Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients.

The cerebral cortex of Alzheimer's and Down syndrome patients is characterized by the presence of protein deposits in neurofibrillary tangles, neuritic plaques, and neuropil threads. These structures were shown to contain forms of beta amyloid precursor protein and ubiquitin-B that are aberrant (+1 proteins) in the carboxyl terminus. The +1 proteins were not found in young control patients, whereas the presence of ubiquitin-B+1 in elderly control patients may indicate early stages of neurodegeneration. The two species of +1 proteins displayed cellular colocalization, suggesting a common origin, operating at the transcriptional level or by posttranscriptional editing of RNA. This type of transcript mutation is likely an important factor in the widely occurring nonfamilial early- and late-onset forms of Alzheimer's disease.

What influences contracture formation in lower motor neuron disorders, severity of denervation or residual muscle function? An analysis of the elbow contracture in 100 children with unilateral Brachial Plexus Birth Injury.

PURPOSE: As in other neuromuscular disorders, both denervation and muscle paresis/imbalance are implicated as aetiological factors for contractures in children with a Brachial Plexus Birth Injury (BPBI). Although both factors are related, it is unclear which factor is dominant. The aim of this study is to assess whether contracture formation in children is predominantly related to denervation or to residual muscle function/imbalance. This might be relevant for understanding contracture formation in other neuromuscular disorders. METHODS: A total of 100 children (61 boys; mean age 10.4 years, 4 to 18) with unilateral BPBI were included in this cross-sectional study. Severity of the denervation was classified according to Narakas. Muscle function of flexors and extensors of both elbows was measured (in Newtons) using a hand-held dynamometer and flexion contractures were measured with a goniometer. The relation between denervation, muscle function/muscle balance and flexion contracture was assessed using univariate and multivariate analysis. RESULTS: Of the children, 57 were Narakas class I, 13 class II and 30 class III. Mean flexion contracture was 25° (90° to -5°). At the affected side the forearm flexion force was 47% and extension force was 67% of the force of the unaffected side. Contractures were more severe in children with higher Narakas classifications (p = 0.001), after neurosurgery (Mann-Whitney U test, p = 0.009) and were related to age (Spearman's Rho = -0.3, p = 0.008) and to paresis of the extensors (Rho = 0.4, p = 0.000). Flexor paresis as a percentage of unaffected side (Rho = 0.06, p = 0.6) and muscle balance had no influence. CONCLUSION: In BPBI, elbow contractures are related to the severity of the neurological lesion, not to residual muscle function. LEVEL OF EVIDENCE: Level II - prognostic study.

Malunion of the distal radius in children: accurate prediction of the expected remodeling.

PURPOSE: Malunions of fractures in children have a natural tendency to remodel. However, quantitative data of this well-known process are scarce. The extent of the correction depends inter alia on the type of bone and the location of the deformity and growth remaining. The aim of this study was to quantify the remodeling process of distal radius malunions in children to allow better future prediction. METHODS: Data were derived from two published patient series. Analysis included 63 malunions of distal radius fractures in 62 children (38 boys), with a mean age of 8.5 years (range 2-14.5 years). RESULTS: The mean initial dorsovolar angulation was 25º [standard deviation (SD) 7.8°], remodeling time 22 (SD 18) months, and angulation at follow-up 6.7° (SD 5.8°). Based on these findings, the remodeling process can be described as an exponential function with angulation (A 0) as a factor and the remodeling time (RT) as a negative exponent of e (R (2) = 0.47). The function allows accurate prediction of the expected correction in over 76 % of the malunions. From this model, a formula was derived for calculation of the time needed for complete remodeling, but this formula lacked precision when compared to findings in the literature and needs to be validated. CONCLUSIONS: The remodeling of distal radius malunions can be described as an exponential function with starting speed dependent on the initial angulation. The current model proves to be more accurate than models described previously in the literature. These findings allow for better patient information and optimal planning of eventual surgical intervention. The postulated model could serve as a basis for the description of correction of other malunions by adaptation of the coefficients in this model.

Mutant ubiquitin expressed in Alzheimer's disease causes neuronal death.

Ubiquitin-B+1 (UBB+1) is a mutant ubiquitin that accumulates in the neurones of patients with Alzheimer's disease (AD). Here we report on the biochemical and functional differences between ubiquitin and UBB+1 and the effect of the mutant protein on neuronal cells. UBB+1 lacks the capacity to ubiquitinate, and although it is ubiquitinated itself, UBB+1 is not degraded by the ubiquitin-proteasomal system and is quite stable in neuronal cells. Overexpression of UBB+1 in neuroblastoma cells significantly induces nuclear fragmentation and cell death. Our results demonstrate that accumulation of UBB+1 in neurones is detrimental and may contribute to neuronal dysfunction in AD patients.

