Evaluation of Goniometry and Electrogoniometry of Carpus and Elbow Joints in the Barred Owl (Strix varia).

The motion of wing joints is a critical factor for successful flight in avian patients, but little information is available about goniometry in birds. Elbow and carpus joints in flexed and extended positions from 10 orthopedically normal wings of 6 adult wild barred owls (Strix varia) were evaluated with the animals under general anesthesia using a modified universal plastic goniometer and an electrogoniometer. These measurements were compared to those obtained using radiographic assessment. Intra- and interobserver reliability was calculated. Measurements in live animals were compared to those obtained from frozen-thawed carcasses. Results showed that the modified universal plastic goniometer can be used to obtain accurate results for elbow flexion and extension and for carpal flexion with good to excellent reliability compared to measurements collected from radiographic assessment. Measurements obtained using an electrogoniometer were less accurate and less reliable than those obtained with a plastic goniometer, possibly because of the size and configuration of the model used. Comparison of measurements from live animals and carcasses revealed no significant differences between mean measurements and suggested that further evaluation of carcasses as a model for study of goniometry measurements in avian wing joints should be considered.

Evidence of a permanent electric polarisation in highly strained Cr2O3 clusters measured by a second harmonic generation technique.

We investigate the second harmonic generation (SHG) signal in strained Cr2O3 clusters. We show that the SHG signal generated by nanometric Cr2O3 clusters embedded in MgO varies under an applied electric field, at room temperature. The variation of the intensity follows a Langevin law as a function of the electric field, which is consistent with a super-paraelectric clusters assembly. This reveals the presence of a weak spontaneous electric dipole in Cr2O3 when in the shape of highly strained epitaxial clusters, whereas this material does not posses any permanent electric dipole in the bulk phase. These results indicate that the multiferroic state recently observed at low temperature in those clusters, which was associated to a giant magneto-electric effect, might still exist at room temperature: this opens the way to new applications based on chromium oxide strained nanoparticles.

Optical Writing of Magnetic Properties by Remanent Photostriction.

We present an optically induced remanent photostriction in BiFeO_{3}, resulting from the photovoltaic effect, which is used to modify the ferromagnetism of Ni film in a hybrid BiFeO_{3}/Ni structure. The 75% change in coercivity in the Ni film is achieved via optical and nonvolatile control. This photoferromagnetic effect can be reversed by static or ac electric depolarization of BiFeO_{3}. Hence, the strain dependent changes in magnetic properties are written optically, and erased electrically. Light-mediated straintronics is therefore a possible approach for low-power multistate control of magnetic elements relevant for memory and spintronic applications.

Localized states in advanced dielectrics from the vantage of spin- and symmetry-polarized tunnelling across MgO.

Research on advanced materials such as multiferroic perovskites underscores promising applications, yet studies on these materials rarely address the impact of defects on the nominally expected materials property. Here, we revisit the comparatively simple oxide MgO as the model material system for spin-polarized solid-state tunnelling studies. We present a defect-mediated tunnelling potential landscape of localized states owing to explicitly identified defect species, against which we examine the bias and temperature dependence of magnetotransport. By mixing symmetry-resolved transport channels, a localized state may alter the effective barrier height for symmetry-resolved charge carriers, such that tunnelling magnetoresistance decreases most with increasing temperature when that state is addressed electrically. Thermal excitation promotes an occupancy switchover from the ground to the excited state of a defect, which impacts these magnetotransport characteristics. We thus resolve contradictions between experiment and theory in this otherwise canonical spintronics system, and propose a new perspective on defects in dielectrics.

Size-induced enhanced magnetoelectric effect and multiferroicity in chromium oxide nanoclusters.

