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1.
Sci Rep ; 13(1): 13042, 2023 08 10.
Article in English | MEDLINE | ID: mdl-37563224

ABSTRACT

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare neurological disorder caused by the mutations in the DARS2 gene, which encodes the mitochondrial aspartyl-tRNA synthetase. The objective of this study was to understand the impact of DARS2 mutations on cell processes through evaluation of LBSL patient stem cell derived cerebral organoids and neurons. We generated human cerebral organoids (hCOs) from induced pluripotent stem cells (iPSCs) of seven LBSL patients and three healthy controls using an unguided protocol. Single cells from 70-day-old hCOs were subjected to SMART-seq2 sequencing and bioinformatic analysis to acquire high-resolution gene and transcript expression datasets. Global gene expression analysis demonstrated dysregulation of a number of genes involved in mRNA metabolism and splicing processes within LBSL hCOs. Importantly, there were distinct and divergent gene expression profiles based on the nature of the DARS2 mutation. At the transcript level, pervasive differential transcript usage and differential spliced exon events that are involved in protein translation and metabolism were identified in LBSL hCOs. Single-cell analysis of DARS2 (exon 3) showed that some LBSL cells exclusively express transcripts lacking exon 3, indicating that not all LBSL cells can benefit from the "leaky" nature common to splice site mutations. At the gene- and transcript-level, we uncovered that dysregulated RNA splicing, protein translation and metabolism may underlie at least some of the pathophysiological mechanisms in LBSL. To confirm hCO findings, iPSC-derived neurons (iNs) were generated by overexpressing Neurogenin 2 using lentiviral vector to study neuronal growth, splicing of DARS2 exon 3 and DARS2 protein expression. Live cell imaging revealed neuronal growth defects of LBSL iNs, which was consistent with the finding of downregulated expression of genes related to neuronal differentiation in LBSL hCOs. DARS2 protein was downregulated in iNs compared to iPSCs, caused by increased exclusion of exon 3. The scope and complexity of our data imply that DARS2 is potentially involved in transcription regulation beyond its canonical role of aminoacylation. Nevertheless, our work highlights transcript-level dysregulation as a critical, and relatively unexplored, mechanism linking genetic data with neurodegenerative disorders.


Subject(s)
Aspartate-tRNA Ligase , Leukoencephalopathies , Humans , Spinal Cord/metabolism , Aspartate-tRNA Ligase/genetics , Aspartate-tRNA Ligase/metabolism , RNA Splicing , Mutation , Leukoencephalopathies/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism
2.
Stem Cell Res ; 48: 102001, 2020 10.
Article in English | MEDLINE | ID: mdl-32971458

ABSTRACT

Autosomal dominant mutations in transcription factor 4 (TCF4) are associated with a rare syndromic form of Autism Spectrum Disorder (ASD) called Pitt-Hopkins Syndrome (PTHS). Here, we report the generation of a collection of induced pluripotent stem cells (iPSCs) from 5 patients diagnosed with PTHS and 5 familial controls. These patient-derived iPSCs contain a variety of mutations within the TCF4 gene, possess a normal karyotype and express all the appropriate pluripotent stem cell markers. These novel patient lines will be a useful resource for the research community to study PTHS and the function of TCF4.


Subject(s)
Autism Spectrum Disorder , Induced Pluripotent Stem Cells , Autism Spectrum Disorder/genetics , Facies , Humans , Hyperventilation/genetics , Intellectual Disability
3.
Adv Drug Deliv Rev ; 148: 60-67, 2019 08.
Article in English | MEDLINE | ID: mdl-31100303

ABSTRACT

The focus of regenerative therapies is to replace or enrich diseased or injured cells and tissue in an attempt to replenish the local environment and function, while slowing or halting further degeneration. Targeting neurological diseases specifically is difficult, due to the complex nature of the central nervous system, including the difficulty of bypassing the brain's natural defense systems. While cell-based regenerative therapies show promise in select tissues, preclinical and clinical studies have been largely unable to transfer these successes to the brain. Advancements in nanotechnologies have provided new methods of central nervous system access, drug and cell delivery, as well as new systems of cell maintenance and support that may bridge the gap between regenerative therapies and the brain. In this review, we discuss current regenerative therapies for neurological diseases, nanotechnology as nanocarriers, and the technical, manufacturing, and regulatory challenges that arise from inception to formulation of nanoparticle-regenerative therapies.


