ABSTRACT
The genetic, mutational and phenotypic spectrum of deafness-causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non-syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher syndrome (USH). Variants in the CIB2 gene have been previously reported to cause hearing loss at the DFNB48 locus and deaf-blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non-syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss-of-function (LOF) variants, 2 families segregated missense variants (1 novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here, we provide evidence disqualifying CIB2 as an USH-causing gene.
Subject(s)
Calcium-Binding Proteins/genetics , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/genetics , Usher Syndromes/genetics , Adult , Female , Frameshift Mutation/genetics , Genetic Linkage , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/physiopathology , Humans , Loss of Function Mutation/genetics , Male , Middle Aged , Pedigree , Usher Syndromes/diagnosis , Usher Syndromes/physiopathologyABSTRACT
It is well known that soils are influenced by the plant species that grow in them. Here we consider the effects of management-induced changes to plant communities and their soils during restoration within a 20-year manipulative experiment where the aim was to change a late-successional community dominated by the weed, Pteridium aquilinum, to an earlier-successional grass-heath one. The ecological restoration treatments altered the above- and below-ground components of the community substantially. Untreated plots maintained a dense Pteridium cover with little understory vegetation, cutting treatments produce significant reductions of Pteridium, whereas herbicide (asulam) produced significant immediate reductions in Pteridium but regressed towards the untreated plots within 10 years. Thereafter, all asulam-treated plots were re-treated in year 11, and then were spot-sprayed annually. Both cutting and asulam treatments reduced frond density to almost zero and resulted in a grass-heath vegetation. There was also a massive change in biomass distribution, untreated plots had a large above-ground biomass/necromass that was much reduced where Pteridium was controlled. Below-ground in treated plots, there was a replacement of the substantive Pteridium rhizome mass with a much greater root mass of other species. The combined effects of Pteridium-control and restoration treatment, reduced soil total C and N as and available P concentrations, but increased soil pH and available N. Soil biological activity was also affected with a reduction in soil N mineralization rate, but an increased soil-root respiration. Multivariate analysis showed a clear trend along a pH/organic matter gradient, with movement along it correlated to management intensity from the untreated plots with low pH/high organic matter and treated plots with to a higher pH/lower organic matter in the sequence asulam treatment, cut once per year to cut twice per year. The role that these changed soil conditions might have in restricting Pteridium recovery are discussed.
Subject(s)
Ecosystem , Herbicides , Pteridium , Ecology , Soil/chemistryABSTRACT
Recent advances in targeted genomic enrichment with massively parallel sequencing (TGE+MPS) have made comprehensive genetic testing for non-syndromic hearing loss (NSHL) possible. After excluding NSHL subjects with causative mutations in GJB2 and the MT-RNR1 (1555A>G) variant by Sanger sequencing, we completed TGE+MPS on 194 probands with presumed NSHL identified across Japan. We used both publicly available minor allele frequency (MAF) datasets and ethnic-specific MAF filtering against an in-house database of 200 normal-hearing Japanese controls. Ethnic-specific MAF filtering allowed us to re-categorize as common 203 variants otherwise annotated as rare or novel in non-Japanese ethnicities. This step minimizes false-positive results and improves the annotation of identified variants. Causative variants were identified in 27% of probands with solve rates of 35%, 35% and 19% for dominant, recessive and sporadic NSHL, respectively. Mutations in MYO15A and CDH23 follow GJB2 as the frequent causes of recessive NSHL; copy number variations in STRC are a major cause of mild-to-moderate NSHL. Ethnic-specific filtering by allele frequency is essential to optimize the interpretation of genetic data.
ABSTRACT
In sub-Saharan Africa GJB2-related nonsyndromic hearing impairment (NSHI) is rare. Ten Cameroonian families was studied using a platform (OtoSCOPE®) with 116 genes. In seven of 10 families (70%), 12 pathogenic variants were identified in six genes. Five of the 12 (41.6%) variants are novel. These results confirm the efficiency of comprehensive genetic testing in defining the causes of NSHI in sub-Saharan Africa.
