ABSTRACT
BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.
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BACKGROUND: Diet has been suggested to play a role in determining the age at natural menopause; however, the evidence is inconsistent. OBJECTIVE: We systematically reviewed and evaluated published research about associations between diet and onset of natural menopause (ONM). METHODS: We searched 6 databases (Medline, Embase, Cochrane, PubMed, Web of Science and Google Scholar) through January 21,2021 to identify prospective studies assessing the association between diet and ONM. Two independent reviewers extracted data using a predesigned data-collection form. Pooled hazard risks (HRs) were calculated using random effect models. RESULTS: Of the 6,137 eligible references we reviewed, we included 15 articles in our final analysis. Those 15 articles included 91,554 women out of 298,413 who experienced natural menopause during follow-up. Overall, there were 89 food groups investigated, 38 macronutrients and micronutrients, and 6 dietary patterns. Among the food groups, higher intake of green and yellow vegetables was associated with earlier age of ONM, while high intakes of some dairy products, such as low-fat, skimmed milk, and low intake of alcohol were associated with a later onset. We observed no consistent association between macronutrient and micronutrient intake and ONM. Our results suggests that a vegetarian diet could be associated with early ONM; we did not observe any other consistent effect from other dietary patterns. Limitations included the number of studies, lack of replication studies and the research being of an observational nature; most studies (11/15) were at medium risk of bias. CONCLUSION: Although some food items were associated with ONM, the overall evidence about associations between diet and ONM remains controversial. Prospero id: CRD42021232087.
Subject(s)
Dairy Products , Menopause , Diet/adverse effects , Female , Humans , Prospective StudiesABSTRACT
Cardiovascular disease (CVD) and type 2 diabetes (T2D) remain the top disease and mortality burdens worldwide. Oats have been shown to benefit cardiovascular health and improve insulin resistance. However, the evidence linking oat consumption with CVD, T2D and all-cause mortality remains inconclusive. We conducted a comprehensive systematic review and meta-analysis of prospective cohort studies to evaluate the associations between oat consumption and risks of T2D, CVD and all-cause mortality in the general population. Five electronic databases were searched until September, 2020. Study specific relative risks (RR) were meta-analyzed using random effect models. Of 4686 relevant references, we included 9 articles, based on 8 unique studies and 471,157 participants. Comparing oat consumers versus non-consumers, RRs were 0.86 (95% CI 0.72-1.03) for T2D incidence and 0.73 (95% CI 0.5-1.07) for combined CVD incidence. Comparing participants with highest versus lowest oat intake, RRs were 0.78 (95% CI 0.74-0.82) for T2D incidence, 0.81 (95% CI 0.61-1.08) for CHD incidence and 0.79 (95% CI 0.59-1.07) for stroke. For all-cause mortality one study based on three cohorts found RR for men and women were 0.76 (95% CI 0.69-0.85) and 0.78 (95% CI 0.70-0.87), respectively. Most studies (n = 6) were of fair to good quality. This meta-analysis suggests that consumption of oat could reduce the risk for T2D and all-cause mortality, while no significant association was found for CVD. Future studies should address a lack of standardized methods in assessing overall oat intake and type of oat products, and investigate a dose-dependent response of oat products on cardiometabolic outcomes in order to introduce oat as preventive and treatment options for the public.
Subject(s)
Avena , Cardiovascular Diseases/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Mortality , Whole Grains , Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/prevention & control , Female , Humans , Incidence , Male , Risk , Stroke/epidemiology , Stroke/prevention & controlABSTRACT
Objectives The gut microbiome harbors substantially more genetic material than our body cells and has an impact on a huge variety of physiological mechanisms including the production of neurotransmitters and the interaction with brain functions through the gut-brain-axis. Products of microbiota can affect methylation according to preclinical studies. The current investigation aimed at analyzing the correlation between gut microbiome diversity and the methylation of the clock gene ARNTL in individuals with Bipolar Disorder (BD). Methods Genomic DNA was isolated from fasting blood of study participants with BD (n = 32). The methylation analysis of the ARNTL CG site cg05733463 was performed by bisulfite treatment of genomic DNA with the Epitect kit, PCR and pyrosequencing. Additionally, DNA was extracted from stool samples and subjected to 16S rRNA sequencing. QIIME was used to analyze microbiome data. Results Methylation status of the ARNTL CpG position cg05733463 correlated significantly with bacterial diversity (Simpson index: r= -0.389, p = 0.0238) and evenness (Simpson evenness index: r= -0.358, p = 0.044). Furthermore, bacterial diversity differed significantly between euthymia and depression (F(1,30) = 4.695, p = 0.039). Discussion The results of our pilot study show that bacterial diversity differs between euthymia and depression. Interestingly, gut microbiome diversity and evenness correlate negatively with methylation of ARNTL, which is known to regulate monoamine oxidase A transcription. We propose that alterations in overall diversity of the gut microbiome represent an internal environmental factor that has an epigenetic impact on the clock gene ARNTL which is thought to be involved in BD pathogenesis.