Subject(s)
Nanomedicine , Nanotechnology , Nervous System Diseases/drug therapy , Regenerative Medicine , Animals , Drug Delivery Systems , Humans
4.
Clin Genet ; 93(6): 1254-1256, 2018 06.
Article in English | MEDLINE | ID: mdl-29368331

ABSTRACT

Identification of a novel compound heterozygous of GNB5 in a patient with intellectual developmental disorder with cardiac arrhytmia (IDDCA), from non-consaguineous family. Three-dimensional modelling and in silico predictions suggest that GNB5 variants are causative of the phenotype, extending the number of IDDCA patients so far identified.


Subject(s)
Arrhythmias, Cardiac/complications , Arrhythmias, Cardiac/genetics , GTP-Binding Protein beta Subunits/genetics , Intellectual Disability/complications , Intellectual Disability/genetics , Mutation/genetics , Amino Acid Sequence , Child, Preschool , Evolution, Molecular , GTP-Binding Protein beta Subunits/chemistry , Heterozygote , Humans , Infant , Male , Pedigree
5.
Clin Genet ; 93(4): 752-761, 2018 04.
Article in English | MEDLINE | ID: mdl-28881385

ABSTRACT

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.


Subject(s)
Body Dysmorphic Disorders/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Methyltransferases/genetics , Adolescent , Adult , Body Dysmorphic Disorders/diagnosis , Body Dysmorphic Disorders/physiopathology , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 3/genetics , Developmental Disabilities/diagnosis , Developmental Disabilities/physiopathology , Female , Humans , Infant , Intellectual Disability/diagnosis , Intellectual Disability/physiopathology , Male , Middle Aged , Mutation/genetics , Penetrance , Phenotype , Exome Sequencing , Young Adult
6.
Acta Biomater ; 65: 292-304, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29127065

ABSTRACT

Additive manufacturing (AM) techniques enable fabrication of bone-mimicking meta-biomaterials with unprecedented combinations of topological, mechanical, and mass transport properties. The mechanical performance of AM meta-biomaterials is a direct function of their topological design. It is, however, not clear to what extent the material type is important in determining the fatigue behavior of such biomaterials. We therefore aimed to determine the isolated and modulated effects of topological design and material type on the fatigue response of metallic meta-biomaterials fabricated with selective laser melting. Towards that end, we designed and additively manufactured Co-Cr meta-biomaterials with three types of repeating unit cells and three to four porosities per type of repeating unit cell. The AM meta-biomaterials were then mechanically tested to obtain their normalized S-N curves. The obtained S-N curves of Co-Cr meta-biomaterials were compared to those of meta-biomaterials with same topological designs but made from other materials, i.e. Ti-6Al-4V, tantalum, and pure titanium, available from our previous studies. We found the material type to be far more important than the topological design in determining the normalized fatigue strength of our AM metallic meta-biomaterials. This is the opposite of what we have found for the quasi-static mechanical properties of the same meta-biomaterials. The effects of material type, manufacturing imperfections, and topological design were different in the high and low cycle fatigue regions. That is likely because the cyclic response of meta-biomaterials depends not only on the static and fatigue strengths of the bulk material but also on other factors that may include strut roughness, distribution of the micro-pores created inside the struts during the AM process, and plasticity. STATEMENT OF SIGNIFICANCE: Meta-biomaterials are a special class of metamaterials with unusual or unprecedented combinations of mechanical, physical (e.g. mass transport), and biological properties. Topologically complex and additively manufactured meta-biomaterials have been shown to improve bone regeneration and osseointegration. The mechanical properties of such biomaterials are directly related to their topological design and material type. However, previous studies of such biomaterials have largely neglected the effects of material type, instead focusing on topological design. We show here that neglecting the effects of material type is unjustified. We studied the isolated and combined effects of topological design and material type on the normalized S-N curves of metallic bone-mimicking biomaterials and found them to be more strongly dependent on the material type than topological design.


