Assessment of proximal femur microarchitecture using ultra-high field MRI at 7 Tesla.

PURPOSE: The purpose of this study was to investigate bone microarchitecture of cadaveric proximal femurs using ultra-high field (UHF) 7-Tesla magnetic resonance imaging (MRI) and to compare the corresponding metrics with failure load assessed during mechanical compression test and areal bone mineral density (ABMD) measured using dual-energy X-ray absorptiometry. MATERIALS AND METHODS: ABMD of ten proximal femurs from five cadavers (5 women; mean age=86.2±3.8 (SD) years; range: 82.5-90 years) were investigated using dual-energy X-ray absorptiometry and the bone volume fraction, trabecular thickness, trabecular spacing, fractal dimension, Euler characteristics, connectivity density and degree of anisotropy of each femur was quantified using UHF MRI. The whole set of specimens underwent mechanical compression tests to failure. The inter-rater reliability of microarchitecture characterization was assessed with the intraclass correlation coefficient (ICC). Associations were searched using correlation tests and multiple regression analysis. RESULTS: The inter-rater reliability for bone microarchitecture parameters measurement was good with ICC ranging from 0.80 and 0.91. ABMD and the whole set of microarchitecture metrics but connectivity density significantly correlated with failure load. Microarchitecture metrics correlated to each other but did not correlate with ABMD. Multiple regression analysis disclosed that the combination of microarchitecture metrics and ABMD improved the association with failure load. CONCLUSION: Femur bone microarchitecture metrics quantified using UHF MRI significantly correlated with biomechanical parameters. The multimodal assessment of ABMD and trabecular bone microarchitecture using UHF MRI provides more information about fracture risk of femoral bone and might be of interest for future investigations of patients with undetected osteoporosis.

Patients with ankylosing spondylitis have been breast fed less often than healthy controls: a case-control retrospective study.

OBJECTIVE: Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and pelvis of young adults. On the HLA-B27 genetic background, the occurrence of AS is influenced by the intestinal microbiota. The goal of our study was to test whether breast feeding, which influences microbiota, can prevent the development of AS. METHODS: First, 203 patients with HLA-B27-positive AS fulfilling the modified New York criteria were recruited in the Department of Rheumatology, Ste Marguerite hospital in Marseilles. A total of 293 healthy siblings were also recruited to make up a control group within the same families. Second, 280 healthy controls, and 100 patients with rheumatoid arthritis and their siblings were recruited. The data collected were age, gender, number of brothers and sisters, age at disease onset, type and duration of feeding (breast or bottle). RESULTS: Patients with AS had been breast fed less often than healthy controls. In families where children were breast fed, the patients with AS were less often breast fed than their healthy siblings (57% vs 72%), giving an OR for AS onset of 0.53 (95% CI (0.36 to 0.77), p value=0.0009). Breast feeding reduced familial prevalence of AS. The frequency of breast feeding was similar in the AS siblings and in the 280 unrelated controls. However, patients with AS were less often breast fed compared with the 280 unrelated controls (OR 0.6, 95% CI (0.42 to 0.89), p<0.01). CONCLUSIONS: Our study suggests a breastfeeding-induced protective effect on the occurrence of AS. To our knowledge, this is the first study of breastfeeding history in patients with AS.

Segmentation of fascias, fat and muscle from magnetic resonance images in humans: the DISPIMAG software.

Segmentation of human limb MR images into muscle, fat and fascias remains a cumbersome task. We have developed a new software (DISPIMAG) that allows automatic and highly reproducible segmentation of lower-limb MR images. Based on a pixel intensity analysis, this software does not need any previous mathematical or statistical assumptions. It displays a histogram with two main signals corresponding to fat and muscle, and permits an accurate quantification of their relative spatial distribution. To allow a systematic discrimination between muscle and fat in any subject, fixed boundaries were first determined manually in a group of 24 patients. Secondly, an entirely automatic process using these boundaries was tested by three operators on four patients and compared to the manual approach, showing a high concordance.

In vivo and in vitro characterization of skeletal muscle metabolism in patients with statin-induced adverse effects.