Subject(s)
ARNTL Transcription Factors/genetics , Bipolar Disorder/genetics , Bipolar Disorder/microbiology , ARNTL Transcription Factors/metabolism , Adult , Bipolar Disorder/physiopathology , Circadian Rhythm/genetics , Circadian Rhythm/physiology , DNA Methylation , Depression/genetics , Depressive Disorder/genetics , Epigenesis, Genetic/genetics , Epigenomics/methods , Female , Gastrointestinal Microbiome/genetics , Gastrointestinal Microbiome/physiology , Humans , Male , Microbiota/genetics , Middle Aged , Pilot Projects , RNA, Ribosomal, 16S/geneticsABSTRACT
We investigated HLA-A, HLA-B, and HLA-DRB1 gene frequencies in 1368 unrelated Austrian umbilical cord blood samples. HLA-C gene frequencies were investigated in a subgroup of 503 samples. HLA typing was performed via sequenced-based typing (SBT). The aim of this study was to examine the HLA diversity in a large Austrian population sample. In addition we present results of a subsample of 100 samples at a subtype level. This study is the first systematic investigation of donated umbilical cord blood samples in the Austrian population.
Subject(s)
Alleles , Fetal Blood , Gene Frequency , HLA Antigens/genetics , Austria , Fetal Blood/cytology , Genetic Linkage , Genetics, Population , HLA-A Antigens/genetics , HLA-B Antigens/genetics , HLA-C Antigens/genetics , HLA-DRB1 Chains/genetics , Haplotypes , Histocompatibility Testing , Humans , Linkage DisequilibriumABSTRACT
BACKGROUND AND AIMS: Classic autosomal-dominant familial adenomatous polyposis (FAP) is clinically defined by the development of hundreds to thousands of colorectal adenomas beginning in childhood and adolescence. A variant of FAP characterized by polyposis in combination with osteomas or soft tissue tumours is called Gardner's syndrome. FAP is caused by germline inactivation of the APC (adenomatous polyposis coli) tumour-suppressor gene located on the long arm of chromosome 5 (5q21-5q22). Cytogenetically visible deletions of chromosome 5q encompassing APC have very rarely been reported. Here, we aimed to phenotypically and genetically characterize a patient with a heterozygous 5q deletion resulting in Gardner's syndrome. METHODS AND RESULTS: A 26-year-old female patient with mild mental handicap and dysmorphic features due to a cytogenetically visible deletion on chromosome 5q (microscopically estimated region 5q14-5q23) presented at our tertiary referral centre because of mild adenomatous polyposis (<500 polyps). Twenty months after prophylactic proctocolectomy with definitive ileostomy, three rapidly growing desmoids were observed. Tumour-associated complications necessitated a multidisciplinary approach including medical treatment, surgery and radiation therapy. The characterization of the deletion by comparative genomic hybridization identified a large 5q deletion expanding over a 20-Mb region (5q21.3-5q23.3) including the APC gene. CONCLUSION: Chromosome deletions must be suspected in patients presenting with FAP together with mental handicap and dysmorphic features. This case also impressively shows that FAP-associated desmoids need multimodal treatment taking into account the patient's individual symptoms, disease progression and tumour location.
Subject(s)
Abdominal Neoplasms/therapy , Adenomatous Polyposis Coli/therapy , Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Fibromatosis, Aggressive/therapy , Gardner Syndrome/therapy , Abdominal Neoplasms/diagnosis , Abdominal Neoplasms/genetics , Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/genetics , Adult , Combined Modality Therapy , Comparative Genomic Hybridization , Facies , Female , Fibromatosis, Aggressive/diagnosis , Fibromatosis, Aggressive/genetics , Gardner Syndrome/diagnosis , Gardner Syndrome/genetics , Humans , Magnetic Resonance ImagingABSTRACT
Since most current techniques analysing spermatozoa will inevitably exclude these gametes from further use, attempts have been made to enrich semen samples with physiological spermatozoa with good prognosis using special sperm-processing methods. A particular sperm-selection chamber, called the Zech-selector, was found to be effective in completely eliminating spermatozoa with DNA strand breaks. The aim of this study was to further analyse the subgroup of spermatozoa accumulated using the Zech-selector. In detail, the potential of the chamber to select for proper sperm morphology, DNA status and chromatin condensation was tested. Two samples, native and processed semen, of 53 patients were analysed for sperm morphology (×1000, ×6300), DNA packaging (fragmentation, chromatin condensation) and chromosomal status (X, Y, 18). Migration time (the time needed for proper sperm accumulation) was significantly correlated to fast progressive motility (P=0.002). The present sperm-processing method was highly successful with respect to all parameters analysed (P<0.001). In particular, spermatozoa showing numeric (17.4% of patients without aneuploidy) or structural chromosomal abnormalities (90% of patients without strand-breaks) were separated most effectively. To summarize, further evidence is provided that separating spermatozoa without exposure to centrifugation stress results in a population of highly physiological spermatozoa.
