a similar phenotype has been attributed to the digenic inheritance of TIA1 c.1070A>G (p.Asn357Ser) and SQSTM1 c.1175C>T (p.Pro392Leu) variants. We describe two unrelated Spanish patients presenting with slowly progressive gait disturbance, distal-predominant weakness, and mildly elevated creatine kinase (CK) levels since their 6th decade. Electromyography revealed abnormal spontaneous activity and a myopathic pattern. Muscle magnetic resonance imaging (MRI) showed marked fatty replacement in distal leg muscles. A muscle biopsy, performed on one patient, revealed myopathic changes with rimmed vacuoles. Both patients carried the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variants. Digenic inheritance is supported by evidence from unrelated pedigrees and a plausible biological interaction between both proteins in protein quality control processes. Recent functional studies and additional case descriptions further support this. Clinical suspicion is necessary to seek both variants.

A prospective study of MRI biomarkers in the brain and lower limb muscles for prediction of lower limb motor recovery following stroke.

The aim of this prospective observational longitudinal study was to explore and decipher the predictive value of prospective MRI biomarkers in the brain and lower limb muscles for 3-month lower limb motor recovery following stroke. In the brain, we measured the integrity of the corticospinal tract (fractional anisotropy/"FA"). In the muscles, we measured volume, fatty replacement (fat fraction analysis and proton spectroscopy) and oedema. Measurements were taken at two time points: (1) within 4 weeks of stroke (baseline measurement, clinical and imaging) and (2) 3 months following stroke (follow up measurement, clinical only). Clinical measurements consisted of assessments of functional ability and strength (Fugl-Meyer score, motor NIHSS, Functional Ambulation Category/"FAC", and muscle dynamometry). Twenty-three patients completed imaging and clinical assessments at baseline and follow-up; five patients had partial imaging assessment. The results provided some evidence that damage to the corticospinal tract would result in less motor recovery: recovery of the Fugl-Meyer score and dynamometric ankle plantarflexion, ankle dorsiflexion, and knee extension correlated positively and significantly with fractional anisotropy (0.406-0.457; p = 0.034-p = 0.016). However, fractional anisotropy demonstrated a negative correlation with recovery of the Functional Ambulation Category (-0.359, p = 0.046). For the muscle imaging, significant inverse correlation was observed between vastus lateralis fat fraction vs. NIHSS recovery (-0.401, p = 0.04), and a strong positive correlation was observed between ratio of intra- to extra-myocellular lipid concentrations and the recovery of knee flexion (0.709, p = 0.007). This study supports previous literature indicating a positive correlation between the integrity of the corticospinal tract and motor recovery post-stroke, expanding the limited available literature describing this relationship specifically for the lower limb. However, recovery of functional ambulation behaved differently to other clinical recovery markers by demonstrating an inverse relationship with corticospinal tract integrity. The study also introduces some muscle imaging biomarkers as potentially valuable in the prediction of 3-month lower limb motor recovery following stroke.

FSHD muscle shows perturbation in fibroadipogenic progenitor cells, mitochondrial function and alternative splicing independently of inflammation.

Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy. FSHD is highly heterogeneous, with patients following a variety of clinical trajectories, complicating clinical trials. Skeletal muscle in FSHD undergoes fibrosis and fatty replacement that can be accelerated by inflammation, adding to heterogeneity. Well controlled molecular studies are thus essential to both categorize FSHD patients into distinct subtypes and understand pathomechanisms. Here, we further analyzed RNA-sequencing data from 24 FSHD patients, each of whom donated a biopsy from both a non-inflamed (TIRM-) and inflamed (TIRM+) muscle, and 15 FSHD patients who donated peripheral blood mononucleated cells (PBMCs), alongside non-affected control individuals. Differential gene expression analysis identified suppression of mitochondrial biogenesis and up-regulation of fibroadipogenic progenitor (FAP) gene expression in FSHD muscle, which was particularly marked on inflamed samples. PBMCs demonstrated suppression of antigen presentation in FSHD. Gene expression deconvolution revealed FAP expansion as a consistent feature of FSHD muscle, via meta-analysis of 7 independent transcriptomic datasets. Clustering of muscle biopsies separated patients in an unbiased manner into clinically mild and severe subtypes, independently of known disease modifiers (age, sex, D4Z4 repeat length). Lastly, the first genome-wide analysis of alternative splicing in FSHD muscle revealed perturbation of autophagy, BMP2 and HMGB1 signalling. Overall, our findings reveal molecular subtypes of FSHD with clinical relevance and identify novel pathomechanisms for this highly heterogeneous condition.