The control of the magnetization of a material with an electric field would make the design and the integration of novel electronic devices possible. This explains the renewed interest in multiferroic materials. Progress in this field is currently hampered by the scarcity of the materials available and the smallness of the magnetoelectric effects. Here we present a proof-of-principle experiment showing that engineering large strains through nanoscale size reduction is an efficient route for increasing magnetoelectric coefficients by orders of magnitude. The archetype magnetoelectric material, Cr2O3, in the form of epitaxial clusters, exhibits an unprecedented 600% change in magnetization magnitude under 1 V. Furthermore, a multiferroic phase, with both magnetic and electric spontaneous polarizations, is found in the clusters, while absent in the bulk.

A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands.

NF1 mutations are the underlying cause of neurofibromatosis type 1 (NF1), a neuro-cardio-facio-cutaneous syndrome (NCFC). Because of the clinical overlap between NCFCs, genetic analysis of NF1 is necessary to confirm a clinical diagnosis NF1. This report describes the clinical and genetic findings of 18 years of NF1 molecular diagnostics in the Netherlands. A pathogenic mutation was found in 59.3% (1178/1985) of the index patients, mostly de novo (73.8%). The majority of the index patients (64.3%) fulfilled the National Institute of Health NF1 criteria, a pathogenic mutation was found in 80.9% of these patients. Seventy-four percent of the index patients with an NF1 pathogenic mutation and not fulfilling the NF1 criteria is <12 years, in agreement with the fact that some NF1 symptoms appear after puberty. Genotype-phenotype correlations were studied for 527 index patients. NF1 patients with a type 1 microdeletion have a sixfold higher risk of special education vs NF1 patients with an intragenic mutation. No evidently milder NF1 phenotype for patients with a missense mutation was observed. Forty-six prenatal analyses were performed in 28 (2.4%) families, of which 29 (63%) showed heterozygosity for the familial pathogenic mutation. This indicates that there is a need for prenatal NF1 testing.

Considering Fabry, but Diagnosing MPS I: Difficulties in the Diagnostic Process.

INTRODUCTION: Recent studies have indicated that a proportion of patients with renal failure, left ventricular hypertrophy, or cryptogenic stroke have sequence variants in their aGal A gene (Fabry disease), which has resulted in an increase in diagnostic activities for this disorder. The diagnostic process for lysosomal storage disorders may result in findings of unknown clinical significance. Here we report such an unexpected outcome. CASE: A 32-year-old male presented at the emergency department because of a transient ischemic attack. Extensive investigations revealed no cause and an initial diagnosis of cryptogenic stroke was made. Subsequently, aGal A activity was measured in a bloodspot and was shown to be normal, but the activity of alpha-L-iduronidase (IDUA), used as reference enzyme, was unexpectedly low: 0.5 umol/L (ref = 1.7-14.3). A diagnosis of IDUA deficiency, mucopolysaccharidosis type 1S or Scheie disease was considered. IDUA gene analysis revealed two homozygous sequence alterations: a silent sequence change (979C > T) in exon 7 (N297N) and an unknown missense mutation 875A > T (R263W). Physical examination was completely normal, without clinical signs of mucopolysaccharidosis type I (MPS I). Leukocyte IDUA activity was also low: 2.1 nmol/mg prot/h (ref = 14-40 nmol prot/h), but higher than the patient range of <0.1 nmol/mg prot/h. Urinary glycosaminoglycan levels were normal both quantitatively and qualitatively. It was concluded that there was low IDUA activity without clinical symptoms and the diagnosis of mucopolysaccharidosis I was discarded. CONCLUSION: The diagnostic process for lysosomal storage disorders may result in biochemical abnormalities of unknown clinical significance. Early evaluation by a specialist in inborn errors of metabolism may help to avoid anxiety in patients and unnecessary additional analyses.

Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a combination of neurological symptoms and hamartomatous growths, and caused by mutations in the TSC1 and TSC2 genes. Overall, TSC2 mutations are associated with a more severe disease phenotype. We identified the c.3598C>T (R1200W) change in the TSC2 gene in seven different families. The clinical phenotypes in the families were mild, characterized by mild skin lesions, remitting epilepsy and a lack of severe mental retardation or major organ involvement. Functional analysis of the TSC2 R1200W variant, and four other TSC2 missense variants associated with a mild TSC phenotype, confirmed that the changes disrupted the TSC1-TSC2 function. Interestingly however, in each case, the TSC1-TSC2 interaction was not affected by the amino acid substitution.

N-acetylaspartylglutamate in CNS hypomyelination.

CSF N-acetylaspartylglutamate (NAAG) has been found to be elevated in some hypomyelinating disorders. This study addressed the question whether it could be used as a marker for hypomyelination and as a means to distinguish between hypomyelinating disorders biochemically. We have measured CSF NAAG in a cohort of 28 patients with hypomyelination with known and unknown aetiology. NAAG was found to be elevated in 7 patients, but was normal in the majority, including patients with defined hypomyelinating disorders. CSF NAAG is not a universal marker of hypomyelination, and the mechanism of its elevation remains poorly understood.

Movement disorder and neuronal migration disorder due to ARFGEF2 mutation.

We report a child with a severe choreadystonic movement disorder, bilateral periventricular nodular heterotopia (BPNH), and secondary microcephaly based on compound heterozygosity for two new ARFGEF2 mutations (c.2031_2038dup and c.3798_3802del), changing the limited knowledge about the phenotype. The brain MRI shows bilateral hyperintensity of the putamen, BPNH, and generalized atrophy. Loss of ARFGEF2 function affects vesicle trafficking, proliferation/apoptosis, and neurotransmitter receptor function. This can explain BPNH and microcephaly. We hypothesize that the movement disorder and the preferential damage to the basal ganglia, specifically to the putamen, may be caused by an increased sensitivity to degeneration, a dynamic dysfunction due to neurotransmitter receptor mislocalization or a combination of both.

Filamin A mutation, a common cause for periventricular heterotopia, aneurysms and cardiac defects.

Filamin A is an important gene involved in the development of the brain, heart, connective tissue and blood vessels. A case is presented illustrating the challenge in recognising patients with filamin A mutations. The patient, a 71-year-old woman, was known to have heart valve disease and bilateral periventricular nodular heterotopia when she died of a subarachnoid haemorrhage. Autopsy showed typical cerebral bilateral periventricular heterotopia and vascular abnormalities. Postmortally, the diagnosis of a filamin A mutation was confirmed. Recognition during life may prevent cardiovascular problems and provide possibilities for genetic counselling.

Novel Oscillation Period of the Interlayer Exchange Coupling in Fe/Cr/Fe Due to MgO Capping.

A novel period of the interlayer exchange coupling as a function of Cr thickness is observed in epitaxial Fe/Cr/Fe (001) sandwiches capped with MgO. This additional period, equal to 3 chromium atomic layers, vanishes when the capping is Cr. A strong oscillation of the magnetic coupling is also observed as a function of the thickness of the Fe layer next to the MgO capping layer. This effect is attributed to the formation of quantum well states in this Fe layer. It is believed that this confinement modifies the reflection coefficient at the Cr/Fe interface for electrons of a particular symmetry and leads to the new coupling period which is linked to the Fermi surface topology of chromium.

A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting.