Subject(s)
Alloys/chemistry , Biocompatible Materials/chemistry , Materials Testing , Stress, Mechanical , Chromium/chemistry , Cobalt/chemistry , Manufactured Materials , Microscopy, Electron, Scanning , Porosity
7.
Clin Genet ; 91(5): 697-707, 2017 May.
Article in English | MEDLINE | ID: mdl-27598823

ABSTRACT

Identification of rare genetic variants in patients with intellectual disability (ID) has been greatly accelerated by advances in next generation sequencing technologies. However, due to small numbers of patients, the complete phenotypic spectrum associated with pathogenic variants in single genes is still emerging. Among these genes is ZBTB18 (ZNF238), which is deleted in patients with 1q43q44 microdeletions who typically present with ID, microcephaly, corpus callosum (CC) abnormalities, and seizures. Here we provide additional evidence for haploinsufficiency or dysfunction of the ZBTB18 gene as the cause of ID in five unrelated patients with variable syndromic features who underwent whole exome sequencing revealing separate de novo pathogenic or likely pathogenic variants in ZBTB18 (two missense alterations and three truncating alterations). The neuroimaging findings in our cohort (CC hypoplasia seen in 4/4 of our patients who underwent MRI) lend further support for ZBTB18 as a critical gene for CC abnormalities. A similar phenotype of microcephaly, CC agenesis, and cerebellar vermis hypoplasia has been reported in mice with central nervous system-specific knockout of Zbtb18. Our five patients, in addition to the previously described cases of de novo ZBTB18 variants, add to knowledge about the phenotypic spectrum associated with ZBTB18 haploinsufficiency/dysfunction.


Subject(s)
Intellectual Disability/genetics , Mutation , Repressor Proteins/genetics , Abnormalities, Multiple/genetics , Adult , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 1/genetics , Exome , Female , Haploinsufficiency , Humans , Magnetic Resonance Imaging , Male , Microcephaly/genetics , Mutation, Missense , Pregnancy
8.
Mol Psychiatry ; 21(5): 665-79, 2016 May.
Article in English | MEDLINE | ID: mdl-26390831

ABSTRACT

The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10(-6)), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10(-5)) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10(-5)) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.


Subject(s)
Genetic Predisposition to Disease , Panic Disorder/genetics , Polymorphism, Genetic , Anxiety/genetics , Humans
9.
Lupus ; 23(11): 1211-6, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24833666

ABSTRACT

AIM: The aim of this study was to determine systemic lupus erythematosus (SLE) survival in adult patients and its predictors in Iran. METHODS: The adult patients diagnosed with SLE and admitted to our referral general hospital from 1992 to 2011 were studied. Demographic, clinical and laboratory data at the time of diagnosis were obtained retrospectively and analyzed. Survival rates were calculated by the Kaplan-Meier method. Predictors of mortality were assessed by Cox regression analysis. RESULTS: In total, 417 were enrolled in the study; 23 were lost to follow-up. Mean (SD) age of SLE onset was 30 (9.7) years. During the study period 35 patients (8.9%) died. The most common causes of death were active SLE (43%), infections (28.6%) and circulatory diseases (20%). Overall survival rates after 5, 10, 15 and 20 years were 93%, 90%, 90% and 80%, respectively. Poor survival predictors in univariate analysis were pericarditis, seizure and hematuria. With multivariate Cox regression analysis, no pericarditis (p = 0.007, HR = 0.22, 95%CI: 0.075-0.657) and no seizure (p = 0.019, HR = 0.35, 95%CI: 0.149-0.846) at the time of SLE diagnosis were found as protective factors in patients' survival. CONCLUSION: Our study revealed that the survival rate of SLE is comparable with the acceptable worldwide trend. Presenting with pericarditis and seizure at the time of SLE diagnosis prominently decreased the survival rate. Prospective and multicenter studies are needed to better identify the behavior of SLE in Iran.


Subject(s)
Lupus Erythematosus, Systemic/physiopathology , Pericarditis/epidemiology , Seizures/epidemiology , Adult , Age of Onset , Aged , Female , Follow-Up Studies , Humans , Iran , Kaplan-Meier Estimate , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/mortality , Male , Middle Aged , Multivariate Analysis , Regression Analysis , Retrospective Studies , Survival Rate , Young Adult
10.
Iran J Ped Hematol Oncol ; 3(3): 86-90, 2013.
Article in English | MEDLINE | ID: mdl-24575277