Using Longitudinal MRI to Manage Proton Range Uncertainty for Pediatric Proton Craniospinal Irradiation

Clinical evidence has shown that proton therapy can effectively reduce side effects for pediatric patients undergoing vertebral body-sparing craniospinal irradiation (VBS CSI), compared to conventional photon treatment modalities. However, radiation-induced growth impairment remains challenging for VBS CSI due to proton range uncertainty, compromising vertebral body sparing for growing children. Previous studies have shown that fatty marrow replacement can be observed in vertebral bodies 4-48 weeks after treatment is complete. This study aims to detect and quantify the fatty marrow replacement in vertebral bodies using longitudinal magnetic resonance (MR) to manage proton range uncertainty. A prospective clinical trial of proton VBS CSI was designed, and ten pediatric patients were enrolled with prescribed doses of 15-36 Gy. The thecal sac and neural foramina were the clinical target volumes, and a Monte Carlo planning system was used to robustly optimize treatment plans with a 3.5% range margin. We analyzed patients' T1/T2 MR images acquired before, during, and after proton treatment to investigate the hematopoietic marrow transformation induced by irradiation. A metric was defined to calculate the ratio of fatty and hematopoietic marrow based on relative MR intensity histograms. We proposed a machine learning method via Gaussian fitting process (ML-GFP) to explore hidden correlations between marrow transition and radiation dose to 2 cm3 of the bone marrow (D2cc). We also leveraged this method to embed uncertainty to support potential proton range management for VBS enhancement. The results indicated that fatty marrow replacement could be observed during inter-fractional treatment. For instance, an individual patient showed that the fatty marrow generation ratios were 0.54, 0.74, and 0.45, corresponding to 11, 18, and 65 days after the treatment started. Using ML-GFP, the fatty marrow transition was found to be quadratically correlated to treatment fractions, and the maximum transformation ranged from 40 to 50 days. Then marrow regeneration was observed due to the decrease in fatty marrow ratios. The fatty marrow ratios were also positively correlated to the D2cc doses ranging from 10 Gy to 36 Gy. Limited by insufficient low-dose data, the ML-GFP model extrapolated the data to predict the marrow transformation below 10 Gy. We demonstrated the feasibility of using non-invasive longitudinal MR to quantify the fatty marrow transition from inter-fractional treatment. Based on this prospective study, the method can detect early fatty marrow generation in vertebrae caused by proton irradiation due to the conservative range margin used for robust optimization. The proposed method could be used to validate the actual proton range, allowing an accurate range margin to be defined to preserve bone marrow. Future investigation will likely focus on clinical implementation to improve life quality for pediatric CSI patients.

Muscle magnetic resonance imaging of a large cohort of distal hereditary motor neuropathies reveals characteristic features useful for diagnosis

Distal motor neuropathies (dHMN) are an heterogenous group of diseases characterized by progressive muscle weakness affecting predominantly the distal muscles of the lower and upper limbs. Our aim was to study the imaging features and pattern of muscle involvement in muscle magnetic resonance imaging (MRI) in dHMN patients of suspected genetic origin (dHMN). We conducted a retrospective study collecting clinical, genetic and muscle imaging data. Muscle MRI included T1-weighted and T2 weighted Short Tau Inversion Recovery images (STIR-T2w) sequences. Muscle replacement by fat was quantified using the Mercuri score. Identification of selective patterns of involvement was performed using hierarchical clustering. Eighty-four patients with diagnosis of dHMN were studied. Fat replacement was predominant in the distal lower leg muscles (82/84 cases), although also affected thigh and pelvis muscles. Asymmetric involvement was present in 29% of patients. The superficial posterior compartment of the leg, including the soleus and gastrocnemius muscles, was the most affected area (77/84). We observed a reticular pattern of fatty replacement progressing towards what is commonly known as “muscle islands” in 79.8%. Hyperintensities in STIR-T2w were observed in 78.6% patients mainly in distal leg muscles. Besides features common to all individuals, we identified and describe a pattern of muscle fat replacement characteristic of BICD2, HSPB1 and DYNC1H1 patients. We conclude that muscle MRI of patients with suspected dHMN reveals common features helpful in diagnosis process.

