Functional impairment and quality of life in newly diagnosed adults attending a tertiary ADHD clinic in Ireland.

BACKGROUND: Attention Deficit-Hyperactive Disorder (ADHD) is a neurodevelopmental disorder, often persisting into adulthood. AIMS: To investigate the levels of functionality and quality of life (QoL) in adult patients newly diagnosed with ADHD and to compare with those without an ADHD diagnosis. METHODS: Consecutive patients who were referred to and assessed in a tertiary adult ADHD clinic enrolled in the study. Diagnosis of ADHD was based on DSM-5 criteria. Functionality was measured using the Weiss Functional Impairment Rating Scale (WFIRS) and the Global Assessment of Functioning Scale (GAF). QoL was assessed with the Adult ADHD Quality of Life Questionnaire (AAQoL). RESULTS: Three-hundred and forty participants were recruited, 177 (52.1%) females. Of them 293 (86.2%) were newly diagnosed with ADHD. Those with ADHD had significant lower functionality as it was measured with the WFIRS and GAF, and worse QoL (AAQoL) compared to those without. In addition, a significant correlation between GAF and WFIRS was found. CONCLUSIONS: The results show that adults with ADHD have decreased functionality and worse QoL when compared against those presenting with a similar symptomatology, but no ADHD diagnosis. ADHD is not just a behavioural disorder in childhood, but a lifelong condition with accumulating problems that can lead to lower QoL and impaired functioning throughout adulthood.

Comparative Analysis of Anterior Chamber Flare Grading between Clinicians with Different Levels of Experience and Semi-automated Laser Flare Photometry.

PURPOSE: To assess correlation for anterior chamber flare grading between clinicians with different levels of experience and with semi-automated flare reading in a cohort of patients with heterogeneous uveitic entities. METHODS: Fifty-nine observations from 36 patients were recorded and analyzed for statistical association. In each patient, flare was assessed objectively using the Kowa FM-700 laser flare photometer, and subjective masked grading by two clinicians was performed. RESULTS: The study demonstrated disparity in flare readings between clinical graders with one step disagreement in clinical grading in 26 (44.06%) eyes (p < 0.001) and concordance between the flare readings by experienced grader and flare photometry. After review of semi-automated flare readings, management was changed in 11% of the patients. CONCLUSION: Laser flare photometry can be a valuable tool to remove the observer bias in grading flare for selected cohort of uveitis patients. It can be further applied to titrate therapy in intraocular inflammation.

Classification of semi-automated flare readings using the Kowa FM 700 laser cell flare meter in patients with uveitis.

PURPOSE: To propose a classification system to grade semi-automated flare readings and assess its correlation with clinical flare grading and also to explore the utility of an additional step in clinical flare assessment between grades 0 and 1. METHODS: Semi-automated flare readings from 103 eyes with uveitis were taken using the Kowa FM 700 laser flare meter and classified into two models (LFCM and LFCM_1), and introduction of a 0.5 step in flare grading was explored. RESULTS: Good correlation was present between the conventional SUN clinical flare and the proposed clinical classification for flare (weighted kappa (WK) = 89.64%, p < 0.001). Semi-automated flare grading (LFCM and LFCM_1) had WK agreement of 82.52% and 79.85% (p < 0.001) with conventional SUN clinical flare grading. CONCLUSIONS: The proposed classification system for semi-automated laser flare readings (LFCM) allows stratification of measurements into grades analogous to clinical flare grades and correlates well with conventional clinical flare grading.

Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.

The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (If) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific If silencing caused altered [Ca(2+)]i release and Ca(2+) handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of If silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in If-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.

Do tobacco stimulate the production of nitric oxide by up regulation of inducible nitric oxide synthesis in cancer: Immunohistochemical determination of inducible nitric oxide synthesis in oral squamous cell carcinoma--a comparative study in tobacco habituers and non-habituers.

BACKGROUND: Oral cancer accounts for 6% of all cancers. The most prevalent form of oral cancer is oral squamous cell carcinoma (OSCC), which accounts for 90% of the oral cancer cases. The major risk factor for development of OSCC is the use of tobacco in various forms. NO has been studied widely over the years due to its role in various physiological and pathophysiological processes, including its complex role in carcinogenesis. MATERIALS AND METHODS: A total of 20 cases of OSCC in tobacco habituers and tobacco non-habituers were retrieved respectively from the archival biopsy specimens. Immunohistochemistry was done to assess the inducible nitric oxide synthase (iNOS) protein. RESULTS: This study was performed to assess the correlation between tobacco and nitric oxide in OSCC in order to know the association of these two in the process of carcinogenesis. The results showed the enhanced expression of iNOS in tobacco habituers in comparison with tobacco non-habituers. Though the increased expression of iNOS is found, significant difference is not obtained with scores, but significant difference was found with intensity of staining. CONCLUSIONS: The results of the present study indicate the enhanced expression in OSCC of tobacco habituers when compared to OSCC of tobacco non-habituers indicating the effect of tobacco on nitric oxide. Carcinogenic chemical compounds in Tobacco induce nitric oxide production by iNOS, by its tumor-promoting effects which may enhance the process of carcinogenesis.

