Objective: To determine the histopathologic abnormalities within the cochlea in Alport syndrome.
Background: Alport syndrome, which manifests as hereditary nephritis and sensorineural hearing loss ...(SNHL), is caused by mutations in genes that code for the ∝3, ∝4, and ∝5 chains of type IV collagen. The ∝3, ∝4, and ∝5 chains of type IV collagen are present in the basement membrane of the organ of Corti. Previous temporal bone studies have failed to identify histopathologic correlates for the SNHL.
Methods: We examined temporal bones from nine individuals with a clinical diagnosis of Alport syndrome. One of our cases also had genetic testing that showed a mutation in the type IV collagen ∝5 chain gene.
Results: By light microscopy, eight of nine cases demonstrated two unique pathologic changes: 1) a “zone of separation” between the basilar membrane and overlying cells of the organ of Corti and 2) presence of cells filling the tunnel of Corti and extracellular spaces of Nuel. The cytologic losses of hair cells, stria vascularis, and cochlear neuronal cells were insufficient to account for the observed SNHL in our cases. Electron microscopy was performed in four cases; all four demonstrated the following: 1) the zone of separation that was observed at light microscopy occurred between the basement membrane and the basilar membrane, 2) the cells within the tunnel of Corti and spaces of Nuel were morphologically similar to supporting cells, and 3) the basement membrane of strial capillaries and the spiral vessel (under the basilar membrane) were normal.
Conclusions: The histopathologic correlates of cochlear involvement in Alport syndrome are abnormalities of the basement membrane of cells of the organ of Corti and dysmorphogenesis (cellular infilling of the tunnel and extracellular spaces) of the organ of Corti. We hypothesize that these abnormalities result in SNHL by altering cochlear micromechanics.
To investigate the effect on the sleep EEG, a 1-mg oral dose of SR 46349B, a novel 5-HT2 antagonist, was administered three hours before bedtime. The drug enhanced slow wave sleep (SWS) and reduced ...stage 2 without affecting subjective sleep quality. In nonREM sleep (NREMS) EEG slow-wave activity (SWA; power within 0.75–4.5 Hz) was increased and spindle frequency activity (SFA; power within 12.25–15 Hz) was decreased. The relative NREMS power spectrum showed a bimodal pattern with the main peak at 1.5 Hz and a secondary peak at 6 Hz. A regional analysis based on bipolar derivations along the antero-posterior axis revealed significant ‘treatment’ × ‘derivation’ interactions within the 9–16 Hz range. In enhancing SWA and attenuating SFA, the 5-HT2 receptor antagonist mimicked the effect of sleep deprivation, whereas the pattern of the NREMS spectrum differed.
Response to the editorial by Dr Geraghty White, Peter D; Chalder, Trudie; Sharpe, Michael ...
Journal of health psychology,
08/2017, Volume:
22, Issue:
9
Journal Article
Peer reviewed
Open access
This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we ...led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty’s views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.
This innovating edited volume provides a broad but detailed overview of a relatively recent significant development in church organisation, the megachurch. Its aim is to capture empirically and ...theoretically the megachurch phenomenon as a unique form of religious expression through author contributions from several academic disciplines including the Sociology of Religion, Religious Studies, Church History and Theology.
International climate negotiations have stressed the importance of considering emissions from forest degradation under the planned REDD+ (Reducing Emissions from Deforestation and forest Degradation ...+ enhancing forest carbon stocks) mechanism. However, most research, pilot-REDD+ projects and carbon certification agencies have focused on deforestation and there appears to be a gap in knowledge on complex mosaic landscapes containing degraded forests, smallholder agriculture, agroforestry and plantations. In this paper we therefore review current research on how avoided forest degradation '... may affect emissions of greenhouse gases ...' (GHG) and expected co-benefits in terms of biodiversity and livelihoods. There are still high uncertainties in measuring and monitoring emissions of carbon and other GHG from mosaic landscapes with forest degradation since most research has focused on binary analyses of forest vs. deforested land. Studies on the impacts of forest degradation on biodiversity contain mixed results and there is little empirical evidence on the influence of REDD+ on local livelihoods and tenure security, partly due to the lack of actual payment schemes. Governance structures are also more complex in landscapes with degraded forests as there are often multiple owners and types of rights to land and trees. Recent technological advances in remote sensing have improved estimation of carbon stock changes but establishment of historic reference levels is still challenged by the availability of sensor systems and ground measurements during the reference period. The inclusion of forest degradation in REDD+ calls for a range of new research efforts to enhance our knowledge of how to assess the impacts of avoided forest degradation. A first step will be to ensure that complex mosaic landscapes can be recognised under REDD+ on their own merits.