OBJECTIVE: Statins (3-hydroxymethylglutaryl-coenzyme A reductase inhibitor) are widely used to treat hypercholesterolemia. They are generally well tolerated, but myotoxic effects have been reported and the corresponding mechanisms are still a matter of debate. The aim of the present study was to determine whether impairment of calcium homeostasis and/or mitochondrial impairment could account for the adverse effects of statins in skeletal muscle. METHODS: Eleven patients with increased creatine kinase levels and myalgias after statin treatment were evaluated using in vitro contracture tests (IVCTs), histology, and 31P magnetic resonance spectroscopy (31P-MRS). RESULTS: IVCT results were abnormal in 7 of the 9 patients, indicating an impaired calcium homeostasis. The 31P-MRS investigation disclosed no anomaly at rest, and the aerobic function assessed during the postexercise recovery period was normal. On the contrary, the pH recovery kinetics was significantly slowed down as indicated by a reduced proton efflux, which could be ultimately linked to a failure of calcium homeostasis. Overall, our observations indicate a normal mitochondrial function and raise the possibility that statins may unmask a latent pathology involving an impairment of calcium homeostasis such as malignant hyperthermia (MH). CONCLUSION: In case of susceptibility to MH, statins treatment must be administered with caution, and signs of adverse effects should be checked.

[Non-invasive investigation of muscle function using 31P magnetic resonance spectroscopy and 1H MR imaging]. / Explorations de la fonction musculaire par spectrométrie et imagerie de résonance magnétique.

31P MRS and 1H MRI of skeletal muscle have become major new tools allowing a complete non invasive investigation of muscle function both in the clinical setting and in basic research. The comparative analysis of normal and diseased muscle remains a major requirement to further define metabolic events surrounding muscle contraction and the metabolic anomalies underlying pathologies. Also, standardized rest-exercise-recovery protocols for the exploration of muscle metabolism by P-31 MRS in healthy volunteers as well as in patients with intolerance to exercise have been developed. The CRMBM protocol is based on a short-term intense exercise, which is very informative and well accepted by volunteers and patients. Invariant metabolic parameters have been defined to characterize the normal metabolic response to the protocol. Deviations from normality can be directly interpreted in terms of specific pathologies in some favorable cases. This protocol has been applied to more than 4,000 patients and healthy volunteers over a period of 15 years. On the other hand, MRI investigations provide anatomical and functional information from resting and exercising muscle. From a diagnostic point of view, dedicated pulse sequences can be used in order to detect and quantify muscle inflammation, fatty replacement, muscle hyper and hypotrophy. In most cases, MR techniques provide valuable information which has to be processed in conjunction with traditional invasive biochemical, electrophysiological and histoenzymological tests. P-31 MRS has proved particularly useful in the therapeutic follow-up of palliative therapies (coenzyme Q treatment of mitochondriopathies) and in family investigations. It is now an accepted diagnostic tool in the array of tests which are used to characterize muscle disorders in clinical routine. As a research tool, it will keep bringing new information on the physiopathology of muscle diseases in animal models and in humans and should play a role in the metabolic characterization of gene and cell therapy.

[Posture and movement analysis and sports medicine]. / Analyse de la posture et du mouvement et médecine du sport.

The use of posture and movement analysis methods has developed during the past 15 years. These methods are of special interest in the field of sport sciences and have allowed to improve the understanding of physiology of posture and movement in athletes. More recently these methods have been used in the field of sport medicine. In some cases, they have helped to identify abnormalities which cannot be seen on standard clinical examination and to understand the mechanism of lesions occurring during sport activities. For the future these methods should provide useful information for understanding the physiopathology of lesions, for developing prevention of pathologies related to sport and for elaborating and assessing new treatment protocols in the field of sport medicine.

Comparative analysis of in vitro contracture tests with ryanodine and a combination of ryanodine with either halothane or caffeine: a comparative investigation in malignant hyperthermia.