Volumetric breast composition analysis: reproducibility of breast percent density and fibroglandular tissue volume measurements in serial mammograms.

BACKGROUND: Volumetric breast composition analysis represents a useful tool for assessing changes in breast composition over time. However, no data exist on the reproducibility of this method in serial mammograms. PURPOSE: To assess the reproducibility of two volumetric breast composition parameters, breast percent density (PD) and fibroglandular tissue volume (FTV), in consecutive mammograms. MATERIAL AND METHODS: Volumetric breast composition analysis to determine PD and FTV was performed in two consecutive unilateral mammograms of 211 patients. All mammograms were obtained on the same digital mammography unit within a maximum interval of 24 months. Volumetric data for analysis for both examinations were available for 174 patients. Thirty-two patients had successful volumetric analysis of additional consecutive examinations on a second digital mammography unit. Inter-examination correlation of measurements and absolute differences were analyzed. Bland-Altman analysis was performed to compare readings from different mammography units. RESULTS: Mean FTV remained constant over the study period. A reduction in PD of 0.5% and a mean increase in breast volume (BV) of 3% were observed. FTV measurements obtained on the same mammography unit were significantly more reproducible than PD measurements (Pearson correlation coefficients of 0.947 and 0.920, respectively; P < 0.05). A 15% difference between mean absolute volume measurements (FTV and BV) obtained on different mammography units was observed (P ≤ 0.001), while mean PD was close to the expected value. CONCLUSION: Volumetric breast composition analysis is highly reproducible in serial mammograms in normal women. FTV is a more reproducible parameter than PD, indicating that absolute quantification of breast parenchyma may be preferable to the measurement of relative parameters such as PD. However, a disadvantage of using FTV is that it is susceptible to systematic differences when measurements are obtained on different imaging platforms.

Clinical and molecular features associated with cystic visceral lesions in von hippel-lindau disease.

BACKGROUND: Von Hippel-Lindau (VHL) is an uncommon oncogenic disorder which occurs as a result of genetic mutations on chromosome 3p. Retinal capillary haemangiomas and CNS haemangioblastomas have been well-characterised in genotypic-phenotypic analyses, but cystic visceral lesions are less common and have been less frequently studied. The aim of this study was to perform genotypic and phenotypic analysis of a cohort of VHL patients that developed cystic visceral lesions to determine whether their genotype differs from that seen in other manifestations of VHL and whether the ocular manifestations differ. METHODS: This study reports a prospective case series of twenty-one patients identified from the Hammersmith Hospital Genetics Service database as having VHL mutations. Patients underwent regular ocular and systemic screening as well as genotypic analysis. The main outcome measures were the development of VHL lesions, either ocular or systemic. RESULTS: Cystic visceral lesions were detected in six of the 21 patients from the clinic (29%). These included renal cysts in four patients, pancreatic cysts in three patients, and an epididymal cystadenoma in one patient. Renal cysts were not associated with any specific genotype. Pancreatic cysts appeared to occur in association with VHL gene deletions and all developed CNS haemangioblastomas. Only one patient developed ocular manifestations, which occurred in this patient in the form of two retinal capillary haemangiomas. CONCLUSIONS: VHL gene deletions appeared to be associated with pancreatic cysts and the development of CNS haemangioblastomas. Ocular manifestations are uncommon in this group of patients.

Behçet disease: visual prognosis and factors influencing the development of visual loss.

PURPOSE: To assess the visual prognosis of patients with ocular Behçet disease and to determine factors predictive of visual loss and severe visual loss. DESIGN: Retrospective case series. METHODS: One hundred seventy-five eyes of 107 patients diagnosed with ocular Behçet disease were included. The main outcome measures were visual loss (best-corrected visual acuity, worse than 20/40) and severe visual loss (best-corrected visual acuity, 20/200 or worse). RESULTS: The mean duration of follow-up was 6.5 years. Presenting visual acuity was worse than 20/40 in 50% of eyes and 20/200 or worse in 21% of eyes; approximately one third of this was reversible with treatment. The most common cause of irreversible severe visual loss was ischemic maculopathy. At 10 years, there was a 39% risk of visual loss and a 24% risk of severe visual loss, the latter figure being reduced to 13% if patients with irreversible visual loss at presentation were excluded. After controlling for potentially confounding variables, male sex, unilateral disease, and left eye involvement all were statistically significant risk factors for severe visual loss at 5 and 10 years. Patients who were treated with biologic agents were less likely to have severe visual loss in either eye at both 5 and 10 years. CONCLUSIONS: Many patients with ocular Behçet disease still have irreversible visual loss at presentation. However, the visual prognosis is otherwise improved, with a 10-year risk of severe visual loss of 13% in this cohort. The use of biologic agents is associated with a lower risk of severe visual loss at 5 and 10 years.