BACKGROUND AND AIMS: In Lynch syndrome, the clinical phenotype in MSH6 mutation families differs from that in MLH1 and MSH2 families. Therefore, MSH6 mutation families are less likely to fulfil diagnostic criteria such as the Amsterdam II criteria (AC II) and the revised Bethesda guidelines (rBG), and will be underdiagnosed. The aim of the present study was to evaluate the contribution of MSH6 gene mutations in families that were analysed for Lynch syndrome in a diagnostic setting. METHODS: Families that had molecular analysis for Lynch syndrome were included in this study. Complete molecular screening of the MLH1, MSH2 and MSH6 genes was performed in all families. Microsatellite instability (MSI) and immunohistochemical (IHC) analysis was performed in almost all families. Clinical data were collected from medical records and family pedigrees. RESULTS: A total of 108 families were included. MSI and IHC analysis was performed in 97 families, and in 40 an MSI-high phenotype with absent protein expression was found. Germline mutation analysis detected mutations in 23 families (7 MLH1, 4 MSH2 and 12 MSH6). The majority of MSH6 families were AC II negative, but fulfilled the rBG. CONCLUSIONS: There is a high incidence of MSH6 mutations in families tested for Lynch syndrome in a diagnostic setting. Many of these families remain underdiagnosed using the AC II. The rBG are more useful to select these families for further analysis. However, to optimise the detection of MSH6 families, MSI and IHC analysis should also be performed in families with clustering of late-onset endometrial carcinoma.

Cognitive impairment in tuberous sclerosis complex is a multifactorial condition.

OBJECTIVE: In patients with tuberous sclerosis complex (TSC), associations between tuber number, infantile spasms, and cognitive impairment have been proposed. We hypothesized that the tuber/brain proportion (TBP), the proportion of the total brain volume occupied by tubers, would be a better determinant of seizures and cognitive function than the number of tubers. We investigated tuber load, seizures, and cognitive function and their relationships. METHODS: Tuber number and TBP were characterized on three-dimensional fluid-attenuated inversion recovery MRI with an automated tuber segmentation program. Seizure histories and EEG recordings were obtained. Intelligence equivalents were determined and an individual cognition index (a marker of cognition that incorporated multiple cognitive domains) was calculated. RESULTS: In our sample of 61 patients with TSC, TBP was inversely related to the age at seizure onset and to the intelligence equivalent and tended to be inversely related to the cognition index. Further, a younger age at seizure onset or a history of infantile spasms was related to lower intelligence and lower cognition index. In a multivariable analysis, only age at seizure onset and cognition index were related. CONCLUSIONS: Our systematic analysis confirms proposed relationships between tuber load, epilepsy and cognitive function in tuberous sclerosis complex (TSC), but also indicates that tuber/brain proportion is a better predictor of cognitive function than tuber number and that age at seizure onset is the only independent determinant of cognitive function. Seizure control should be the principal neurointervention in patients with TSC.

Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations.

OBJECTIVE: The purpose of this study was to systematically analyze the associations between different TSC1 and TSC2 mutations and the neurologic and cognitive phenotype in patients with tuberous sclerosis complex (TSC). METHODS: Mutation analysis was performed in 58 patients with TSC. Epilepsy variables, including EEG, were classified. A cognition index was determined based on a comprehensive neuropsychological assessment. On three-dimensional fluid-attenuated inversion recovery MR images, an automated tuber segmentation program detected and calculated the number of tubers and the proportion of total brain volume occupied by tubers (tuber/brain proportion [TBP]). RESULTS: As a group, patients with a TSC2 mutation had earlier age at seizure onset, lower cognition index, more tubers, and a greater TBP than those with a TSC1 mutation, but the ranges overlapped considerably. Familial cases were older at seizure onset and had a higher cognition index than nonfamilial cases. Patients with a mutation deleting or directly inactivating the tuberin GTPase activating protein (GAP) domain had more tubers and a greater TBP than those with an intact GAP domain. Patients with a truncating TSC1 or TSC2 mutation differed from those with nontruncating mutations in seizure types only. CONCLUSIONS: Although patients with a TSC1 mutation are more likely to have a less severe neurologic and cognitive phenotype than those with a TSC2 mutation, the considerable overlap between both aspects of the phenotype implies that prediction of the neurologic and cognitive phenotypes in individuals with tuberous sclerosis complex should not be based on their particular TSC1 or TSC2 mutation.

Evidence of a symmetry-dependent metallic barrier in fully epitaxial MgO based magnetic tunnel junctions.