BACKGROUND: The diagnosis of susceptibility to malignant hyperthermia (MH) is currently performed on muscle biopsies subjected to halothane-caffeine in vitro contracture tests (IVCTs). There is a consensus on our need to improve the diagnostic potential of IVCTs if we are to maximize the information available for research and diagnosis in MH. This study was designed as a pilot comparative study and we aimed at comparing the ryanodine test and new tests using a combination of ryanodine, halothane and caffeine. METHODS: One hundred and thirty-two subjects (52 MHS and 80 MHN) were included in this study and new IVCTs were performed in additional muscle biopsy specimens. The contracture time-course was compared considering the onset time of contracture (OT) and the time to reach a 10 mN contracture (10T). Cut-off values were determined using ROC analyses. RESULTS: For the ryanodine test, sensitivity and specificity calculated for OT were 84.6% and 90.4%, respectively, and were better than those obtained using 10T. Combined tests using either caffeine and ryanodine or halothane and ryanodine did provide higher sensitivities (from 85.3 to 93.9%). A better specificity was only observed for the IVC tests combining halothane (cumulated) and caffeine both with ryanodine (93.9% for both). The largest sensitivity was observed when halothane was used as a bolus and combined with ryanodine. The specificity was always larger with the combined tests as compared to the test using ryanodine alone (from 79.1 to 90.9%). This superiority was confirmed, at least in part, when comparing genetic investigations and the results of new tests in a subgroup of subjects. CONCLUSIONS: This pilot study showed a clear diagnostic potential for new IVC tests combining halothane, the triggering agent of MH, and ryanodine acting at the calcium release channel, and should be considered as a first step in the investigation of combined tests.

P-31 magnetic resonance spectroscopy. A tool for diagnostic purposes and pathophysiological insights in muscle diseases.

31P Magnetic Resonance Spectroscopy (MRS) is a potent tool allowing the investigation of muscle energetics in a noninvasive manner in humans. This review details the contribution of 31P MRS to the diagnosis of metabolic myopathies and provides some clues for the use of this technique in a clinical perspective. Finally, the contribution of 31P MRS to our understanding of the physiopathology of several other diseases is highlighted.

Metabolic determinants of the onset of acidosis in exercising human muscle: a 31P-MRS study.

Onset of intracellular acidosis during muscular exercise has been generally attributed to activation or hyperactivation of nonoxidative ATP production but has not been analyzed quantitatively in terms of H(+) balance, i.e., production and removal mechanisms. To address this issue, we have analyzed the relation of intracellular acidosis to H(+) balance during exercise bouts in seven healthy subjects. Each subject performed a 6-min ramp rhythmic exercise (finger flexions) at low frequency (LF, 0.47 Hz), leading to slight acidosis, and at high frequency (HF, 0.85 Hz), inducing a larger acidosis. Metabolic changes were recorded using (31)P-magnetic resonance spectroscopy. Onset of intracellular acidosis was statistically identified after 3 and 4 min of exercise for HF and LF protocols, respectively. A detailed investigation of H(+) balance indicated that, for both protocols, nonoxidative ATP production preceded a change in pH. For HF and LF protocols, H(+) consumption through the creatine kinase equilibrium was constant in the face of increasing H(+) generation and efflux. For both protocols, changes in pH were not recorded as long as sources and sinks for H(+) approximately balanced. In contrast, a significant acidosis occurred after 4 min of LF exercise and 3 min of HF exercise, whereas the rise in H(+) generation exceeded the rise in H(+) efflux at a nearly constant H(+) uptake associated with phosphocreatine breakdown. We have clearly demonstrated that intracellular acidosis in exercising muscle does not occur exclusively as a result of nonoxidative ATP production but, rather, reflects changes in overall H(+) balance.

Citrulline/malate promotes aerobic energy production in human exercising muscle.

