Cessation of ambulation results in a dramatic loss of trabecular bone density in boys with Duchenne muscular dystrophy (DMD).

Glucocorticoids are currently used to improve muscle strength and prolong ambulation in boys with DMD although the effect on bone health is still unclear. The aim of this study was to compare bone strength in healthy children and boys with DMD and investigate the interaction between diminished muscle function, loss of ambulation and high dose oral steroids, over a two year time frame. Fifty children were studied, 14 healthy boys (HB), 13 boys with DMD who remained ambulant (DMD-RA) and 23 boys with DMD who lost ambulation (DMD-LA). All boys with DMD had taken oral glucocorticoids. Peripheral quantitative computed tomography was used to measure bone geometry, density, strength and muscle mass of the non-dominant tibia and radius. Measurements were made at baseline, 12 and 24 months at the distal metaphysis and mid diaphysis sites. Differences between the three groups were evaluated using ANOVA and a repeated measures model. There were no significant differences in age between the groups: mean age was 9.4, 8.7 and 8.8 years for HB, DMD-RA and DMD-LA, respectively. There was no significant difference in steroid exposure between the DMD groups. However, boys who lost ambulation had significantly lower muscle function at baseline (North Star Ambulatory Assessment DMD-RA 23.6 vs. DMD-LA 18.8; p < 0.05). At baseline, healthy boys had significantly greater trabecular bone density at the distal radius /ulna (23%/27%) and distal tibia/fibula (30%/46%) than boys with DMD (p < 0.05). They also had significantly larger diaphyseal tibiae/fibulae (74%/36%) and radii/ulnae (49%/31%) with thicker corticies and consequently greater bone strength. In contrast, boys with DMD had greater cortical density (4%). Over time, there were small significant differences in the rate of change of both muscle and bone parameters between healthy boys and boys with DMD. For both ambulant and non-ambulant boys with DMD the greatest changes in cortical bone were evident at the tibia. After two years boys with DMD had on average, 63% less bone strength than healthy boys. However, the most strikingly significant difference was in trabecular bone density for boys who became non-ambulant. By 2 years non-ambulant DMD boys had 53% less trabecular bone density at distal tibia than their healthy age matched peers compared with boys who remained ambulant who had 27% less trabecular bone density. In conclusion, bone and muscle strength is reduced for all boys with DMD even while they remain ambulant. However, tibia trabecular bone density loss is significantly accelerated in DMD boys who lose independent ambulation compared to DMD boys who remain ambulant despite equivalent levels of corticosteroid exposure.

Episodes of particle ejection from the surface of the active asteroid (101955) Bennu.

Active asteroids are those that show evidence of ongoing mass loss. We report repeated instances of particle ejection from the surface of (101955) Bennu, demonstrating that it is an active asteroid. The ejection events were imaged by the OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) spacecraft. For the three largest observed events, we estimated the ejected particle velocities and sizes, event times, source regions, and energies. We also determined the trajectories and photometric properties of several gravitationally bound particles that orbited temporarily in the Bennu environment. We consider multiple hypotheses for the mechanisms that lead to particle ejection for the largest events, including rotational disruption, electrostatic lofting, ice sublimation, phyllosilicate dehydration, meteoroid impacts, thermal stress fracturing, and secondary impacts.

The unexpected surface of asteroid (101955) Bennu.