We assessed whether HIV status was associated with white matter hyperintensities (WMH), a neuroimaging correlate of cerebral small vessel disease (CSVD), in men aged ≥50 years. A cross-sectional ...substudy was nested within a larger cohort study. Virologically suppressed men living with HIV (MLWH) and demographically matched HIV-negative men aged ≥50 underwent magnetic resonance imaging (MRI) at 3 Tesla. Sequences included volumetric three-dimensional (3D) T1-weighted, fluid-attenuated inversion recovery and pseudocontinuous arterial spin labeling. Regional segmentation by automated image processing algorithms was used to extract WMH volume (WMHV) and resting cerebral blood flow (CBF). The association between HIV status and WMHV as a proportion of intracranial volume (ICV; log-transformed) was estimated using a multivariable linear regression model. Thirty-eight MLWH median age 59 years (interquartile range, IQR 55-64) and 37 HIV-negative median 58 years (54-63) men were analyzed. MLWH had median CD4
count 570 (470-700) cells/μL and a median time since diagnosis of 20 (14-24) years. Framingham 10-year risk of cardiovascular disease was 6.5% in MLWH and 7.4% in controls. Two (5%) MLWH reported a history of stroke or transient ischemic attack and five (13%) reported coronary heart disease compared with none of the controls. The total WMHV in MLWH was 1,696 μL (IQR 1,229-3,268 μL) or 0.10% of ICV compared with 1,627 μL (IQR 1,032-3,077 μL), also 0.10% of ICV in the HIV-negative group (
= .43). In the multivariable model, WMHV/ICV was not associated with HIV status (
= .86). There was an age-dependent decline in cortical CBF -3.9 mL/100 mL/min per decade of life (95% confidence interval 1.1-6.7 mL) but no association between CBF and HIV status (
> .2 in all brain regions analyzed). In conclusion, we found no quantitative MRI evidence of an increased burden of CSVD in MLWH aged 50 years and older.
A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis ...and biological activity of this new series of substituted 8,9-benzoaphenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzoaphenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j‘ ‘). In vivo activity has been demonstrated for 4-methoxy-benzoaphenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.
Purpose of the Study: There is lack of consensus on the best method of functional assessment, and there is a paucity of studies on daily functioning in centenarians. We sought to compare associations ...between performance-based, self-report, and proxy report of functional status in centenarians. We expected the strongest relationships between proxy reports and observed performance of basic activities of daily living (BADLs) and instrumental activities of daily living (IADLs). We hypothesized that the discrepancy between self-report and observed daily functioning would be modified by cognitive status. We additionally sought to provide clinicians with estimates of centenarians' observed daily functioning based on their mental status in combination with subjective measures of activities of daily living (ADLs). Design and Methods: Two hundred and forty-four centenarians from the Georgia Centenarian Study were included in this cross-sectional population-based study. Measures included the Direct Assessment of Functional Status, self-report and proxy report of functional status, and the Mini-Mental State Examination (MMSE). Results: Associations between observed and proxy reports were stronger than between observed and self-report across BADL and IADL measures. A significant MMSE by type of report interaction was found, indicating that lower MMSE performance is associated with a greater discrepancy between subjective and objective ADL measures. Implications: Results demonstrate associations between 3 methods of assessing functional status and suggest proxy reports are generally more accurate than self-report measures. Cognitive status accounted for some of the discrepancy between observed and self-reports, and we provide clinicians with tables to estimate centenarians' performance on observed functional measures based on MMSE and subjective report of functional status.