BACKGROUND: Previous studies have shown an antiasthenic effect of citrulline/malate (CM) but the mechanism of action at the muscular level remains unknown. OBJECTIVE: To investigate the effects of CM supplementation on muscle energetics. METHODS: Eighteen men complaining of fatigue but with no documented disease were included in the study. A rest-exercise (finger flexions)-recovery protocol was performed twice before (D-7 and D0), three times during (D3, D8, D15), and once after (D22) 15 days of oral supplementation with 6 g/day CM. Metabolism of the flexor digitorum superficialis was analysed by (31)P magnetic resonance spectroscopy at 4.7 T. RESULTS: Metabolic variables measured twice before CM ingestion showed no differences, indicating good reproducibility of measurements and no learning effect from repeating the exercise protocol. CM ingestion resulted in a significant reduction in the sensation of fatigue, a 34% increase in the rate of oxidative ATP production during exercise, and a 20% increase in the rate of phosphocreatine recovery after exercise, indicating a larger contribution of oxidative ATP synthesis to energy production. Considering subjects individually and variables characterising aerobic function, extrema were measured after either eight or 15 days of treatment, indicating chronological heterogeneity of treatment induced changes. One way analysis of variance confirmed improved aerobic function, which may be the result of an enhanced malate supply activating ATP production from the tricarboxylic acid cycle through anaplerotic reactions. CONCLUSION: The changes in muscle metabolism produced by CM treatment indicate that CM may promote aerobic energy production.

[Non invasive investigation of muscle diseases using 31P magnetic resonance spectroscopy: potential in clinical applications]. / Spectrométrie de résonance magnétique du phosphore-31 et maladies musculaires. Avantages, limites et perspectives en clinique.

P-31 MRS has become in a very short time, a major new tool to explore muscle metabolism for clinical diagnostic purposes, while offering a unique non-invasive way to conduct advanced basic research in muscle physiopathology. The comparative analysis of normal and diseased muscle remains a major requirement to further define metabolic events surrounding muscle contraction and the metabolic anomalies underlying pathologies. Also, standardized rest-exercise-recovery protocols for exploration of muscle metabolism by P-31 MRS in healthy volunteers as well as in patients with intolerance to exercise need to be developed. Our protocol is based on a short term intense exercise which is very informative and well accepted by volunteers and patients. Invariant metabolic parameters have been defined to characterize the normal metabolic response to the protocol. Deviations from normality can be directly interpreted in terms of specific pathologies in some favorable cases. In most cases, P-31 MRS provides valuable information which has to be processed in conjunction with traditional invasive biochemical, electrophysiological and histoenzymological tests. For malignant and exercise hyperthermias, P-31 MRS constitutes a diagnostic tool with 100p.cent sensitivity, as compared to contracture tests on muscle biopsies. P-31 MRS has proved particularly useful in the therapeutic follow-up of palliative therapies (coenzyme Q treatment of mitochondriopathies) and in family investigations. It is now an accepted diagnostic tool in the array of tests which are used to characterize muscle disorders in clinical routine. As a research tool, it will keep bringing new information on the physiopathology of muscle diseases in animal models and in humans and should play a role in the metabolic characterization of gene therapy.

Investigation of fluoroquinolone-induced myalgia using (31)P magnetic resonance spectroscopy and in vitro contracture tests.

OBJECTIVE: To investigate muscle function in patients with severe myalgia resulting from fluoroquinolone (FQ) treatment. We used histology, in vitro contracture tests (IVCTs), and (31)P magnetic resonance spectroscopy ((31)P MRS) to explore muscle contraction and metabolism. METHODS: We studied 3 patients with myalgia, hyperalgia tendinopathy, and arthralgia following FQ treatment and 3 normal subjects after taking FQs. Results were compared with those of a control group of 9 subjects free of any muscle disease and not taking FQs. Muscle biopsies were performed on the left biceps, and IVCTs were performed in accordance with the protocol recommended by the European Malignant Hyperthermia Group. (31)P MR spectra of forearm flexor muscles were recorded at 4.7T throughout a rest-exercise-recovery protocol. RESULTS: (31)P MRS showed a significant reduction of pH changes measured at the end of exercise and a faster rate of proton efflux measured during recovery in all patients. IVCTs diagnosed 1 patient as being susceptible to malignant hyperthermia. No specific histologic anomalies were observed in muscle biopsy samples, which showed normal mitochondria. CONCLUSION: The adverse effects recorded in the 3 patients are related to a preexisting muscular anomaly revealed by FQ treatment.

Antiphospholipid syndrome and factor V Leiden. Three cases with recurrent venous thrombosis.