NASA'S Origins, Spectral Interpretation, Resource Identification and Security-Regolith Explorer (OSIRIS-REx) spacecraft recently arrived at the near-Earth asteroid (101955) Bennu, a primitive body that represents the objects that may have brought prebiotic molecules and volatiles such as water to Earth1. Bennu is a low-albedo B-type asteroid2 that has been linked to organic-rich hydrated carbonaceous chondrites3. Such meteorites are altered by ejection from their parent body and contaminated by atmospheric entry and terrestrial microbes. Therefore, the primary mission objective is to return a sample of Bennu to Earth that is pristine-that is, not affected by these processes4. The OSIRIS-REx spacecraft carries a sophisticated suite of instruments to characterize Bennu's global properties, support the selection of a sampling site and document that site at a sub-centimetre scale5-11. Here we consider early OSIRIS-REx observations of Bennu to understand how the asteroid's properties compare to pre-encounter expectations and to assess the prospects for sample return. The bulk composition of Bennu appears to be hydrated and volatile-rich, as expected. However, in contrast to pre-encounter modelling of Bennu's thermal inertia12 and radar polarization ratios13-which indicated a generally smooth surface covered by centimetre-scale particles-resolved imaging reveals an unexpected surficial diversity. The albedo, texture, particle size and roughness are beyond the spacecraft design specifications. On the basis of our pre-encounter knowledge, we developed a sampling strategy to target 50-metre-diameter patches of loose regolith with grain sizes smaller than two centimetres4. We observe only a small number of apparently hazard-free regions, of the order of 5 to 20 metres in extent, the sampling of which poses a substantial challenge to mission success.

Growth, bone health & ambulatory status of boys with DMD treated with daily vs. intermittent oral glucocorticoid regimen.

Oral glucocorticoids (GC) preserve muscle strength and prolong walking in boys with Duchenne muscular dystrophy (DMD). Although vertebral fractures have been reported in boys taking GC, fracture rates for different GC regimes have not been investigated. The aim of this pragmatic longitudinal study was to compare growth, body mass, bone mineral density (BMD), vertebral fractures (VF) and ambulatory status in boys with DMD on daily (DAILY) or intermittent (INTERMITTENT), oral GC regimens. A convenience sample of 50 DMD boys from two centres was included in the study; 25 boys each were on the DAILY or INTERMITTENT regimen. Size adjusted lumbar spine BMD (LS BMAD), total body less head BMD (TBLH), by DXA and distal forearm bone densities by pQCT, GC exposure, VF assessment and ambulatory status were analysed at three time points; baseline, 1 and 2 years. At baseline, there were no differences in age, GC duration or any bone parameters. However, DAILY boys were shorter (height SDS DAILY = -1.4(0.9); INTERMITTENT = -0.8(1.0), p = 0.04) with higher BMI (BMI SDS DAILY = 1.5(0.9); INTERMITTENT = 0.8(1.0), p = 0.01). Over 2 years, DAILY boys got progressively shorter (delta height SDS DAILY = -0.9(1.1); INTERMITTENT = +0.1(0.6), p < 0.001). At their 2 year assessment, 5 DAILY and 10 INTERMITTENT boys were non-ambulant. DAILY boys had more VFs than INTERMITTENT boys (10 versus 2; χ2 p = 0.008). BMAD SDS remained unchanged between groups. TBLH and radius BMD declined significantly but the rate of loss was not different. In conclusion, there was a trend for more boys on daily GCs to remain ambulant but at the cost of more VFs, greater adiposity and markedly diminished growth. In contrast, boys on intermittent GCs had fewer vertebral fractures but there was a trend for more boys to loose independent ambulation.

SEPN1-related myopathies: clinical course in a large cohort of patients.

OBJECTIVE: To assess the clinical course and genotype-phenotype correlations in patients with selenoprotein-related myopathy (SEPN1-RM) due to selenoprotein N1 gene (SEPN1) mutations for a retrospective cross-sectional study. METHODS: Forty-one patients aged 1-60 years were included. Clinical data including scoliosis, respiratory function, and growth measurements were collected by case note review. RESULTS: Mean age at onset was 2.7 years, ranging from birth to the second decade of life. All but 2 remained independently ambulant: one lost ambulation at age 5 years and another in his late 50s. The mean age of starting nocturnal noninvasive ventilation (NIV) was 13.9 years. One child required full-time NIV at the age of 1 year while in 2 cases NIV was started at 33 years. Two patients died from respiratory failure at the age of 10 and 22 years, respectively. The mean age at scoliosis onset was 10 years, in most cases preceded by rigidity of the spine. Fourteen patients had successful spinal surgery (mean age 13.9 years). Twenty-one were underweight; however, overt feeding difficulties were not a feature. CONCLUSIONS: This study describes the largest population affected by SEPN1-RM reported so far. Our findings show that the spectrum of severity is wider than previously reported. Respiratory insufficiency generally develops by 14 years but may occur as early as in infancy or not until the fourth decade. Motor abilities remain essentially static over time even in patients with early presentation. Most adult patients remain ambulant and fully employed.