ABSTRACT

BACKGROUND: Blood transfusion is associated with side effects caused by residual leukocytes in blood and blood components. Using leukodepleted blood components can decrease some of these adverse effects. Among the various methods to remove leukocytes in blood components, prestorage leukoreduction has been most efficient, but the evidence of clinical side effects awaits further studies. We evaluated changes of electrolytes in prestorage leukocyte-reduced red blood cells. MATERIALS AND METHODS: In this case-control study, one hundred twenty eight packed cells were studied: 64 unfiltered packed cells and 64 prestorage filtered packed cell. Two groups were matched as sex and age. Electrolytes such as Calcium, Sodium, and Potassium of two groups were measured, and compared during preparation. RESULTS: In this study, mean of Calcium in unfiltered and filtered group were 6.16±1.09 mg/dl and 5.57±2.21 mg/dl, respectively (P-value<0.055). Mean of Sodium in unfiltered group also was 155.91+/-9.51meq/l and in filtered group, 153.05+/-13.21meq/l (P-value<0.163), and mean of Potassium in unfiltered group was 5.01+/-1.72 meq/l and in filtered group, 7.42+/-2.45meq/l (P-value<0.001). CONCLUSION: Releasing of Potassium during preparation of prestorage leukoreduction can cause increased Potassium level and hemoglobin concentration changes in prestorage filtered packed cell.

11.
Neurology ; 64(10): 1739-45, 2005 May 24.
Article in English | MEDLINE | ID: mdl-15911801

ABSTRACT

BACKGROUND: In adrenomyeloneuropathy (AMN) conventional MRI detects only spinal cord atrophy in the late stages. OBJECTIVE: To apply a magnetization transfer-weighted (MTw) imaging to patients with AMN and AMN-like syndrome in order to visualize and quantitatively assess the pathology of white matter tracts in the cervical spinal cord. METHODS: MTw studies were conducted in nine men with AMN, eight symptomatic heterozygous women, and 10 age- and sex-matched controls and compared to the Expanded Disability Status Scale (EDSS) and quantitative tests of vibratory sense and postural sway. MTw data sets were obtained at the level of C1 to C3 using a three-dimensional gradient echo acquisition technique, these images were then standardized between subjects by using the in-slice CSF signal as a normalization reference, allowing a quantitative assessment of the MTw signal. RESULTS: In contrast to conventional MRI, MTw images showed signal hyperintensities in the lateral and dorsal columns of all patients. The MT signal quantified in the dorsal column showed significant differences between patients with AMN, X-linked adrenoleukodystrophy heterozygotes, and controls. MT hyperintensity in the dorsal column correlated with EDSS, vibratory sense, and postural sway. CONCLUSION: Magnetization transfer-weighted imaging is a sensitive modality for the visual and quantitative assessment of spinal cord pathology in adrenomyeloneuropathy, and is a potential tool for evaluation of new therapies.


Subject(s)
Adrenoleukodystrophy/diagnosis , Adrenoleukodystrophy/pathology , Magnetic Resonance Imaging/methods , Spinal Cord Diseases/diagnosis , Spinal Cord Diseases/pathology , Spinal Cord/pathology , Adrenoleukodystrophy/physiopathology , Adult , Atrophy/etiology , Atrophy/pathology , Atrophy/physiopathology , Cervical Vertebrae , Female , Humans , Male , Middle Aged , Nerve Fibers, Myelinated/pathology , Neural Pathways/pathology , Neural Pathways/physiopathology , Predictive Value of Tests , Somatosensory Disorders/etiology , Somatosensory Disorders/pathology , Somatosensory Disorders/physiopathology , Spinal Cord/physiopathology , Spinal Cord Diseases/physiopathology
12.
Neurology ; 64(2): 304-10, 2005 Jan 25.
Article in English | MEDLINE | ID: mdl-15668429