Subject(s)
Connexins/genetics , Deafness/genetics , High-Throughput Nucleotide Sequencing , Cameroon , Deafness/physiopathology , Female , Genomics , Genotype , Humans , Male , Mutation , PedigreeABSTRACT
BACKGROUND: Although autism spectrum disorder (ASD) is an increasingly common chronic disability, primary care provider (PCPs) report deficits in providing primary care for children with ASD, and parents report lapses in receipt of medical home services. In this study, we describe parental experiences with specific medical home components for their children with ASD. METHODS: We analysed data from all children within the National Survey of Children with Special Health Care Needs database with ASD and a usual place for care (n = 2859). We evaluated the receipt of core medical home components: accessible, comprehensive, coordinated, family centred and compassionate and culturally sensitive care. RESULTS: Children were mean age 10.1 years, and respondents were 75% mothers and 95% reported having a primary care provider (PCP). Seventy-one percent reported care to be usually comprehensive, over three-fourths of respondents reported care to be family centred and compassionate and 87% reported care to be culturally sensitive. Of the parents who reported a need for care coordination (n = 1049), only 14% of parents reported usually getting the help they needed. More educated, English-speaking, non-Hispanic White mothers of older children supported by private insurance were more likely to report never getting as much help coordinating care as desired. Coordination with education services are especially important for children with ASD, yet 27% of parents reported dissatisfaction with PCPs' communication with schools or early intervention. CONCLUSION: Although parents report a high level of access to PCPs and places for care as well as receiving most core components of the medical home, care coordination activities are lacking for children with ASD. More resourced families are particularly likely to report unmet needs.
Subject(s)
Autism Spectrum Disorder/therapy , Child Health Services/standards , Health Services Accessibility/standards , Parents/psychology , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/psychology , Child , Child Health Services/economics , Cross-Sectional Studies , Family Characteristics , Female , Health Care Surveys , Health Services Accessibility/economics , Humans , Male , Needs Assessment , Parent-Child Relations , Social Perception , Socioeconomic Factors , Surveys and Questionnaires , United States/epidemiologyABSTRACT
Fistula formation between the pericardium and the gastrointestinal tract is rare. Enteropericardial fistulae may present dramatically, many have prodromal symptoms even though they are not symptoms usually associated with esophageal disease. Prompt diagnosis and expedient surgery can result in survival. We describe three cases of enteropericardial fistulae diagnosed during emergency surgery for sepsis or hemorrhage. All had previous surgery though the details were not available to the operating surgeons because of the time that had passed since their original operation. All three patients survived, albeit with prolonged hospital stay and repeated surgery. A review of the English language literature revealed 95 cases (Table 1). Fifty-eight had a history of previous surgery, particularly fundoplication or esophagectomy. Ten had advanced malignancy and were treated conservatively. All eight patients with fistulae, which were iatrogenic or due to foreign bodies, survived without aggressive surgery. For more extensive pathology, a successful outcome was achieved in 32 of the 36 cases when the upper gastrointestinal (GI) tract was defunctioned because of the presence of major sepsis or because the healthy vascularized tissue was transposed into the area at risk for further fistula formation. Where less aggressive surgery was performed only 12 of 27 patients survived (P < 0.0001). Esophageal surgeons need to be aware of the late complications and associated atypical symptoms of historical procedures which are no longer in common usage. Where an enteropericardial fistula is present, defunctioning of the upper GI tract or repair with transposition of vascularized tissue gives a better chance of a successful outcome. [Table: see text].
Subject(s)
Fistula/diagnosis , Fistula/therapy , Intestinal Fistula/diagnosis , Intestinal Fistula/therapy , Pericardium , Adult , Anti-Bacterial Agents/therapeutic use , Drainage , Echocardiography , Esophagostomy , Fistula/complications , Gastrostomy , Hematemesis/etiology , Humans , Intestinal Fistula/complications , Jejunostomy , Male , Melena/etiology , Middle Aged , Pericardial Effusion/diagnostic imaging , Pericardial Effusion/etiology , Pericarditis/drug therapy , Pericarditis/etiology , Sepsis/drug therapy , Sepsis/etiologyABSTRACT
X-ray crystallography unequivocally confirmed the stereochemistry of the C atom at position 2 in the carbon scaffold of the title mol-ecule, C(10)H(18)O(4). The pyran-ose ring exists in a chair conformation with the methyl group on the C atom in the 2 position in an equatorial configuration. The absolute stereochemistry was determined from the starting material. The crystal structure consists of O-Hâ¯O hydrogen-bonded chains of mol-ecules running parallel to the b axis.