Muscle histology vs MRI in Duchenne muscular dystrophy.

OBJECTIVE: There are currently no effective treatments to halt the muscle breakdown in Duchenne muscular dystrophy (DMD), although genetic-based clinical trials are being piloted. Most of these trials have as an endpoint the restoration of dystrophin in muscle fibers, hence requiring sufficiently well-preserved muscle of recruited patients. The choice of the muscles to be studied and the role of noninvasive methods to assess muscle preservation therefore require further evaluation. METHODS: We studied the degree of muscle involvement in the lower leg muscles of 34 patients with DMD >8 years, using muscle MRI. In a subgroup of 15 patients we correlated the muscle MRI findings with the histology of open extensor digitorum brevis (EDB) muscle biopsies. Muscle MRI involvement was assigned using a scale 0-4 (normal-severe). RESULTS: In all patients we documented a gradient of involvement of the lower leg muscles: the posterior compartment (gastrocnemius > soleus) was most severely affected; the anterior compartment (tibialis anterior/posterior, popliteus, extensor digitorum longus) least affected. Muscle MRI showed EDB involvement that correlated with the patient's age (p = 0.055). We show a correlation between the MRI and EDB histopathologic changes, with MRI 3-4 grades associated with a more severe fibro-adipose tissue replacement. The EDB was sufficiently preserved for bulk and signal intensity in 18/22 wheelchair users aged 10-16.6 years. CONCLUSION: This study provides a detailed correlation between muscle histology and MRI changes in DMD and demonstrates the value of this imaging technique as a reliable tool for the selection of muscles in patients recruited into clinical trials.

Implementation of "the consensus statement for the standard of care in spinal muscular atrophy" when applied to infants with severe type 1 SMA in the UK.

The diagnosis of severe type 1 spinal muscular atrophy (SMA) should be confirmed by an expert in paediatric neuromuscular disease. Invasive investigations are not usually necessary as the diagnosis is confirmed with a DNA blood test. Care thereafter should be delivered close to home by a multidisciplinary team with a clear point of access during times of crisis. The aim of care is to keep the infant as well as possible with the best possible quality of life. There are many forms of active respiratory management which can help maintain the well-being of infants with severe type 1 SMA. These include approaches to reduce the risk of infection and aspiration and appropriate techniques of airway and secretion clearance. The use of non-invasive ventilation may be helpful for some, usually less-severely affected infants, particularly to assist extubation. Long-term invasive ventilation is not recommended. Active assessment of feeding and nutrition is vital, and most babies can be managed well with nasogastric feeds. Gastrostomy may be considered for some infants, but the benefits should be carefully weighed against the risks. It is vital to share information and formulate an anticipatory care plan with the infant's parents from the point of diagnosis.

Lamotrigine poisoning presenting as seizures: a case of deliberate poisoning.

Features of Lamotrigine poisoning are not clearly described in children. We report a child who presented with seizures and bizarre neurological symptoms, later attributed to lamotrigine poisoning.

Muscle connective tissue content of endurance-trained and inactive individuals.