Proteus syndrome: a rare cause of hemihypertrophy and macrodactyly on bone scanning.

Proteus syndrome is a rare, sporadic genetic disorder characterized by overgrowth of multiple different tissues in a mosaic pattern. It is associated with connective tissue nevi, epidermal nevi, disproportionate overgrowth of multiple tissues, vascular malformations, characteristic tumors, and specific facial anomalies. Joseph Merrick, popularly known as the Elephant Man, is now believed to have suffered from Proteus syndrome. A case of Proteus syndrome and associated findings on bone scintigraphy are presented.

The head-shaft angle of the hip in early childhood: a comparison of reference values for children with cerebral palsy and normally developing hips.

The recognition of hips at risk of displacement in children with cerebral palsy (CP) is a difficult problem for the orthopaedic surgeon. The Gross Motor Function Classification System (GMFCS) and head-shaft angle (HSA) are prognostic factors for hip displacement. However, reference values for HSA are lacking. This study describes and compares the development of HSA in normal hips and children with CP. We selected 33 children from a retrospective cohort with unilateral developmental dysplasia of the hip (DDH) (five boys, 28 girls) and 50 children (35 boys, 15 girls) with CP with GMFCS levels II to V. HSA of normal developing hips was measured at the contralateral hip of unilateral DDH children (33 hips) and HSA of CP children was measured in both hips (100 hips). Measurements were taken from the radiographs of the children at age two, four and seven years. The normal hip HSA decreased by 2° per year (p < 0.001). In children with CP with GMFCS levels II and III HSA decreased by 0.6° (p = 0.046) and 0.9° (p = 0.049) per year, respectively. The HSA did not alter significantly in GMFCS levels IV and V. Between the ages of two and eight years, the HSA decreases in normal hips and CP children with GMFCS level, II to III but does not change in GMFCS levels IV to V. As HSA has a prognostic value for hip displacement, these reference values may help the orthopaedic surgeon to predict future hip displacement in children with CP.

The prognostic value of the head-shaft angle on hip displacement in children with cerebral palsy.

BACKGROUND: Hip displacement is the second most common deformity in cerebral palsy (CP). The risk for hip displacement is related to the Gross Motor Function Classification System (GMFCS). Recently, the head-shaft angle (HSA) has been identified as a predictor for hip displacement and the aim of this study is to assess the predictive value of the HSA for hip displacement in CP. METHODS: In this retrospective cohort, we performed radiological measurements in 50 children on both hips. In children with GMFCS level II (30 hips), III (30 hips), IV (20 hips) and V (20 hips), we measured the HSA and migration percentage (MP) in three age intervals: age two years (T1), age four years (T2) and age seven years (T3). RESULTS: At T1, the HSA was larger (more valgus) in hips that will displace than in hips that will not displace (174° vs. 166°; p = 0.001) and was also larger in higher GMFCS levels (IV-V vs. II-III) (172° vs. 165°; p < 0.001). At T1, GMFCS [odds ratio (OR) 14.7; p = 0.001] and HSA (OR 1.102; p = 0.043) were predictors for hip displacement at T3, but at T2, MP (OR 1.071; p = 0.010) was the only predictor for hip displacement at T3. CONCLUSIONS: The HSA at two years is larger in hips that will displace and larger in children with higher GMFCS levels (IV-V). At age two years, GMFCS and HSA are valuable predictors for hip displacement, but at the age of four years, only MP should be used in the prediction of hip displacement. LEVEL OF EVIDENCE: Prognostic study, level II.

Molecular misreading: a new type of transcript mutation expressed during aging.