Subject(s)
Aneuploidy , Cell Separation/methods , DNA Packaging , Sperm Motility , Spermatozoa/physiology , Adult , Cell Separation/instrumentation , DNA Fragmentation , Humans , Male , Middle Aged , Prospective Studies , Semen Analysis , Spermatozoa/cytologyABSTRACT
A great number of syndromes and inborn errors of metabolism associated with impaired development have been observed, but the aetiology of mental retardation remains unclear in a considerable proportion of cases. Here, we present the clinical and molecular data from a patient with a new de novo subtelomeric deletion on chromosome 20 [46,XX.ish del(20)(qter-)]. For further refinement, bacterial artificial chromosome clones are used. The deletion spans exactly two genes called MYT1 and PCMTD2. Both genes play an important role in myelination and regulating neural differentiation. Loss of these two genes seems to be responsible for the severe mental retardation and mild facial dysmorphic features in our young patient. It might show the phenotypic picture of this specified deletion.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 20/genetics , Intellectual Disability/genetics , Telomere/genetics , Child, Preschool , DNA-Binding Proteins/deficiency , Female , Humans , Transcription Factors/deficiencyABSTRACT
Basal ganglia calcification (striatopallidodentate calcifications) can be caused by several systemic and neurological disorders. Familial Idiopathic Basal Ganglia Calcification (IBGC, "Fahr's disease"), is characterized by basal ganglia and extrabasal ganglia calcifications, parkinsonism and neuropsychiatric symptoms. Because of an increased use of neuroimaging procedures, calcifications of the basal ganglia are visualized more often and precociously. In 1999, a major American family with IBGC was linked to a locus on chromosome 14q (IBGC1). Another small kindred, from Spain, has also been reported as possibly linked to this locus. Here we report the main findings of the first 30 candidate genes sequenced at the IBGC1 locus during the process of searching for a mutation responsible for familial IBGC. During the sequencing process, we identified a heterozygous nonsynonymous single nucleotide polymorphism (exon 20 of the MGEA6/c-TAGE gene) shared by the affected and not present in the controls. This SNP was randomly screened in the general population (348 chromosomes) in a minor allele frequency to 0.0058 (two heterozygous among 174 subjects). Another variation in this gene, in the exon 9, was found in the Spanish family. However, this variation was extremely common in the general population. Functional and population studies are necessary to fully access the implications of the MGEA6 gene in familial IBGC, and a complete sequencing of the IBGC1 locus will be necessary to define a gene responsible for familial IBGC.