ABSTRACT

BACKGROUND: Adrenomyeloneuropathy (AMN) is the adult variant of X-linked adrenoleukodystrophy. The disease pathology is usually limited to spinal cord and peripheral nerves, and when this is the case, it is referred to as "pure" AMN. Histopathology shows cerebral involvement even in pure AMN; however, not much is known about the nature, extent, and clinical relevance of these findings. OBJECTIVE: To investigate brain involvement in AMN patients with normal MRI, employing multislice MR spectroscopic imaging. METHODS: Twelve men with pure AMN were compared with 19 age-matched healthy volunteers. Metabolite ratios (N-acetylaspartate [NAA]/choline [Cho], NAA/creatine [Cr], and Cho/Cr) were measured from seven brain regions. Global metabolite ratios were generated as an average of these seven regional ratios. The Expanded Disability Status Scale (EDSS) was used for neurologic evaluation. RESULTS: The patients with AMN showed reduced global NAA/Cho (AMN 1.40 +/- 0.16 vs controls 1.75 +/- 0.34; p = 0.003)) and global NAA/Cr (AMN 2.32 +/- 0.13 vs controls 2.62 +/- 0.43; p = 0.03). Regionally, NAA/Cho was lowered in the internal capsule (AMN 1.30 +/- 0.20 vs controls 1.69 +/- 0.37; p = 0.002) and in parieto-occipital white matter (AMN 1.45 +/- 0.19 vs controls 1.78 +/- 0.55; p = 0.04). NAA/Cr was lowered in parieto-occipital white matter (AMN 2.34 +/- 0.31 vs controls 2.83 +/- 0.71; p = 0.04). EDSS demonstrated an inverse association with global NAA/Cr (r = -0.65, p = 0.02) and NAA/Cr in centrum semiovale (r = -0.73, p = 0.006) and in parieto-occipital white matter (r = -0.64, p = 0.02). Cho/Cr was not significantly elevated. CONCLUSIONS: (1)H-MR spectroscopic imaging is able to detect biochemical abnormalities suggestive of axonal damage even in the brains of patients with pure adrenomyeloneuropathy. The axonopathy is most prominent in internal capsule and parieto-occipital white matter and may contribute to clinical disability.


Subject(s)
Adrenoleukodystrophy/metabolism , Aspartic Acid/analogs & derivatives , Axons/chemistry , Brain Chemistry , Choline/analysis , Creatine/analysis , Magnetic Resonance Spectroscopy , Adrenoleukodystrophy/pathology , Adult , Aspartic Acid/analysis , Axons/pathology , Biomarkers , Brain/pathology , Cross-Sectional Studies , Disability Evaluation , Female , Gait Disorders, Neurologic/etiology , Humans , Magnetic Resonance Imaging , Male , Middle Aged
13.
Neurology ; 62(7): 1206-9, 2004 Apr 13.
Article in English | MEDLINE | ID: mdl-15079028

ABSTRACT

We describe three cases of the rare syndrome of leukoencephalopathy, brain calcifications, and cysts. Conventional MRI, proton spectroscopy, and diffusion-weighted imaging yielded additional information on the disease. Imaging findings favor increased water content rather than a demyelinating process in the pathophysiology of this disease. Clinical features of Coats disease and consanguinity were also encountered.


Subject(s)
Aspartic Acid/analogs & derivatives , Brain Diseases/diagnosis , Brain/pathology , Calcinosis/diagnosis , Central Nervous System Cysts/diagnosis , Retinal Diseases/diagnosis , Adolescent , Aspartic Acid/metabolism , Brain/metabolism , Brain Diseases/complications , Brain Diseases/pathology , Calcinosis/complications , Central Nervous System Cysts/complications , Child , Choline/metabolism , Creatine/metabolism , Diffusion Magnetic Resonance Imaging , Disease Progression , Female , Humans , Lactic Acid/metabolism , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Rare Diseases/diagnosis , Retinal Diseases/complications , Syndrome , Tomography, X-Ray Computed
14.
Neurology ; 61(3): 369-74, 2003 Aug 12.
Article in English | MEDLINE | ID: mdl-12913200

ABSTRACT

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) has variants with widely different outcomes, hampering clinical counseling and evaluation of therapies. OBJECTIVE: To evaluate the degree to which MRI patterns can predict lesion progression. METHODS: Two hundred six boys and men with cerebral X-ALD (median age 12.2 years, mean age 18.5 years, age range 1.7 to 73.8 years) were studied. In 140 individuals, follow-up MRI were available. Data after bone marrow transplantation (BMT) were excluded. The patterns of MRI abnormalities were subdivided into five groups based on the anatomic location of the initial T2 signal hyperintensity (pattern 1: parieto-occipital white matter, pattern 2: frontal white matter, pattern 3: corticospinal tract, pattern 4: cerebellar white matter, pattern 5: concomitant parieto-occipital and frontal white matter). The X-ALD MRI Severity Scale, a 34-point scale previously described, was used in the analysis. RESULTS: Pattern 1 patients had rapid progression if contrast enhancement was present and if the MRI abnormality manifested at an early age. The latter was also true for pattern 2 patients. Based on these variables, predictive formulas were constructed for these two patterns using multiple regressions. MRI progression was much slower in pattern 3 and 4 patients, whereas in the few pattern 5 patients, it was more rapid than in any other of the patterns. Patterns 1 and 5 occurred mainly in childhood, patterns 2 and 4 in adolescence, and pattern 3 in adults. CONCLUSIONS: MRI progression in X-ALD depends on patient age, initial MRI Severity Scale score, and anatomic location of the lesion. When used in combination, these data aid the prediction of disease course and the selection of patients for BMT.