Dinucleotide deletions (e.g. DeltaGA, DeltaGU) are created by molecular misreading in or adjacent to GAGAG motifs of neuronal mRNAs. As a result, the reading frame shifts to the +1 frame, and so-called "+1 proteins" are subsequently synthesized. +1 Proteins have a wild-type N-terminus, but an aberrant C-terminus downstream from the site of the dinucleotide deletion. Molecular misreading was discovered in the rat vasopressin gene associated with diabetes insipidus and subsequently in human genes linked to Alzheimer's disease (AD), e.g. beta amyloid precursor protein (betaAPP) and ubiquitin-B (UBB). Furthermore, betaAPP(+1) and UBB(+1) proteins accumulate in the neuropathological hallmarks (i.e. in the tangles, neuritic plaques, and neuropil threads) of AD. As these +1 proteins were also found in elderly nondemented controls, but not in younger ones (<51 years), molecular misreading in nondividing cells might act as a factor that only becomes manifest at an advanced age. Frameshift mutations (UBB(+1)) and pretangle staining (Alz-50 and MC1) seem to occur independently of each other during early stages of AD. We recently detected +1 proteins, not only in proliferating cells present in non-neuronal tissues such as the liver and epididymis, but also in neuroblastoma cell lines. These observations suggest that molecular misreading is a general source of transcript errors that are involved in cellular derangements in various age-related pathologies.

The reliability of the Mankin score for osteoarthritis.

For the histopathological classification of the severity of osteoarthritic lesions of cartilage, the Mankin score is frequently used. A necessary constraint on the validity of this scoring system is the consistency with which cartilage lesions are classified. The intra- and interobserver agreement of the Mankin score was determined. The intra- and interobserver agreement of the 14-point Mankin score was adequate. Between observers 95% of differences were less than approximately 7 points. By a more strict definition of the elements of the Mankin score, the intraobserver differences were reduced only for some observers. The interobserver differences were only slightly reduced: between observers 95% of differences were less than approximately 6 points. We found the Mankin score to be an adequate histopathological tool.

Retroversion of the humeral head in children with an obstetric brachial plexus lesion.

We undertook a prospective MRI study to measure the retroversion of the humeral head in 33 consecutive infants with a mean age of 1 year 10 months (3 months to 7 years 4 months) who had an obstetric brachial plexus lesion (OBPL). According to a standardised MRI protocol both shoulders and humeral condyles were examined and the shape of the glenoid and humeral retroversion determined. The mean humeral retroversion of the affected shoulder was significantly increased compared with the normal contralateral side (-28.4 +/- 12.5 degrees v -21.5 +/- 15.1 degrees, p = 0.02). This increase was found only in the children over the age of 12 months. In this group humeral retroversion was -29.9 +/- 12.9 degrees compared with -19.6 +/- 15.6 degrees in the normal shoulder (p = 0.009), giving a mean difference of 10.3 degrees (95% confidence interval 3.3 to 17.3). This finding is of importance when considering the operative treatment for subluxation of the shoulder in children with an OBPL.

Deformities of the shoulder in infants younger than 12 months with an obstetric lesion of the brachial plexus.

We performed a prospective study using MRI in 16 consecutive infants with a mean age of 5.2 months (2.7 to 8.7) who had shown inadequate recovery from an obstetric lesion of the brachial plexus in the first three months of life, in order to identify early secondary deformities of the shoulder. Shoulders were analysed according to a standardised MRI protocol. Measurements were made of the appearance of the glenoid, glenoid version and the position of the humeral head. The appearance of the glenoid on the affected side was normal in only seven shoulders. In the remainder it was convex in seven and bioconcave in three. The degree of subluxation of the humeral head was significantly greater (p = 0.01) in the affected shoulders than in normal shoulders (157 degrees v 170 degrees). The presence of an abnormal appearance of the glenoid, retroversion of the glenoid and subluxation of the humeral head increased with age. There was a statistical difference (p = 0.05) between infants younger than five months and those who were older.

Secondary deformities of the shoulder in infants with an obstetrical brachial plexus lesions considered for neurosurgical treatment.

OBJECT: The authors performed a prospective study in which magnetic resonance (MR) imaging was conducted in 26 consecutive infants (mean age 5.6 months, range 2.7-14.5 months) in whom recovery from an obstetric lesion of the brachial plexus had been inadequate in the first 3 months of life. The purpose was to identify early secondary deformations of the shoulder in obstetrical brachial plexus lesions (OBPLs). METHODS: Features of the shoulders were analyzed according to a standardized MR imaging protocol in patients with OBPLs. Measurements were made of the appearance of the glenoid, glenoid version, and the position of the humeral head. The appearance of the glenoid on the affected side was normal in only 11 shoulders. In the remainder it was convex in eight and biconcave in seven cases. The degree of humeral head subluxation was significantly greater (p = 0.001) in affected shoulders than in normal shoulders (152 and 170 degrees, respectively). The presence of abnormal glenoid retroversion and humeral head subluxation increased with age: there was a statistical difference (p = 0.001) between infants younger than 5 months of age and those who were older. CONCLUSIONS: Magnetic resonance imaging demonstrates shoulder-related anatomical and nerve root lesion, allowing evaluation of neural, osseous, and cartilaginous structures in younger children.