The FSHD muscle-blood biomarker: a circulating transcriptomic biomarker for clinical severity in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. Clinical trials for FSHD are hindered by heterogeneous biomarkers poorly associated with clinical severity, requiring invasive muscle biopsy. Macroscopically, FSHD presents with slow fatty replacement of muscle, rapidly accelerated by inflammation. Mis-expression of the transcription factor DUX4 is currently accepted to underlie pathogenesis, and mechanisms including PAX7 target gene repression have been proposed. Here, we performed RNA-sequencing on MRI-guided inflamed and isogenic non-inflamed muscle biopsies from the same clinically characterized FSHD patients (n = 24), alongside isogenic peripheral blood mononucleated cells from a subset of patients (n = 13) and unaffected controls (n = 11). Multivariate models were employed to evaluate the clinical associations of five published FSHD transcriptomic biomarkers. We demonstrated that PAX7 target gene repression can discriminate control, inflamed and non-inflamed FSHD muscle independently of age and sex (P < 0.013), while the discriminatory power of DUX4 target genes was limited to distinguishing FSHD muscle from control. Importantly, the level of PAX7 target gene repression in non-inflamed muscle associated with clinical assessments of FSHD severity (P = 0.04). DUX4 target gene biomarkers in FSHD muscle showed associations with lower limb fat fraction and D4Z4 array length but not clinical assessment. Lastly, PAX7 target gene repression in FSHD muscle correlated with the level in isogenic peripheral blood mononucleated cells (P = 0.002). A refined PAX7 target gene biomarker comprising 143/601 PAX7 target genes computed in peripheral blood (the FSHD muscle-blood biomarker) associated with clinical severity in FSHD patients (P < 0.036). Our new circulating biomarker validates as a classifier of clinical severity in an independent data set of 54 FSHD patient and 29 matched control blood samples, with improved power in older patients (P = 0.03). In summary, we present the minimally invasive FSHD muscle-blood biomarker of FSHD clinical severity valid in patient muscle and blood, of potential use in routine disease monitoring and clinical trials.

Multidetector computed tomography evaluation of normal thymus and variations with age.

Thymus is a T-cell-producing lymphoid organ that appears prominent in the paediatric population and involutes in size with ageing. The gland shows a wide variety of appearances across different age groups. The purpose of the study is to evaluate the computed tomography (CT) appearance of thymus gland in the normal population with a focus on size, CT attenuation and fatty infiltration in different age groups. This is a retrospective study done after taking approval from the Institutional Ethics Committee. Patients undergone CT scans of the thorax were identified from our database. All evaluations were done in non-contrast CT scans. Patients having underlying diseases that may have associated thymic abnormality were excluded. The appearance of thymus and the presence of fatty replacement were assessed. The size of thymus (length and thickness of right limb and left limb) and non-contrast CT Hounsfield unit (HU) value of thymic tissue were measured and compared in various age groups. Four hundred and fifty patients were included, 262 (58.2%) were male. Mean age was 33.6 ± 17.1 years, range (3 months-80 years). The size of thymus was observed to decrease with increasing age. The mean age of complete fatty replacement in our study was 45 years. Complete fatty replacement was noted in all cases with an age of more than 60 years. The most common shape was arrowhead, and the most common location was pre-aortic and para-aortic location. Non-contrast CT HU value was maximum in infants and gradually decreased with advancing age. Even normal thymus can show varied appearance on CT which changes with the age of the patient being imaged. A comparison with normative data could help differentiate normal from abnormal glands to avoid unnecessary intervention.