Although it is known that exercise exerts a positive regulatory effect on collagen synthesis, the effects of endurance training on muscle endomysial connective tissue in man are not so well documented. To investigate this, a single muscle biopsy was collected from two groups of volunteers - endurance-trained sports participants and age-matched healthy untrained individuals. Endomysial staining intensity of types I, III and IV collagen was quantified by immunohistochemical staining and image analysis methods. Gelatinase activity in the endomysium was also quantified histochemically. Mean cycling VO2peak values of 53+/-6 (SD) and 32+/-8 mL/kg/min (P<0.01) were recorded for the trained and untrained groups, respectively. The staining intensity of types I, III and IV collagen and gelatinase activity in the trained group were not significantly different from the untrained group. However, when the data for all 11 volunteers were pooled, significant negative correlations were found for type III collagen staining intensity and capillary/fiber ratio; and for the relationship between type IV collagen staining intensity and VO2peak. These results suggest a negative association between aerobic capacity and the intensity of staining for types III and IV collagen in muscle endomysium.

Mild ichthyosis in a 4-year-old boy with multiple sulphatase deficiency.

We report a 4-year-old boy with multiple sulphatase deficiency (MSD). His early health was good. By the end of his first year there were concerns about developmental delay but by 26 months he showed clear evidence of regression in that he was barely able to sit unsupported and had lost all fine motor and communication skills. At that time he also had widespread mild ichthyosis that cleared completely with the use of emollients. The neurological deterioration suggested a diagnosis of metachromatic leucodystrophy, and a reduction in the leucocyte arylsulphatase A activity was detected. The ichthyosis suggested steroid sulphatase deficiency, and a reduction in the leucocyte steroid sulphatase activity was detected. The enzyme deficiency was much less marked for steroid sulphatase than for arylsulphatase A in this boy. This diversity in enzyme activities is typical of MSD and correlates with the mild ichthyosis in this child. This case shows that even mild ichthyosis should prompt measurement of steroid sulphatase activity in a child of either sex with unexplained neurological deterioration.

Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores.

Central core disease (CCD) is a congenital myopathy due to dominant mutations in the skeletal muscle ryanodine receptor gene (RYR1). The authors report three patients from two consanguineous families with symptoms of a congenital myopathy, cores on muscle biopsy, and confirmed linkage to the RYR1 locus. Molecular genetic studies in one family identified a V4849I homozygous missense mutation in the RYR1 gene. This report suggests a congenital myopathy associated with recessive RYR1 mutations.

Mitochondrial cytopathy presenting with focal segmental glomerulosclerosis, hypoparathyroidism, sensorineural deafness, and progressive neurological disease.

A 6 year old boy who presented with steroid unresponsive nephrotic syndrome is reported. He was found to have focal segmental glomerulosclerosis and associated hypoparathyroidism and sensorineural deafness. The child progressed to end stage renal failure and was successfully managed by dialysis and cadaveric renal transplantation. He later developed progressive neurological deterioration and mitochondrial myopathy and neuropathy was diagnosed.

Stereoselective 1,3-dipolar cycloadditions of a chiral nitrone derived from erythrulose. An experimental and DFT theoretical study

We have investigated several 1,3-dipolar cycloadditions of a chiral nitrone prepared from L-erythrulose. While cycloadditions to carbon-carbon multiple bonds of dipolarophiles such as ethyl acrylate, ethyl propiolate, or dimethyl acetylenedicarboxylate were poorly stereoselective, reaction with acrylonitrile provided predominantly one diastereomeric adduct. Furthermore, the regioselectivity exhibited by the two structurally similar dipolarophiles ethyl acrylate and ethyl propiolate was found to be opposite. The molecular mechanisms of these cycloadditions have thus been investigated by means of density functional theory (DFT) methods with the B3LYP functional and the 6-31G and 6-31+G basis sets. A simplified achiral version of nitrone 1 as the dipole, and methyl propiolate or acrylonitrile as the dipolarophiles, were chosen as computational models. The cycloadditions have been shown to take place through one-step pathways in which the C-C and C-O sigma bonds are formed in a nonsynchronous way. For the reaction with methyl propiolate, DFT calculations predict the experimentally observed meta regioselectivity. For the reaction with acrylonitrile, however, the predicted regioselectivity has been found to depend on the computational level used. The calculations further indicate the exo approach to be energetically favored in the case of the latter dipolarophile, in agreement with experimental findings. The main reason for this is the steric repulsion between the nitrile function and one of the methyl groups on the nitrone that progressively develops in the alternative endo approach.