Normal collagen structure in the posterior ankle capsule in different types of clubfeet.

In 21 clubfeet (17 children) of different types (idiopathic, spina bifida, syndromal), the authors analyzed modifications and crosslinks in collagen and their possible relations with clinical stiffness of clubfoot deformity, as measured by the Dimeglio/Bensahel method. In a biopsy of the capsule of the ankle joint, the number of hydroxylysine residues (mean +/- standard deviation; 27.1 +/- 3.4) and the number of pyridinium crosslinks per collagen molecule (0.41 +/- 0.12) were normal. This indicates normal processing of collagen molecules and normal alignment of collagen molecules within fibrils despite the variety of clubfeet, and even in scar tissue.

Bruck syndrome: a rare combination of bone fragility and multiple congenital joint contractures.

Bruck syndrome manifests with combined features of arthrogryposis and osteogenesis imperfecta. It is a distinct autosomal recessive disorder with normal collagen I. The main features are osteoporosis, bowing of the long bones, scoliosis due to vertebral deformities, and congenital joint contractures. The presence of arthrogryposis differentiates this syndrome from "classical" osteogenesis imperfecta. A family with three affected children is presented with a review of the literature.

Restoring wrist extension in obstetric palsy of the brachial plexus by transferring wrist flexors to wrist extensors.

Wrist extension is essential in the development of motor skills in young children. Adequate wrist extension is important for good grip function of the hand, as a slightly extended wrist results in a better and stronger grip. This retrospective study reviews the transfer of the flexor carpi ulnaris (FCU) or flexor carpi radialis (FCR) to the extensor carpi radialis brevis (ECRB) and/or longus (ERCL) to reconstruct wrist extension in 19 patients with obstetric brachial plexus palsy (OBPP). The average age at surgery was 7.2 (range 4-18) years. The mean follow-up was 3 years. Preoperatively, none of the patients had active wrist extension, with an average wrist extension-lag of 37.4 (SD 15.1) degrees. Postoperatively, average active wrist extension was 9.2 (SD 25.5) degrees. Average gain in wrist extension was 46.6 (SD 28.2) degrees, however individual gain varied substantially, i.e. between 0 and 100 degrees. Two patients were unable to reach the neutral wrist position postoperatively and in two patients wrist extension did not increase. The results of the tendon transfer to provide improvement of wrist extension in OBPP were satisfactory in most patients.

Incidence and gender differences of slipped capital femoral epiphysis in the Netherlands from 1998-2010 combined with a review of the literature on the epidemiology of SCFE.

PURPOSE: The incidence of slipped capital femoral epiphysis (SCFE) among children living in the Netherlands has never been published. METHODS: The national hospitalization registration system of the Netherlands was searched for the incidence of surgical procedures for SCFE in the Netherlands among different pediatric age groups between 1998 and 2010. International Classification of Diseases, 9th Revision codes were used. RESULTS AND CONCLUSION: The incidence of surgical procedures for SCFE during the last decade was 11.6 per 100,000 children aged 5 to 19 years. No statistical difference in the incidence of SCFE was found between boys and girls, although the incidence of SCFE did significantly increase in girls during the study period. Based on our analysis, the Netherlands appears to be the first country in which no difference in the incidence of SCFE among boys and girls has been reported. However, during the study period there has been a concomitant increase in the number of girls with SCFE.

Slipped capital femoral epiphysis and its association with endocrine, metabolic and chronic diseases: a systematic review of the literature.

