Reporting of paediatric osteoporotic vertebral fractures in Duchenne muscular dystrophy and potential impact on clinical management: the need for standardised and structured reporting.

BACKGROUND: In boys with Duchenne muscular dystrophy (DMD), initiation of bisphosphonate is recommended upon identification of moderate or severe vertebral fractures, even if asymptomatic. Clear radiological reporting is important for consistency of clinical interpretation and management. OBJECTIVES: To audit radiology reports of spine imaging for vertebral fracture assessment in DMD, and assess potential impact on diagnosis and management. MATERIALS AND METHODS: Lateral thoracolumbar spine imaging (71 lateral spine radiographs and 13 lateral dual energy absorptiometry spine image) in 84 boys with DMD performed across two centres. Anonymised radiology reports by paediatric radiologists were circulated to two neuromuscular clinicians and two endocrinologists. Clinicians determined if there was vertebral fracture, no vertebral fracture, or unclear interpretation. Endocrinologists also determined if bisphosphonate was indicated. A single observer (a clinician with expertise in vertebral fracture assessment) performed vertebral fracture assessment in 37 images and re-reported using a structured format. Structured reports were re-circulated to the four clinicians to re-evaluate the degree of concordance in clinical diagnosis of vertebral fracture and treatment decisions with bisphosphonate. RESULTS: The term "fracture" was used in 25/84 (30%) radiology reports and only in 8/43 (19%) with description of vertebral body abnormalities. Fracture grading was included in 7/43 (16%) radiology reports. Diagnostic concordance by the clinicians was noted in 36/84 (43%). Unclear interpretation was noted in 22% to 51% based on radiology reports. No unclear interpretation was noted with structured reports. Complete diagnostic (37/37, 100%) and treatment (37/37, 100%) concordance was noted with the structured reports, whereas complete diagnostic and treatment concordance was noted in only 16/37 (43%) and 17/37 (46%) of the radiology reports, respectively. CONCLUSION: Only a third of radiology reports of spine imaging in DMD explicitly used the terminology "fracture". Grading was only noted in a small percentage. Variability in diagnostic interpretation by clinicians may lead to differing management plans. As identification of vertebral fracture is a trigger for treatment, developing reporting guidelines for paediatric vertebral fracture assessment will improve care. A structured template should be introduced for radiological reporting of paediatric vertebral fracture assessment.

PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease.

Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of classical PLAN features as well as apparent claval hypertrophy' is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features.

Do phthalates affect steroidogenesis by the human fetal testis? Exposure of human fetal testis xenografts to di-n-butyl phthalate.

CONTEXT: Phthalates are ubiquitous environmental chemicals. Fetal exposure to certain phthalates [e.g. di-n-butyl phthalate (DBP)] causes masculinization disorders in rats, raising concern for similar effects in humans. We investigated whether DBP exposure impairs steroidogenesis by the human fetal testis. OBJECTIVE: The aim of the study was to determine effects of DBP exposure on testosterone production by normally growing human fetal testis xenografts. DESIGN: Human fetal testes (14-20 wk gestation; n=12) were xenografted into castrate male nude mice that were treated for 4-21 d with vehicle, or 500 mg/kg·d DBP, or monobutyl phthalate (active metabolite of DBP); all mice were treated with human chorionic gonadotropin to mimic normal human pregnancy. Rat fetal testis xenografts were exposed for 4 d to DBP as a positive control. MAIN OUTCOME MEASURES: Testosterone production was assessed by measuring host serum testosterone and seminal vesicle (SV) weights at termination, plus testis gene expression (rats). RESULTS: Human fetal testis xenografts showed similar survival (∼80%) and total graft weight (8.6 vs. 10.1 mg) in vehicle and DBP-exposed hosts, respectively. Serum testosterone (0.56 vs. 0.64 ng/ml; P>0.05) and SV weight (67.2 vs. 81.9 mg; P>0.05) also did not differ. Exposure to monobutyl phthalate gave similar results. In contrast, exposure of rat fetal xenografts to DBP significantly reduced SV weight and testis Cyp11a1/StAR mRNA expression and lowered testosterone levels, confirming that DBP exposure can inhibit steroidogenesis in xenografts, further validating the negative findings on testosterone production in the human. CONCLUSIONS: Exposure of human fetal testes to DBP is unlikely to impair testosterone production as it does in rats. This has important safety and regulatory implications.

Intralabyrinthine schwannomas: imaging diagnosis and classification.