Changes in indices of antioxidant status, lipid peroxidation and inflammation in human skeletal muscle after eccentric muscle actions.

This study investigated the effects of chronic muscle inflammation on indices of antioxidant status and muscle injury after eccentric exercise. Eight subjects each performed 70 maximal voluntary eccentric muscle actions on an isokinetic dynamometer, using the knee extensors of a single leg. Venous blood samples were collected into serum and EDTA tubes 5 and 3 days before exercise, immediately before exercise, and then again on days 3, 4, 5, 6, 7, 10 and 12 after the bout. Needle biopsies were taken from the vastus lateralis of six subjects, a week before exercise (baseline), and again on days 4 and 7 post-exercise. The concentrations of malondialdehyde in plasma and muscle were used as markers of lipid peroxidation. Creatine kinase activity, beta-glucuronidase activity and total antioxidant capacity were determined in serum. In muscle, aqueous and bound total antioxidant capacity, the aqueous sulphydryl concentration, and beta-glucuronidase and glucose-6-phosphate dehydrogenase activity were determined. No changes were detected in serum total antioxidant capacity, serum creatine kinase and beta-glucuronidase after the baseline biopsy. After exercise serum creatine kinase and beta-glucuronidase were elevated although other serum measures were unchanged. In muscle, aqueous and bound total antioxidant capacity, sulphydryls, glucose-6-phosphate dehydrogenase and beta-glucuronidase were all elevated. Despite evidence of inflammation in this study, muscle antioxidant status was not compromised, and malondialdehyde was unaltered in muscle and plasma. Therefore, this study provides no evidence that chronic muscle inflammation compromises antioxidant status or increases lipid peroxidation.

Variable presentation of primary hyperoxaluria type 1 in 2 patients homozygous for a novel combined deletion and insertion mutation in exon 8 of the AGXT gene.

Two unrelated patients of Pakistani origin presented with primary hyperoxaluria type 1 (PH1) at 4 months and 3 years of age, respectively. While the younger patient failed to thrive and suffered from early renal failure, the older one showed a relatively benign history with urolithiasis as the main feature of the disease. In both patients the diagnosis was confirmed by assessment of alanine:glyoxylate aminotransferase catalytic and immunoreactivity in liver biopsy specimens. The underlying genetic defect was found to be a combined deletion and insertion in exon 8 which alters the reading frame of the protein. The nucleotide change introduces a Stu1 restriction site which facilitated typing of additional family members. Both patients and a further affected brother were homozygous for this mutation, while their parents were heterozygous for it. This mutation is the first deletion/insertion identified in PH1. Although rare in our PH1 patient cohort (2.5% of alleles), the finding of 2 homozygous apparently unrelated individuals of the same ethnic origin suggests that it may prove worthwhile to screen other Asian patients for this mutation. These PH1 cases present further evidence that factors other than genotype contribute significantly to the clinical presentation and severity of PH1.

A difficult case. Childhood onset insulin dependent diabetes presenting with severe hyperlipidaemia.

Confronted with a child deteriorating during treatment of diabetic ketoacidosis, Godfrey Nyamugunduru and Helen Roper describe how the child's management was complicated by gross hyperlipidaemia. At the point where the child's condition was deteriorating despite conventional management we invited two experts-Gilbert R Thompson and J I Mann-to suggest a course of action. The original authors then describe how they did manage the case, and our experts comment again.

Aplasia cutis congenita with chromosome 12q abnormality.

A 32 week, small for dates baby with aplasia cutis congenita had an unbalanced translocation, being monosomic for distal 12q and trisomic for distal 1q. As far as is known, the association between extensive skin defects and a chromosomal abnormality has not been reported before. Keratin genes have been located in a different area of 12q, but this case may indicate other candidate areas to explore. Karyotyping should be undertaken in all babies with aplasia cutis.