PURPOSE: Puberty, obesity, endocrine and chronic systemic diseases are known to be associated with slipped capital femoral epiphysis (SCFE). The mechanical insufficiency of the physis in SCFE is thought to be the result of an abnormal weakening of the physis. However, the mechanism at the cellular level has not been unravelled up to now. METHODS: To understand the pathophysiology of endocrine and metabolic factors acting on the physis, we performed a systematic review focussing on published studies reporting on hormonal, morphological and cellular abnormalities of the physis in children with SCFE. In addition, we looked for studies of the effects of endocrinopathies on the human physis which can lead to cause SCFE and focussed in detail on hormonal signalling, hormone receptor expression and extracellular matrix (ECM) composition of the physis. We searched in the PubMed, EMBASE.com and The Cochrane Library (via Wiley) databases from inception to 11th September 2012. The search generated a total of 689 references: 382 in PubMed, 232 in EMBASE.com and 75 in The Cochrane Library. After removing duplicate papers, 525 papers remained. Of these, 119 were selected based on titles and abstracts. After excluding 63 papers not related to the human physis, 56 papers were included in this review. RESULTS: Activation of the gonadal axis and the subsequent augmentation of the activity of the growth hormone-insulin-like growth factor 1 (GH-IGF-1) axis are important for the pubertal growth spurt, as well as for cessation of the physis at the end of puberty. The effects of leptin, thyroid hormone and corticosteroids on linear growth and on the physis are also discussed. Children with chronic diseases suffer from inflammation, acidosis and malnutrition. These consequences of chronic diseases affect the GH-IGF-1 axis, thereby, increasing the risk of the development of SCFE. The risk of SCFE and avascular necrosis in children with chronic renal insufficiency, growth hormone treatment and renal osteodystrophy remains equivocal. CONCLUSIONS: SCFE is most likely the result of a multi-factorial event during adolescence when height and weight increase dramatically and the delicate balance between the various hormonal equilibria can be disturbed. Up to now, there are no screening or diagnostic tests available to predict patients at risk.

Management of slipped capital femoral epiphysis: results of a survey of the members of the European Paediatric Orthopaedic Society.

AIM: To determine current practice recommendations for the treatment of slipped capital femoral epiphysis (SCFE) among members of the European Paediatric Orthopaedic Society (EPOS). MATERIALS AND METHODS: A questionnaire with 4 case vignettes of a 12-year-old boy presenting with a stable and unstable SCFE. Each, stable and unstable slips, was of mild (20° epiphyseal-shaft angle) and of severe (60° epiphyseal-shaft angle) degree was sent to all members of EPOS in 2009 in order to ascertain their views on the best management of SCFE. Specifically, respondents were asked about the role of reduction, methods of fixation, prophylactic fixation of the non-affected hip, postoperative management and their view on the anticipated need for secondary surgery. RESULTS: The response rate was 25% (72/287). The participating surgeons' average workload was 76% in paediatric orthopaedics, with mean 16 years of experience. Surgeons were most consistent in their advice for stable slips, where around 90% of the respondents did not recommend a reduction of the slip regardless of severity of slip. Seventy per cent of the respondents recommended the use of only one screw for fixation of a stable slip and for mild unstable slips. For severe unstable slips, 46% of surgeons recommended reduction only by positioning of the hip on the fracture table, 35% by manipulation and 11% advised open reduction. Responders were less consistent in their advice on the anticipated need for secondary osteotomies (in mild slips about 40% and about 60% in severe slips would advise an osteotomy) and on treatment of the contralateral hip (with 32% of surgeons recommending prophylactic fixation of the contralateral hip). CONCLUSION: Within members of EPOS, there is controversy on several aspects of the management of SCFE particularly on aspects of the treatment of unstable SCFE. SIGNIFICANCE: Members of EPOS predominantly use traditional means of treatment for patients with SCFE. In contrast, the more modern treatment concepts, such as open reduction via surgical dislocation, are rarely used.

Diagnosis and treatment of developmental dysplasia of the hip in the Netherlands: national questionnaire of paediatric orthopaedic surgeons on current practice in children less than 1 year old.

PURPOSE: There is no consensus in the literature regarding the diagnosis and treatment of developmental dysplasia of the hip (DDH). We designed a national questionnaire to assess the various opinions and current practice of paediatric orthopaedic surgeons in the Netherlands regarding the diagnosis and treatment of DDH in children less than 1 year old. METHODS: The questionnaire was sent to all members of the Dutch Paediatric Orthopaedic Society (DPOS). It discusses different methods and criteria used in the diagnosis of DDH, the use of different therapies and the use of different imaging techniques to evaluate the result of treatment. RESULTS: With 38 responders, the overall response rate to the survey was 67%. Most surgeons use clinical, radiographic and/or ultrasound examination for the diagnosis. The starting point of treatment is usually on the mild part of the DDH spectrum. The Pavlik harness is most popular in the treatment of dislocated hips, whereas in dysplastic hips, most surgeons use a rigid splint. The duration of treatment has a wide range and evaluation of the effect of treatment is predominantly done by radiography. CONCLUSIONS: The diagnosis and treatment of DDH in the Netherlands has as much diversity as the literature has recommendations about this subject. The lack of consensus on many aspects of DDH diagnosis and treatment should form the basis for a discussion among Dutch paediatric orthopaedic surgeons. Using the available evidence, it should be possible to formulate a more uniform protocol for the diagnosis and treatment of DDH.