Instrumental methods for assessing the state of the paravertebral lumbar muscles in patients with lumbosacral radiculopathy and nonspecific muscle-skeletal pain

Neurological examination plays the main role in diagnostic and management of radiculopathies. In addition, the instrumental methods could be used for diagnosis of the morphological and functional state of paraspinal muscles. Paraspinal muscles are symmetrical back muscles surrounding the spinal column and supporting it. Magnetic resonance imaging (MRI) as well as needle electromyography (EMG) and ultrasound are used for instrumental diagnosis of paraspinal muscles conditions. We provide the review on the current scope of studies on radiculopathies and non-specific back pain. MRI is the principle standard for radiculopathy diagnosis, but other methods such as muscle ultrasound and needle electromyography are also used here. MRI is characterized by a high cost, and it is impossible to carry it out if there are magnetic objects present in the patient’s body. EMG and ultrasound both are not sufficient enough to study the level of the fatty replacement of the paraspinal muscle, while this parameter is quite significant for measuring a radiculopathy outcome. Thus, we consider it rational to recommend using these methods in combination. Indications for the combined examination may be such complex cases as anatomical anomalies of spinal roots, atypical disease pattern.

Muscle magnetic resonance characterization of STIM1 tubular aggregate myopathy using unsupervised learning.

Congenital myopathies are a heterogeneous group of diseases affecting the skeletal muscles and characterized by high clinical, genetic, and histological variability. Magnetic Resonance (MR) is a valuable tool for the assessment of involved muscles (i.e., fatty replacement and oedema) and disease progression. Machine Learning is becoming increasingly applied for diagnostic purposes, but to our knowledge, Self-Organizing Maps (SOMs) have never been used for the identification of the patterns in these diseases. The aim of this study is to evaluate if SOMs may discriminate between muscles with fatty replacement (S), oedema (E) or neither (N). MR studies of a family affected by tubular aggregates myopathy (TAM) with the histologically proven autosomal dominant mutation of the STIM1 gene, were examined: for each patient, in two MR assessments (i.e., t0 and t1, the latter after 5 years), fifty-three muscles were evaluated for muscular fatty replacement on the T1w images, and for oedema on the STIR images, for reference. Sixty radiomic features were collected from each muscle at t0 and t1 MR assessment using 3DSlicer software, in order to obtain data from images. A SOM was created to analyze all datasets using three clusters (i.e., 0, 1 and 2) and results were compared with radiological evaluation. Six patients with TAM STIM1-mutation were included. At t0 MR assessments, all patients showed widespread fatty replacement that intensifies at t1, while oedema mainly affected the muscles of the legs and appears stable at follow-up. All muscles with oedema showed fatty replacement, too. At t0 SOM grid clustering shows almost all N muscles in Cluster 0 and most of the E muscles in Cluster 1; at t1 almost all E muscles appear in Cluster 1. Our unsupervised learning model appears to be able to recognize muscles altered by the presence of edema and fatty replacement.

Early in vivo Radiation Damage Quantification for Pediatric Craniospinal Irradiation Using Longitudinal MRI for Intensity Modulated Proton Therapy

Proton vertebral body sparing craniospinal irradiation (CSI) treats the thecal sac while avoiding the anterior vertebral bodies in an effort to reduce myelosuppression and growth inhibition. However, robust treatment planning needs to compensate for proton range uncertainty, which contributes unwanted doses within the vertebral bodies. This work aimed to develop an early in vivo radiation damage quantification method using longitudinal magnetic resonance (MR) scans to quantify the dose effect during fractionated CSI. Ten pediatric patients were enrolled in a prospective clinical trial of proton vertebral body sparing CSI, in which they received 23.4 to 36 Gy. Monte Carlo robust planning was used, with spinal clinical target volumes defined as the thecal sac and neural foramina. T1/T2-weighted MR scans were acquired before, during, and after treatments to detect a transition from hematopoietic to less metabolically active fatty marrow. MR signal intensity histograms at each time point were analyzed and fitted by multi-Gaussian models to quantify radiation damage. Fatty marrow filtration was observed in MR images as early as the fifth fraction of treatment. Maximum radiation-induced marrow damage occurred 40 to 50 days from the treatment start, followed by marrow regeneration. The mean damage ratios were 0.23, 0.41, 0.59, and 0.54, corresponding to 10, 20, 40, and 60 days from the treatment start. We demonstrated a noninvasive method for identifying early vertebral marrow damage based on radiation-induced fatty marrow replacement. The proposed method can be potentially used to quantify the quality of CSI vertebral sparing and preserve metabolically active hematopoietic bone marrow.