Subject(s)
Adrenoleukodystrophy/diagnosis , Adolescent , Adrenoleukodystrophy/drug therapy , Adult , Age Factors , Aged , Child , Child, Preschool , Disease Progression , Drug Combinations , Erucic Acids/therapeutic use , Follow-Up Studies , Humans , Image Processing, Computer-Assisted , Infant , Linear Models , Magnetic Resonance Imaging , Male , Middle Aged , Predictive Value of Tests , Prognosis , Severity of Illness Index , Triolein/therapeutic use
15.
Neurology ; 60(8): 1301-7, 2003 Apr 22.
Article in English | MEDLINE | ID: mdl-12707433

ABSTRACT

OBJECTIVE: To utilize neuroimaging procedures to assess the extent of cerebral involvement in female subjects heterozygous for X-linked adrenoleukodystrophy (X-ALD). METHODS: Brain MRI studies were performed in 76 female subjects heterozygous for X-ALD (mean age 43 years, range 8 to 75 years). Sixty-five had clinical evidence of spinal cord involvement resembling that in males with adrenomyeloneuropathy (AMN), two had clinical evidence of cerebral involvement, and nine showed no neurologic abnormality. Readers blinded to clinical findings further analyzed abnormal MRI studies. In eight women whose MRI results were normal, four-slice long echo time MRS imaging (MRSI) studies were performed and compared to those of eight age-matched controls. RESULTS: MRI results were normal in 65 subjects and abnormal in 11. In eight of the latter group, the MRI changes were judged to be due to causes other than X-ALD. Lesions were attributed to X-ALD in the remaining three. Two of these patients had lesions that resembled those in male patients with cerebral X-ALD. In one patient with a mild AMN-like syndrome, brain MRI abnormalities were confined to the corticospinal tract. When compared to those of controls, MRSI studies in eight female patients with normal results on brain MRI showed a significant reduction of N-acetylaspartate/creatine and N-acetylaspartate/choline ratios in the internal capsule and corticospinal projection fibers. The N-acetylaspartate/choline ratio was significantly reduced in the parieto-occipital white matter and the choline/creatine ratio was significantly increased in the frontal white matter. CONCLUSION: Brain involvement demonstrable by MRI is rare in female subjects heterozygous for X-ALD, including those who have clinical evidence of spinal cord involvement. Nevertheless, N-acetylaspartate levels are reduced in the corticospinal projection fibers in female subjects with normal results on MRI, suggesting axonal dysfunction.


Subject(s)
Adrenoleukodystrophy/pathology , Aspartic Acid/analogs & derivatives , Brain/pathology , Magnetic Resonance Imaging , Adolescent , Adult , Aged , Aspartic Acid/analysis , Axons/pathology , Cerebral Cortex/chemistry , Cerebral Cortex/pathology , Child , Choline/analysis , Creatinine/analysis , Dosage Compensation, Genetic , Female , Heterozygote , Humans , Magnetic Resonance Imaging/methods , Magnetic Resonance Spectroscopy , Middle Aged , Retrospective Studies , Spinal Cord/pathology
16.
Article in English | MEDLINE | ID: mdl-14720183

ABSTRACT

The effects of fig tree latex in treating teat papillomatosis in cow in comparison with salicylic acid were evaluated. For this purpose, 12 cows of 1-3 years of age (average 2.25) affected by teat papillomatosis were divided into three groups. In group A, four cows were treated by fig tree (Ficus carica) latex; in group B, four cows were treated with 10% salicylic acid solution and in group C, four cows were kept as control animals receiving no treatment. Animals in each treatment group received their treatment once every 5 days. In groups A and B, de-epithelialization and shrinking of the warts began from the fifth day of treatment and all the warts disappeared within 30 days. However, in the control group no changes in the number of warts were observed until day 15 but thereafter a number of warts disappeared spontaneously in some of the animals. Both salicylic acid and fig tree latex were evaluated as having similar therapeutic effects in treating teat papillomatosis in cow.