Subject(s)
Basal Ganglia Diseases , Calcinosis , Basal Ganglia Diseases/genetics , Basal Ganglia Diseases/pathology , Calcinosis/genetics , Calcinosis/pathology , DNA Mutational Analysis , Genetic Linkage , Genetic Predisposition to Disease , Humans , Mutation , Polymorphism, Single NucleotideABSTRACT
We describe a 4-year-old boy with various facial dysmorphic features such as downslanting palpebral fissures, ptosis, hypertelorism, broad nasal bridge, small and low-set ears, broad philtrum, and micrognathia. In addition, profound mental retardation, myopia, muscular hypotonia as well as genital and cardiovascular abnormalities are also present. Refinement of the breakpoints by cytogenetic techniques, in particular the increase of banding resolution in conventional cytogenetic analysis, has enabled the correct diagnosis, as proven by fluorescence in situ hybridisation (FISH) using whole chromosome painting and single copy probes. We were able to demonstrate an unbalanced translocation that the patient inherited from his father resulting in a submicroscopic monosomy 16p13.3 and a trisomy 2p24.2-pter.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 16 , Chromosomes, Human, Pair 2 , Monosomy/genetics , Translocation, Genetic , Trisomy/genetics , Abnormalities, Multiple/pathology , Child, Preschool , Chromosome Banding , Cytogenetic Analysis , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , PhenotypeABSTRACT
Basal ganglia calcification (striatopallidodentate calcifications) can be caused by several systemic and neurological disorders. Familial Idiopathic Basal Ganglia Calcification (IBGC, "Fahr" disease'), is characterized by basal ganglia and extrabasal ganglia calcifications, parkinsonism and neuropsychiatric symptoms. Because of an increased use of neuroimaging procedures, calcifications of the basal ganglia are visualized more often and precociously. In 1999, a major American family with IBGC was linked to a locus on chromosome 14q (IBGC1). Another small kindred, from Spain, has also been reported as possibly linked to this locus. Here we report the main findings of the first 30 candidate genes sequenced at the IBGC1 locus during the process of searching for a mutation responsible for familial IBGC. During the sequencing process, we identified a heterozygous nonsynonymous single nucleotide polymorphism (exon 20 of the MGEA6/c-TAGE gene) shared by the affected and not present in the controls. This SNP was randomly screened in the general population (348 chromosomes) in a minor allele frequency to 0.0058 (two heterozygous among 174 subjects). Another variation in this gene, in the exon 9, was found in the Spanish family. However, this variation was extremely common in the general population. Functional and population studies are necessary to fully access the implications of the MGEA6 gene in familial IBGC, and a complete sequencing of the IBGC1 locus will be necessary to define a gene responsible for familial IBGC.
ABSTRACT
We report on a currently six-year-old patient with a de novo complex chromosome rearrangement (CCR) involving chromosomes 2 and 12. A translocation 2;12 that appeared to be reciprocal after standard banding turned out to be a complex event with seven breaks after molecular cytogenetic analyses. Array CGH analysis showed no imbalances at the breakpoints but revealed an additional microdeletion of about 80 kb on chromosome 11. The same deletion was also present in the phenotypically normal father. The patient showed relatively mild mental retardation, defined mainly as impaired speech development (orofacial dyspraxia) and psychomotor retardation. In addition, mild dysmorphic facial features like hypertelorism, a prominent philtrum and down-turned corners of the mouth were observed. We narrowed down all breakpoint regions to about 100 kb, using a panel of mapped bacterial artificial chromosome (BAC) clones for fluorescence in situ hybridization (FISH). BACs spanning or flanking all seven breakpoints were identified and no chromosomal imbalances were found consistent with the array CGH results. Our investigations resulted in the following karyotype: 46,XY,t(2;12)(2pter-->2p25.3::2p23.3-->2p25.2::2p23.3-->2p14::2q14.3-->2p14::2q14.3-->2q14.3::12q 12-->12qter;12pter-->12q12::2p25.3-->2p25.2::2q14.3-->2qter).
Subject(s)
Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 2 , Intellectual Disability/genetics , Speech Disorders/genetics , Translocation, Genetic , Child , Chromosome Aberrations , Chromosome Breakage , Chromosomes, Artificial, Bacterial , Chromosomes, Human, Pair 11 , Cytogenetic Analysis , Face/abnormalities , Family Health , HumansSubject(s)
Gene Deletion , Mosaicism/genetics , Neoplasm Proteins , Neurofibromatosis 1/genetics , Recombination, Genetic , Transcription Factors/genetics , Adult , Animals , Cell Line , Child , Family Health , Fatal Outcome , Female , Haplotypes/genetics , Humans , In Situ Hybridization, Fluorescence , Mitosis/genetics , Neurofibromatosis 1/pathology , PedigreeABSTRACT
Trisomy 18 is the second most frequent autosomal aneuploidy affecting about 1 in 8,000 new-borns. Similar to trisomy 13 more than 90% of the patients die within the first year. Main causes of death are failure of vital organ function, in most cases of brain, heart, kidney, and gut, sometimes combined with severe infections. The degree to which essential organs are affected at birth and the clinical course differ considerably. Unknown genetic factors and various environmental effects are most likely involved. A less severe course of Edwards syndrome can be caused by a partial trisomy due to a deletion of the extra chromosome 18 or somatic mosaicism with a trisomic and a normal cell-line in the patient. In this report conventional chromosome analysis, FISH, and QF-PCR have been performed on a 19-year-old female patient with trisomy 18 to investigate a large number of cells including non-mitotic cells from various different tissues. This study supports evidence for an apparently pure form of trisomy 18 in this "long-living" patient with Edwards syndrome.