ABSTRACT
The crystal structure of the title compound, C(13)H(14)O(5), establishes (i) the (S) - rather than (R) - configuration at the acetal carbon and (ii) that both the acetal and the lactone form five- rather than six-membered rings; the absolute configuration is determined by the use of 2-C-methyl-d-ribono-1,4-lactone as the starting material. The compound consists of hydrogen-bonded chains of mol-ecules running along the a axis; there are no unusual packing features. Only classical hydrogen bonding has been considered.
ABSTRACT
X-ray crystallography confirmed the structure of the title triazole, C(11)H(15)N(3)O(5), formed from a single-step reaction of a sugar azide with a brominated ylid. The absolute configuration was determined by the use of d-ribose as the starting material. The six-membered ring is in a half-chair conformation. The crystal structure exists as chains of O-Hâ¯O hydrogen-bonded moleclues running parallel to the b axis.
ABSTRACT
The chemical name of the title compound in the paper by Jenkinson, Fenton, Booth, Fleet & Watkin [Acta Cryst. (2009), E65, o610-o611] is corrected.[This corrects the article DOI: 10.1107/S1600536809006357.].
ABSTRACT
The title mol-ecule, C(7)H(15)NO(5), the major product from selective enzymatic oxidation followed by hydrogeno-lysis of the corresponding azido-heptitol, was found by X-ray crystallography to exisit in a chair conformation with three axial hydroxyl groups. One of the hydroxymethyl groups is disordered over two sets of sites in a 0.590â (3):0.410â (3) ratio. In the crystal, O-Hâ¯O, O-Hâ¯(O,O), O-Hâ¯N and N-Hâ¯O hydrogen bonding occurs.
ABSTRACT
The title bicyclic lactone, C(19)H(19)NO(3), is an inter-mediate in the synthesis of chiral α-methyl-prolines and branched C-methyl pyrrolidines; the absolute configuration was determined by the use of d-erythronolactone as the starting material. It exhibits no unusual crystal packing features, and each mol-ecule acts as a donor and acceptor for one C-Hâ¯O hydrogen bond.
ABSTRACT
The relative configuration of tert-butyl 2-de-oxy-4,5-O-iso-propyl-idene-d-gluconate, C(13)H(24)O(6), an inter-mediate in the synthesis of 2-de-oxy sugars, was determined by X-ray crystallography, and the crystal structure consists of chains of O-Hâ¯O hydrogen-bonded mol-ecules running parallel to the a axis. There are two mol-ecules in the asymmetric unit. The absolute configuration was inferred from the use of d-erythrono-lactone as the starting material.
ABSTRACT
The crystalline form of 1-de-oxy-l-mannitol, C(6)H(14)O(5), exists as an extensively hydrogen-bonded structure with each mol-ecule acting as a donor and acceptor for five hydrogen bonds. There are no unusual crystal-packing features; the absolute configuration was determined from the use of 6-de-oxy-l-mannose (l-rhamnose) as the starting material.
ABSTRACT
X-ray crystallography showed that the title compound, C(6)H(12)O(5), crystallizes in the α-pyran-ose form with the six-membered ring in a chair conformation. The crystal structure exists as a three-dimensional hydrogen-bonded network of mol-ecules with each mol-ecule acting as a donor and aceptor for four hydrogen bonds. The absolute configuration was determined by the use of l-fucose as starting material.
ABSTRACT
1-De-oxy-d-galactitol, C(6)H(14)O(5), exists in the crystalline form as hydrogen-bonded layers of mol-ecules running parallel to the ac plane, with each mol-ecule acting as a donor and acceptor of five hydrogen bonds.
ABSTRACT
Although 6-azido-6-de-oxy-l-galactose in aqueous solution is in equilibrium between the open-chain, furan-ose and pyran-ose forms, it crystallizes solely as 6-azido-6-de-oxy-α-l-galactopyran-ose monohydrate, C(6)H(11)N(3)O(5)·H(2)O, with the six-membered ring adopting a chair conformation. The structure exists as hydrogen-bonded chains, with each mol-ecule acting as a donor and acceptor of five hydrogen bonds. There are no unusual crystal packing features and the absolute configuration was determined from the use of 1-azido-1-de-oxy-d-galactitol as the starting material.