Subject(s)
Cattle Diseases/drug therapy , Ficus , Latex/administration & dosage , Papillomavirus Infections/veterinary , Phytotherapy , Tumor Virus Infections/veterinary , Animals , Cattle , Cattle Diseases/pathology , Female , Mammary Glands, Animal , Papillomaviridae , Papillomavirus Infections/drug therapy , Salicylic Acid/administration & dosage , Treatment Outcome , Tumor Virus Infections/drug therapy
17.
Wien Klin Wochenschr ; 113(7-8): 235-44, 2001 Apr 17.
Article in German | MEDLINE | ID: mdl-11383383

ABSTRACT

UNLABELLED: Little is known about sleep disorders in children and adolescents that might affect physical and emotional well-being. Depending on age and size of the cohort group, and differences in questionnaires, prevalence varies between 1-43% in international studies. We examined the prevalence of symptoms characteristic of sleep disorders in school aged children with a questionnaire which allows indication of symptoms by the children themselves. METHODS: An anonymous questionnaire, based on the German Dresden questionnaire, with 22 questions concerning the main symptoms of obstructive sleep apnea syndrome (OSAS), general symptoms of para- and insomnia as well as sociodemographic data, was developed. 332 pupils (age: 11-15 y, mean: 12.75 y; median: 12 y; 56% female, 44% male) in 2 high schools in Vienna were investigated. RESULTS: 28% (n = 93/332) of the examined group reported snoring (the main symptom of OSAS) and/or insomnia (night waking almost every night) or parasomnia (nightmares, night terrors or sleepwalking almost every night). 15% (n = 14/93) of this subgroup reported snoring and para- or insomnia coincidentally. Girls were affected more frequently than boys by nocturnal awakening (79% vs. 56%, p < 0.001) and nightmares (64% vs. 52%, p < 0.01). The snoring group (21% (71/332) of all examined children) was affected more frequently by mouth dryness (16% vs. 4%, p < 0.001), pallor (7% vs. 3%, p < 0.01), night sweats (6% vs. 1%, p < 0.05) and from the following sleep disorders: nightmares (10% vs. 2%, p < 0.01), night terrors (4% vs. 1.5%, p < 0.001), sleepwalking (1.4% vs. 1%, p < 0.05) and nocturnal awakening (16% vs. 5%, p < 0.01). DISCUSSION: Almost every fifth child reports about at least one main symptom characteristic of OSAS. The statistically significant relation between symptoms of OSAS and non-organic sleep disorders shows the necessity of interdisciplinary focusing on sleep disorders. Further epidemiological studies need to be carried out in order to clarify the role of sleep anamnesis in the diagnosis and management of sleep disorders during childhood.


Subject(s)
Parasomnias/epidemiology , Sleep Apnea, Obstructive/epidemiology , Sleep Initiation and Maintenance Disorders/epidemiology , Adolescent , Austria/epidemiology , Child , Female , Health Surveys , Humans , Male , Prevalence , Sleep Wake Disorders , Snoring/epidemiology , Surveys and Questionnaires
18.
Biochemistry ; 37(11): 3588-93, 1998 Mar 17.
Article in English | MEDLINE | ID: mdl-9530285

ABSTRACT

De novo designed signal peptidase I cleavage sites were tested for their biological activity in vivo in an Escherichia coli expression and secretion system. The artificial cleavage site sequences were generated by two different computer-based design techniques, a simple statistical method, and a neural network approach. In previous experiments, a neural network was used for feature extraction from a set of known signal peptidase I cleavage sites and served as the fitness function in an evolutionary design cycle leading to idealized cleavage site sequences. The cleavage sites proposed by the two algorithms were active in vivo as predicted. There seems to be an interdependence between several cleavage site features for the constitution of sequences recognized by signal peptidase. It is concluded that neural networks are useful tools for sequence-oriented peptide design.


Subject(s)
Bacterial Proteins/chemical synthesis , Membrane Proteins , Neural Networks, Computer , Protein Engineering/methods , Recombinant Fusion Proteins/metabolism , Serine Endopeptidases/chemical synthesis , Amino Acid Sequence , Bacterial Outer Membrane Proteins/genetics , Bacterial Outer Membrane Proteins/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Base Sequence , Genetic Vectors/chemical synthesis , Genetic Vectors/metabolism , Hydrolysis , Molecular Sequence Data , Protein Sorting Signals/genetics , Protein Sorting Signals/metabolism , Recombinant Fusion Proteins/chemical synthesis , Sequence Analysis , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism
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