Subject(s)
Chromosomes, Human, Pair 18/genetics , Survival Rate , Trisomy/genetics , Adolescent , Aneuploidy , Chromosome Mapping , Chromosomes, Human, Pair 13/genetics , Female , Humans , Polymerase Chain Reaction , SyndromeSubject(s)
Abnormalities, Multiple/genetics , Chromosome Deletion , Chromosomes, Human, Pair 14/genetics , Microcephaly/pathology , Psychomotor Disorders/pathology , Abnormalities, Multiple/pathology , Anodontia/pathology , Child, Preschool , Chromosome Banding , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Optic Atrophy/pathology , PhenotypeABSTRACT
We report a 2-year-old boy with Prader-Willi Syndrome (PWS) caused by a deletion of the PWS critical region as a result of an unbalanced translocation t(3;15). Additional features, including central visual impairment, relative macrocephaly, retrognathia, preauricular tags, and bilateral club-feet, were noticed. The extension of the deletion was determined by fluorescence in situ hybridization (FISH) analysis using 11 region-specific YAC clones. Nine YACs were found to be deleted, allowing us to determine that the deletion is larger than in patients with typical PWS deletions. The karyotype of this patient can thus be designated: 45,XY,-15,der(3)t(3;15)(qter;q14).ish der(3)t(3;15)(qter;q14) (wcp3+,wcp15+,D15S10-,PML+,D15Z1-,D3S4560+,801_f_9x1, 815_e_6x2) de novo. Molecular analyses using seven polymorphic markers helped to narrow down the breakpoint between marker ACTC.PC3 and the distal end of the YAC 815_e_6. These results provide evidence that haploinsufficiency for genes in 15q13-q14, not affected in common PWS deletions, is associated with the additional features found in the patient, including a central visual impairment.
Subject(s)
Chromosomes, Human, Pair 15/genetics , Gene Deletion , Prader-Willi Syndrome/genetics , Vision Disorders/genetics , Child, Preschool , Chromosome Mapping , Chromosomes, Artificial, Yeast , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Translocation, Genetic/geneticsABSTRACT
We have mapped the LAT gene by radiation hybrid mapping and fluorescence in situ hybridization to chromosome 16p11.2. The complete cDNA sequence of LAT was generated using assembled sequences of cDNA fragments already available. BLAST analysis using the cDNA sequence led to the identification of BAC clone CTB-134H23 (GenBank Accession No. AC112166). The genomic structure of the human LAT gene consists of 11 exons, encompassing 5.7 kb. Alternative splicing variants were identified.
Subject(s)
Adaptor Proteins, Signal Transducing , Carrier Proteins/genetics , Chromosomes, Human, Pair 16 , Membrane Proteins , Phosphoproteins/genetics , Amino Acid Sequence , Base Sequence , Chromosome Mapping , DNA, Complementary , Humans , Hybrid Cells/radiation effects , In Situ Hybridization, Fluorescence , Molecular Sequence DataABSTRACT
A new-born infant was found to have multiple congenital anomalies Including bilateral cleft of lip and palate, club-hands and feet, and heart defects. High resolution chromosome analysis showed a de novo tandem duplication of the terminal part of the short arm of chromosome 16, resulting in a dup(16)(pter-->p13). Fluorescent in situ hybridization with a chromosome 16-specific paint confirmed that the extra material belonged to chromosome 16.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 16/ultrastructure , Chromosome Aberrations , Cleft Lip/genetics , Cleft Palate/genetics , Foot Deformities, Congenital/genetics , Hand Deformities, Congenital/genetics , Humans , Infant, Newborn , Karyotyping , Male , Tandem Repeat Sequences , TrisomyABSTRACT
Duplication of distal 4p results in a recognizable clinical phenotype. We report here on a 3 year old girl with a de novo inverse duplication of the chromosome segment 4p16.3-p15.3. The symptoms in this patient are milder than those of previously described patients with 4p duplication syndrome and include a deep hairline, deep-set eyes, short pug nose, full cheeks, simian crease, clinodactily of the fifth digit, no speech development and a moderate psychomotor retardation. Fluorescence in situ hybridization (FISH) using a chromosome 4 painting probe confirmed that the extra material is of chromosome 4 origin. Further analysis with the Wolf-Hirschhorn critical region probe demonstrated the duplication of this region. The lysosomal hydrolase alpha-L-iduronidase (IDUA) gene which is mutated in mucopolysaccaridosis type I (MPS I) and mapped to 4p16.3 might be responsible for some of the MPS like facial features. A phenotype-genotype correlation analysis in combination with literature review was undertaken to allow a further delineation of partial trisomy 4p syndromes.