ABSTRACT
OBJECTIVES: Deciding on the optimal treatment strategy for high risk aortic valve replacement is challenging. Transcatheter Aortic Valve implantation (TAVI) has been available in our centre as an alternative treatment modality for patients since 2008. We present our early experience of TAVI and SAVR (surgical Aortic Valve Replacement) in high risk patients who required SAVR because TAVI could not be performed. METHODS: The database for Surgical aortic valve and Transcatheter aortic valve replacement referrals was interrogated to identify relevant patients. RESULTS: Survival to hospital discharge was 95.5% in the forty five patients who had SAVR when TAVI was deemed technically unsuitable. One year survival was 86%. CONCLUSION: Defining who is appropriate for TAVI or high risk SAVR is challenging and multidisciplinary team discussion has never been more prudent in this field of evolving technology with ever decreasing risks of surgery. The introduction of TAVI at our institution has seen a rise in our surgical caseload by approximately by 25%. Overall, the option of aortic valve intervention is being offered to more patients in general which is a substantial benefit in the treatment of aortic valve disease.
Subject(s)
Aortic Valve Stenosis , Heart Valve Prosthesis Implantation , Risk Assessment/methods , Transcatheter Aortic Valve Replacement , Age Factors , Aged , Aged, 80 and over , Aortic Valve Stenosis/epidemiology , Aortic Valve Stenosis/surgery , Comorbidity , Databases, Factual , Female , Heart Valve Prosthesis Implantation/adverse effects , Heart Valve Prosthesis Implantation/methods , Heart Valve Prosthesis Implantation/statistics & numerical data , Humans , Ireland/epidemiology , Male , Outcome and Process Assessment, Health Care , Risk Factors , Survival Analysis , Time Factors , Transcatheter Aortic Valve Replacement/adverse effects , Transcatheter Aortic Valve Replacement/methods , Transcatheter Aortic Valve Replacement/statistics & numerical dataABSTRACT
BACKGROUND: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease. OBJECTIVES: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001. DESIGN: Randomized, phase 2, interventional study. TRIAL REGISTRATION: Clinicaltrials.gov ID NCT01227564. PARTICIPANTS: Individuals with early Alzheimer's disease (Mini-Mental State Examination scores ≥25, a global Clinical Dementia Rating of 0.5, and evidence of elevated baseline brain amyloid burden). INTERVENTION: Participants were randomized to ACC-001 3 µg or 10 µg with QS-21 adjuvant (50 µg), or placebo. MEASUREMENTS: The primary endpoint was change in brain amyloid burden by 18F-florbetapir positron emission tomography in composite cortical standard uptake value ratio. RESULTS: A total of 63 participants were randomized and 51 completed the study. At week 104, no significant differences were observed in 18F-florbetapir positron emission tomography composite cortical standard uptake value ratio between either ACC-001 dose compared with placebo. In both ACC-001 + QS-21 treatment groups, following the initial immunization, the anti-amyloid-beta geometric mean titers increased after each subsequent vaccination and then declined, with less apparent decline after the later compared with earlier immunizations. The majority of treatment-emergent adverse events in the ACC-001 + QS-21 groups were injection site reactions, which occurred at a greater rate in active treatment groups than in the placebo group. No amyloid-related imaging abnormalities of edema or effusion were reported. CONCLUSION: No statistically significant differences were observed between groups in the change from baseline brain amyloid burden despite apparently robust systemically measured anti-amyloid-beta antibody response at both dose levels. Insufficient antibody titers, poor quality immune response, short duration of treatment, or small sample size may have resulted in these findings. The safety and tolerability profile was acceptable.
ABSTRACT
EPR spectra of the low-spin cyanide complex of myeloperoxidase have been measured in the absence and presence of halide substrates; chloride, bromide and iodide. Halide-dependent spectral changes are found at acidic pH. The electronic structure of the low-spin ferric iron in cyanide complex appears to be modulated by halide binding to a protonated amino acid in the distal heme cavity. These findings suggest halide substrates can interact with ferryl oxygen in compound I during enzyme catalysis to form hypohalous acid.