BACKGROUND AND PURPOSE: ILS is a rare lesion that has a different management from the more common "acoustic" schwannoma. To date, only 137 cases have been reported. We present a classification scheme based on labyrinthine anatomy to describe and localize these lesions. Treatment and prognosis hinge on the appropriate localization of these tumors; thus, a concise terminology that can be used by both the otolaryngologist and radiology communities is desirable. MATERIALS AND METHODS: After approval of the institutional review board, a retrospective study of all patients with the diagnosis of ILS imaged between 1996 and 2010 was performed. Clinical and imaging data were collected. Patients were imaged with thin-section high-resolution T2 and contrast-enhanced MR imaging. RESULTS: There were 45 patients with a diagnosis of ILS. Forty-three had complete histories. There were 18 male and 25 female patients with an age range of 21-78 years with a mean age of 53 years. The most common presenting symptom was progressive sensorineural hearing loss. Lesions were characterized on the basis of their location. Intracochlear was most common (14/45) followed by transmodiolar (13/45), intravestibular (7/45), vestibulocochlear (5/45), transmacular (4/45), and transotic (2/45). Sixteen patients underwent surgical resection. The remaining patients were followed clinically and by serial MR imaging. CONCLUSIONS: ILS is an uncommon but under-reported tumor. We characterized the MR imaging appearance of these tumors by using high-resolution techniques. In addition, an anatomically based classification system is presented that will help the radiologist accurately describe ILS within the inner ear and help the surgeon determine which tumors are potential surgical candidates.

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.

Hospice provision and usage amongst young people with neuromuscular disease in the United Kingdom.

AIM: To identify the nature of services for children and young people with progressive neuromuscular disorders (NMD) provided by Children's Hospices in the UK. METHODS: A questionnaire requesting aggregate data on the number of patients with a neuromuscular condition was sent to all children's hospices in the UK, in addition, specific data was collected on services for young people with DMD presenting to a single local hospice. RESULTS: 87% of eligible hospices responded (27/31). 756 young people with an NM condition were being cared for by the hospices. These patients accounted for a mean of 17% of the total hospice population (range 5-35%). The age at which young people were required to leave the children's hospices varied from 18 up to 35 years. 73% of 'visits' were described as 'planned stays'. Although 'end of life care' is provided, few young people with NMD died in a hospice. CONCLUSIONS: Children and young people with NMD form a large proportion of the Children's Hospice's caseload. Many valued services provided by children's hospices are not available through NHS funding. The lack of similar adult based services is a concern as increasing numbers of young people are surviving into adulthood.

The forkhead transcription factor FOXL2 is expressed in somatic cells of the human ovary prior to follicle formation.

Interactions between germ cells and surrounding somatic cells are central to ovarian development as well as later function. Disruption of these interactions arising from abnormalities in either cell type can lead to premature ovarian failure (POF). The forkhead transcription factor FOXL2 is a candidate POF factor, and mutations in the FOXL2 gene are associated with syndromic and non-syndromic ovarian failure. Foxl2-deficient mice display major defects in primordial follicle activation with consequent follicle loss, and earlier roles in gonadal development and sex determination have also been suggested. However, despite its importance no data presently exist on its expression in the developing human ovary. Expression of FOXL2 mRNA was demonstrated in the human fetal ovary between 8 and 19 weeks gestation, thus from soon after sex determination to primordial follicle development. Expression in the ovary was higher after 14 weeks than at earlier gestation weeks and was very low in the fetal testis at all ages examined. Immunolocalization revealed FOXL2 expression to be confined to somatic cells, both adjacent to germ cells and those located in the developing ovarian stroma. These cells are the site of action of oocyte-derived activin signalling, but in vitro treatment of human fetal ovaries with activin failed to reveal any regulation of FOXL2 transcription by this pathway. In summary, the expression of FOXL2 in somatic cells of the developing human ovary before and during follicle formation supports a conserved and continuing role for this factor in somatic/germ cell interactions from the earliest stages of human ovarian development.

Variable phenotype including Leigh syndrome with a 9185T>C mutation in the MTATP6 gene.

We describe 15 members of a Caucasian family with an apparently homoplasmic T-->C mutation at nucleotide position 9185 (9185T>C) in the mtDNA encoded MTATP6 (ATPase 6) gene. The clinical phenotype is extremely variable and includes late-onset Leigh syndrome (LS), isolated demyelinating peripheral neuropathy and neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP). Following recent reports of this same mutation in a single case and in a family with late-onset LS and NARP-like features, our paper emphasises the role of MTATP6 in LS and expands the associated clinical phenotype further.

Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene.

We screened 100 patients with inherited and sporadic lower motor neuron degeneration and identified three novel missense mutations in the glycyl-tRNA synthetase (GARS) gene. One mutation was in the anticodon binding domain and associated with onset in early childhood and predominant involvement of the lower limbs, thus extending the phenotype associated with GARS mutations.

Subdural haematoma and effusion in infancy: an epidemiological study.

AIM: To determine incidence, aetiology, and clinical features of subdural haematoma and effusion (SDH/E) in infancy throughout the British Isles. METHODS: Cases were notified to the British Paediatric Surveillance Unit over 12 months by paediatricians, neurosurgeons, and paediatric and forensic pathologists. RESULTS: A total of 186 infants (121 boys, 65 girls) aged 0-2 years were identified. Annual incidence of SDH/E for the UK and Republic of Ireland is 12.54/100,000 aged 0-2 (95% CI 10.3 to 14.62) and 24.1/100,000 aged 0-1 (95% CI 20.89 to 28.18). A total of 106 infants suffered non-accidental head injury (NAHI), 7 accidental head injury, 26 a perinatal cause, 7 a non-traumatic medical condition, 23 meningitis, and in 17 the cause was undetermined; 35 infants died. Significant differences were found in injury pattern, body weight, and Townsend score between NAHI and SDH/E from other cause. There were fewer diagnostic investigations in non-NAHI cases. Delay in diagnosis of greater than a week occurred in 48/181. CONCLUSION: SDH/E is a significant cause of morbidity and mortality in infancy. NAHI is the predominant cause of SDH/E. SDH/E can present in a non-specific and varied way and must be considered in any infant who is unwell. Determining the cause of the SDH/E in some cases continues to present a diagnostic challenge.

Polyamine-dependent gene expression.

The polyamines spermidine and spermine along with the diamine putrescine are involved in many cellular processes, including chromatin condensation, maintenance of DNA structure, RNA processing, translation and protein activation. The polyamines influence the formation of compacted chromatin and have a well-established role in DNA aggregation. Polyamines are used in the posttranslational modification of eukaryotic initiation factor 5A, which regulates the transport and processing of specific RNA. The polyamines also participate in a novel RNA-decoding mechanism, a translational frame-shift, of at least two known genes, the TY1 transposon and mammalian antizyme. Polyamines are crucial for their own regulation and are involved in feedback mechanisms affecting both polyamine synthesis and catabolism. Recently, it has become apparent that the polyamines are able to influence the action of the protein kinase casein kinase 2. Here we address several roles of polyamines in gene expression.

Magnetic resonance imaging of the infant brain: anatomical characteristics and clinical significance of punctate lesions.

OBJECTIVE: To describe the magnetic resonance imaging (MRI) characteristics of punctate brain lesions in neonates (number, appearance, distribution, and association with other brain abnormalities) and to relate them to neurodevelopmental outcome. METHODS: A retrospective analysis was performed of 110 MRI brain scans from 92 infants admitted in 1998 to the neonatal intensive care unit. Results of routine neurodevelopmental follow up (1998-2001) in those infants with punctate brain lesions were analysed. RESULTS: Punctate lesions were observed in 15/50 preterm and 2/42 term infants. In the preterm group, the number of lesions was < 3 in 20%, 3-10 in 27%, and > 10 in 53%. In 14/15 the lesions were linearly organised and located in the centrum semiovale. Other brain abnormalities were absent or minor--that is, "isolated" punctate lesions--in 8/15 and major in 7/15. In the term group, punctate lesions were organised in clusters and no other brain abnormalities were observed. Isolated punctate lesions were observed in 10/17 infants, and a normal neurodevelopmental outcome was seen in 9/10 (mean follow up 29.5 months). One infant showed a slight delay in language development. In the infants with associated brain lesions (7/17, mean follow up 27.5 months), outcome was normal in only two subjects. CONCLUSIONS: Punctate lesions are predominantly seen in preterm infants, are usually linearly organised, and border the lateral ventricles. Isolated punctate lesions may imply a good prognosis, because most of these subjects have a normal neurodevelopmental outcome so far.

Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise.