We report on the experimental observation of tunneling across an ultrathin metallic Cr spacer layer that is inserted at the interface of a Fe/MgO/Fe(001) junction. We show how this remarkable behavior in a solid-state device reflects a quenching in the transmission of particular electronic states, as expected from the symmetry-filtering properties of the MgO barrier and the band structure of the bcc Cr(001) spacer in the epitaxial junction stack. This ultrathin Cr metallic barrier can promote quantum well states in an adjacent Fe layer.

Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification.

The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific [corrected] VHL manifestation in a patient with familial VHL disease, or, in a [corrected] sporadic patient, at least two or more hemangioblastomas or a single hemangioblastoma in combination with a typical visceral lesion. To evaluate this definition, we studied the frequency of germline VHL mutation in three patients groups: (i) multi-organ involvement (classic VHL), (ii) limited VHL manifestations meeting criteria (non-classic VHL) and (iii) patients with VHL-associated tumors not meeting current diagnostic VHL criteria. In addition, we validated multiplex ligation-dependent probe amplification (MLPA) as a rapid and reliable quantitative method for the identification of germline VHL deletions. The frequency of germline VHL mutations was very high in classic VHL cases with multi-organ involvement (95%), lower in non-classic cases that meet current diagnostic criteria but have limited VHL manifestations or single-organ involvement (24%) and low (3.3%), but tangible in cases not meeting current diagnostic VHL criteria. The detection of germline VHL mutations in patients or families with limited VHL manifestations, or single-organ involvement is relevant for follow-up of probands and early identification of at-risk relatives.

Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype.

BACKGROUND: Pompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is an autosomal recessive lysosomal storage disorder characterized by acid alpha-glucosidase deficiency due to mutations in the GAA gene. Progressive skeletal muscle weakness affects motor and respiratory functions and is typical for all forms of Pompe disease. Cardiac hypertrophy is an additional fatal symptom in the classic infantile subtype. c.-32-13T-->G is the most common mutation in adults. OBJECTIVE: To delineate the disease variation among patients with this mutation and to define the c.-32-13T-->G haplotypes in search for genotype-phenotype correlations. METHODS: We studied 98 compound heterozygotes with a fully deleterious mutation (11 novel mutations are described) and the common c.-32-13T-->G mutation. RESULTS: All patients were Caucasian. None had the classic infantile form of Pompe disease. The clinical course varied far more than anticipated (age at diagnosis <1 to 78 years; age at onset: <1 to 52 years). The acid alpha-glucosidase activities in a subset of patients ranged from 4 to 19.9 nmol/mg/h. Twelve different c.-32-13T-->G haplotypes were identified based on 17 single-nucleotide polymorphisms located in the GAA gene. In 76% of the cases, c.-32-13T-->G was encountered in the second most common GAA core haplotype (DHRGEVVT). In only one case was c.-32-13T-->G encountered in the major GAA core haplotype (DRHGEIVT). CONCLUSION: Patients with the same c.-32-13T-->G haplotype (c.q. GAA genotype) may manifest first symptoms at different ages, indicating that secondary factors may substantially influence the clinical course of patients with this mutation.

[Tuberous sclerosis complex type 1 (TSC1): diagnostic significance of the cutaneous mini-lesions in a familial presentation]. / Complejo esclerosis tuberosa tipo 1 (CET1): importancia diagnóstica de las minilesiones cutáneas en los casos de presentación familiar.

We present a family with tuberous sclerosis complex type 1 (TSC1). The family is formed by six patients. Two sibs, female and male, both patients having minor signs of the disorder. The woman have two daughters, one of them with severe clinical and radiological features of TSC1, and the other who only has a small cutaneous acromic spot. The man has two sons, one with severe features of TSC1, and the other with cutaneous mini-lesions. DNA study of the two cousins, woman and man, with cutaneous mini-lesions, showed a mutation in the chromosome 9 (1749 del GA) (TSC1 ex 15) in both patients. No pathogenic mutation in the TSC2 gene was detected in the two cousins.