Human transscleral albumin permeability and the effect of topographical location and donor age.

PURPOSE: To quantify the permeability coefficient of albumin across human sclera and to assess topographical and age-related variation. METHODS: Equatorial superotemporal scleral tissue from 15 donor eyes (mean age 60 years; range 39-84) was mounted in a modified Ussing chamber. Additional tissue was taken from the anterior and posterior superotemporal regions of six eyes, and equatorial superonasal, and inferotemporal regions of a further six eyes. Fluorescein isothiocyanate (FITC)-labeled, 0.412 mM, bovine albumin was placed in one hemichamber facing the internal scleral surface, and the rate of transscleral flux was determined over 24 hours, at 25 degrees C, with a spectrophotometer. RESULTS: Permeability coefficient for equatorial superotemporal scleral tissue at 25 degrees C (+/-SD) was 0.83 +/- 0.50 x 10(-6) cm . s(-1). The permeability coefficient adjusted for 37 degrees C (+/-SD) was 1.43 +/- 0.86 x 10(-6) cm . s(-1). The effect of donor age was assessed for the 15 equatorial superotemporal samples. Regression analysis showed a significant decline in scleral diffusion of albumin with increasing donor age (P = 0.0166). There was no significant difference in diffusion over the different topographical regions tested. The partition coefficient of permeability to albumin also showed a decline with increasing donor age (P = 0.001). CONCLUSIONS: The permeability and partition coefficients of human sclera both significantly decline with increasing donor age. Permeability coefficient shows no significant variation over the different topographical regions tested. The decrease in albumin permeability with increasing donor age may have pharmacokinetic implications when considering transscleral diffusion of high-molecular-weight compounds.

Adenovirus-delivered short hairpin RNA targeting PKCalpha improves contractile function in reconstituted heart tissue.

PKCalpha has been shown to be a negative regulator of contractility and PKCalpha gene deletion in mice protected against heart failure. Small interfering (si)RNAs mediate gene silencing by RNA interference (RNAi) and may be used to knockdown PKCalpha in cardiomyocytes. However, transfection efficiencies of (si)RNAs by lipofection tend to be low in primary cells. To address this limitation, we developed an adenoviral vector (AV) driving short hairpin (sh)RNAs against PKCalpha (Ad-shPKCalpha) and evaluated its potential to silence PKCalpha in neonatal rat cardiac myocytes and in engineered heart tissues (EHTs), which resemble functional myocardium in vitro. A nonsense encoding AV (Ad-shNS) served as control. Quantitative PCR and Western blotting showed 90% lower PKCalpha-mRNA and 50% lower PKCalpha protein in Ad-shPKCalpha-infected cells. EHTs were infected with Ad-shPKCalpha on day 11 and subjected to isometric force measurements in organ baths 4 days later. Mean twitch tension was >50% higher in Ad-shPKCalpha compared to Ad-shNS-infected EHTs, under basal and Ca(2+)- or isoprenaline-stimulated conditions. Twitch tension negatively correlated with PKCalpha mRNA levels. In summary, AV-delivered shRNA mediated highly efficient PKCalpha knockdown in cardiac myocytes and improved contractility in EHTs. The data support a role of PKCalpha as a negative regulator of myocardial contractility and demonstrate that EHTs in conjunction with AV-delivered shRNA are a useful model for target validation.

Acute traumatic coagulopathy.

BACKGROUND: Traumatic coagulopathy is thought to be caused primarily by fluid administration and hypothermia. METHODS: A retrospective study was performed to determine whether coagulopathy resulting from the injury itself is a clinically important entity in severely injured patients. RESULTS: One thousand eight hundred sixty-seven consecutive trauma patients were reviewed, of whom 1,088 had full data sets. Median Injury Severity Score was 20, and 57.7% had an Injury Severity Score > 15; 24.4% of patients had a significant coagulopathy. Patients with an acute coagulopathy had significantly higher mortality (46.0% vs. 10.9%; chi2, p < 0.001). The incidence of coagulopathy increased with severity of injury, but was not related to the volume of intravenous fluid administered (r2 = 0.25, p < 0.001). CONCLUSION: There is a common and clinically important acute traumatic coagulopathy that is not related to fluid administration. This is a marker of injury severity and is related to mortality. A coagulation screen is an important early test in severely injured patients.