There has been no investigation to determine if the widely used over-the-counter, water-soluble antioxidants vitamin C and N-acetyl-cysteine (NAC) could act as pro-oxidants in humans during inflammatory conditions. We induced an acute-phase inflammatory response by an eccentric arm muscle injury. The inflammation was characterized by edema, swelling, pain, and increases in plasma inflammatory indicators, myeloperoxidase and interleukin-6. Immediately following the injury, subjects consumed a placebo or vitamin C (12.5 mg/kg body weight) and NAC (10 mg/kg body weight) for 7 d. The resulting muscle injury caused increased levels of serum bleomycin-detectable iron and the amount of iron was higher in the vitamin C and NAC group. The concentrations of lactate dehydrogenase (LDH), creatine kinase (CK), and myoglobin were significantly elevated 2, 3, and 4 d postinjury and returned to baseline levels by day 7. In addition, LDH and CK activities were elevated to a greater extent in the vitamin C and NAC group. Levels of markers for oxidative stress (lipid hydroperoxides and 8-iso prostaglandin F2alpha; 8-Iso-PGF2alpha) and antioxidant enzyme activities were also elevated post-injury. The subjects receiving vitamin C and NAC had higher levels of lipid hydroperoxides and 8-Iso-PGF2alpha 2 d after the exercise. This acute human inflammatory model strongly suggests that vitamin C and NAC supplementation immediately post-injury, transiently increases tissue damage and oxidative stress.

Cerebral maturation in premature infants: quantitative assessment using MR imaging.

BACKGROUND AND PURPOSE: The assessment of whether brain development is at an appropriate level for age has become an integral part of clinical MR reporting, although few studies have quantitatively defined the developmental changes occurring in premature infants. We have developed a simple scoring system to assess four parameters of cerebral maturation--myelination, cortical folding, glial cell migration, and germinal matrix distribution--to determine the total maturation score (TMS). The aim of this study was to validate this scoring system in a large population of preterm infants across a range of gestational ages. METHODS: A retrospective analysis was conducted of MR images acquired over a 3-year period with an identical imaging protocol. Infants born more than 14 days before the imaging examination and those with a clinical or radiologic history suggestive of neuroabnormality were excluded from the study. The TMS was derived by consensus. Interobserver agreement was evaluated by using the Bland-Altman plot. RESULTS: Images from 134 infants (23-41 weeks' gestational age) were evaluated. The TMS was significantly related to the postmenstrual age of the infant, with the mean TMS for each age group increasing with advancing postmenstrual age. Interobserver agreement was found to be high (mean difference in score = 0.07, SD = 0.56). CONCLUSION: This scoring system provides a standardized method for assessing cerebral maturation in the premature infant. The TMS is easy to calculate from standard MR images, is reproducible, and can help detect changes occurring within a postnatal age of a few weeks.

Magnetic resonance and cranial ultrasound characteristics of periventricular white matter abnormalities in newborn infants.

OBJECTIVE: To characterize the range of abnormalities within the periventricular white matter (PVWM) in a cohort of newborns using magnetic resonance (MR) brain imaging and to compare the focal MR abnormalities with the cranial ultrasound (CUS) findings. METHODS: Retrospective study of MR brain and CUS findings of infants born in the 18-month period 1998-1999. PVWM abnormalities were identified by MR and focal lesions were characterized by size, number and distribution using a grading scale. Correspondence with CUS findings was assessed. RESULTS: 175 MR examinations corresponding to n = 105 preterm infants, (median GA 28, range 23-36 weeks) and n = 25 term infants (median GA 39, range 37-42 weeks) were analysed for PVWM abnormalities. In the preterm group, MR demonstrated a normal PVWM in n = 76, focal areas of altered signal intensity (SI) in PVWM in n = 26 and venous infarction in n = 3. In the term group, MR demonstrated a normal PVWM in n = 15, focal areas of altered SI in PVWM in n = 4, oedematous PVWM in n = 2 and a middle cerebral artery infarction in n = 4. All infants with normal MR had normal CUS findings. A focal PVWM SI abnormality detectable on MR corresponded with an abnormality on CUS in only n = 10/30. CONCLUSIONS: MR appears considerably more sensitive than CUS in demonstrating the existence and extent of focal PVWM lesions in newborn infants. Satisfactory correspondence between the two imaging investigations is obtained only for cystic PVWM lesions.

Exact sampling from nonattractive distributions using summary states.