Recurrent thrombosis is a common complication of various rheumatic disorders and is part of the definition of antiphospholipid syndrome. We report three cases of recurrent venous thrombosis due not only to antiphospholipid syndrome with a normal activated partial thromboplastin time but also to resistance to activated protein C caused by the factor V Leiden mutation. These three cases confirm that thrombotic disease is frequently multifactorial and suggest that resistance to activated protein C should be looked for routinely in patients with suggestive clinical manifestations, particularly when standard clotting tests are normal.

31P magnetic resonance spectroscopy study of phosphocreatine recovery kinetics in skeletal muscle: the issue of intersubject variability.

We have analyzed by (31)P MRS the relationship between kinetic parameters of phosphocreatine (PCr) recovery and end-of-exercise status under conditions of moderate and large acidosis induced by dynamic exercise. Thirteen healthy subjects performed muscular contractions at 0.47 Hz (low frequency, moderate exercise) and 0.85 Hz (high frequency, heavy exercise). The rate constant of PCr resynthesis (k(PCr)) varied greatly among subjects (variation coefficients: 43 vs. 57% for LF vs. HF exercises) and protocols (k(PCr) values: 1.3+/-0.5 min(-1) vs. 0.9+/-0.5 min(-1) for LF vs. HF exercises, P<0.03). The large intersubject variability can be captured into a linear relationship between k(PCr), the amount of PCr consumed ([PCr(2)]) and pH reached at the end of exercise (pH(end)) (k(PCr)=-3.3+0.7 pH(end)-0.03 [PCr(2)]; P=0.0007; r=0.61). This dual relationship illustrates that mitochondrial activity is affected by end-of-exercise metabolic status and allows reliable comparisons between control, diseased and trained muscles. In contrast to k(PCr), the initial rate of PCr recovery and the maximum oxidative capacity were always constant whatever the metabolic conditions of end-of-exercise and can then be additionally used in the identification of dysfunctions in the oxidative metabolic pathway.

Surgical management of calcific tendinitis of the shoulder: an analysis of 26 cases.

Chronic calcific tendinitis of the shoulder has good results after medical treatment in most cases. Around 10% of the patients resistant to medical treatment require surgery. We report 22 patients operated on using an open procedure. The operation included removal of the calcific deposit and an acromioplasty. The patients were rated preoperatively and postoperatively for pain, limitations in activities of daily living, range of movement and power according to a questionnaire and the Constant assessment. Globally the average score increased from 52.2 points out of 100 at the preoperative examination to 89.3 postoperatively with a mean follow up of 23 months. The most favourable results are obtained in patients with the longest interval between onset of disease and intervention (over 1 year) and with a progressive course of disease. Different techniques are discussed. Arthroscopically assisted procedures and open techniques are compared.

Healing of Charcot's joint by pamidronate infusion.

Treatment of Charcot's joints remains difficult, and involves prolonged periods without weightbearing, immobilization, and surgical salvage procedures to avoid amputation. We describe the efficacy of pamidronate in treating a patient with Charcot's joint, due to hereditary sensory neuropathy, that caused loss of pain sensation. The bone and joint destruction in our patient's left foot was stopped by bisphosphonate treatment, and signs of a reconstructive healing process were observed on the control radiographs. The treatment was administered intravenously every 4 months for 2 years, without restriction on weightbearing, since the patient had refused a plaster cast and an orthotic device. This observation suggests that treatment with bisphosphonates should be used before, or in combination with, other treatment in such cases.

Gender modulates the energy cost of muscle contraction in untrained healthy subjects. A 31P magnetic resonance spectroscopy analysis.

The forearm flexor muscles of 56 untrained volunteers (26 women and 30 men) were examined by 31P magnetic resonance spectroscopy, during a rest-exercise-recovery protocol, in order to document the impact of gender on muscle energetics. Absolute concentrations of high-energy phosphate compounds, intracellular pH and rates of aerobic and anaerobic ATP production were calculated. An inverse correlation was found between body mass index (BMI) and power output in women but not in men. After correcting for power output and BMI, the measured energy cost of contraction was twice larger for women than for men. This increase was also reflected in larger ATP production from aerobic and anaerobic pathways. This higher energy cost might be explained in part by differences in local muscle mass, a higher impact of fatness, but also by a reduced metabolic efficiency of muscle fibers in untrained women.