Propp and Wilson's method of coupling from the past allows one to efficiently generate exact samples from attractive statistical distributions (e.g., the ferromagnetic Ising model). This method may be generalized to nonattractive distributions by the use of summary states, as first described by Huber. Using this method, we present exact samples from a frustrated antiferromagnetic triangular Ising model and the antiferromagnetic q=3 Potts model. We discuss the advantages and limitations of the method of summary states for practical sampling, paying particular attention to the slowing down of the algorithm at low temperature. In particular, we show that such slowing down can occur in the absence of a physical phase transition.

The influence of reduced liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue factor pathway inhibitor.

OBJECTIVES: Recombinant tissue factor pathway inhibitor (rTFPI) has been shown to be an effective treatment in animal models of sepsis and is under investigation for human use. Reduced liver blood flow during septic shock may substantially alter the pharmacokinetics of rTFPI because clearance of rTFPI approaches liver blood flow. The aim of this study was to examine the effect of exercise-induced reduction in liver blood flow on the pharmacokinetics and pharmacodynamics of rTFPI. METHODS: This was a two-way, open-label, randomized crossover study in eight healthy male volunteers. The subjects in both treatment groups received a continuous intravenous infusion of rTFPI (0.2 mg/kg/h) concurrently with intravenous sorbitol (50 mg/min) for 4 hours. Sorbitol was used as a biomarker for liver blood flow. The subjects were randomized to remain supine or to exercise on a bicycle ergometer for 30 minutes starting at the beginning of the third hour of the infusion. RESULTS: Exercise reduced liver blood flow (mean +/- SEM) from 1.44 +/- 0.06 L/min to 0.40 +/- 0.03 L/min. The average clearance of rTFPI decreased from 0.73 +/- 0.04 L/min in the supine position to 0.25 +/- 0.02 L/min during exercise. This decrease in rTFPI clearance resulted in an 80% (95% confidence interval [CI], 60% to 102%) increase in plasma rTFPI levels during exercise. The average maximal prothrombin time and activated partial thromboplastin time values during exercise were 1.4 (95% CI, 0.4 to 2.5) and 4.4 (95% CI, 2.7 to 6.1) seconds higher compared with the supine steady-state level. CONCLUSIONS: Reduction in liver blood flow by exercise markedly increased rTFPI concentrations and induced a slight but variable prothrombin time and activated partial thromboplastin time increase at the rTFPI dose studied.

Evaluating the usage of droperidol in acutely agitated persons with brain injury.

The objective of this study was to compare the effectiveness and safety of intramuscular droperidol to other intramuscularly administered agents used in the management of acutely agitated patients. Twenty-seven inpatients with a history of brain injury were prospectively monitored over a period of 2 months. Data collected for each episode of agitation include: dose, number of doses, time to achieve an adequate response or calming effect, post-episodic functioning, treatment-emergent side effects, and other patient demographics. A retrospective medical records review was also performed on the same cohort, to compare clinical outcomes associated with other intramuscular agents previously used for acute agitation. Time to achieve calming was significantly shorter with intramuscular droperidol (mean = 27.0 minutes) compared to intramuscular haloperidol, lorazepam, or diphenhydramine (group mean = 36.2 minutes, p = 0.02). Of the three comparative agents, the time to achieve calming was the fastest with lorazepam (mean = 35.0 minutes), and slower with diphenhydramine (mean = 42.6 minutes) and haloperidol (mean = 43.0 minutes). Single doses of droperidol controlled agitation more frequently than did single doses of comparative agents, and there was less post-episodic sedation with droperidol following release from seclusion or restraints. Both groups were similar in regard to the incidence of treatment-emergent events. This data represents the first published experience supporting the effectiveness of droperidol in reducing acute agitation in persons with brain injury. Follow-up studies with prospective, double-blind, parallel treatment groups should be performed to validate these preliminary findings.

Neurovascular compression of the trigeminal and glossopharyngeal nerve: three case reports.

Trigeminal neuralgia (TN) is a frequent cause of paroxysmal facial pain and headache in adults. Glossopharyngeal neuralgia (GPN) is less common, but can cause severe episodic pain in the ear and throat. Neurovascular compression of the appropriate cranial nerve as it leaves the brain stem is responsible for the symptoms in many patients, and neurosurgical decompression of the nerve is now a well accepted treatment in adults with both TN and GPN who fail to respond to drug therapy. Neither TN nor GPN are routinely considered in the differential diagnosis when assessing children with paroxysmal facial or head pain, as they are not reported to occur in childhood. Case reports of three children with documented neurovascular compression causing severe neuralgic pain and disability are presented. The fact that these conditions do occur in the paediatric population, albeit rarely, is highlighted, and appropriate investigation and management are discussed.