Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitochondrial oxidative stress in the retinal pigment epithelium leads to localized retinal degeneration.

PURPOSE Oxidative stress in the RPE is widely accepted as a contributing factor to AMD. We have previously shown that ribozyme-mediated reduction in the antioxidant enzyme manganese superoxide dismutase (MnSOD) leads to some of the features of geographic atrophy in mice. To develop a mouse model independent of viral injection, we used a conditional knockout of the Sod2 gene in the RPE to elevate mitochondrial oxidative stress in that cell layer. METHODS Experimental mice in which exon 3 of Sod2 was flanked by loxP sites were also transgenic for PVMD2-rtTA and tetO-PhCMV cre, so that cre recombinase was expressed only in the RPE. Pups of this genotype (Sod2(flox/flox)VMD2cre) were induced to express cre recombinase by feeding doxycycline-laced chow to nursing dams. Controls included mice of this genotype not treated with doxycycline and doxycycline-treated Sod2(flox/flox) mice lacking the cre transgene. Expression of cre in the RPE was verified by immunohistochemistry, and deletion of Sod2 exon 3 in the RPE was confirmed by PCR. Mice were followed up over a period of 9 months by spectral-domain optical coherence tomography (SD-OCT), digital fundus imaging, and full-field ERG. Following euthanasia, retinas were examined by light and electron microscopy or by immunohistochemistry. Contour length of rod outer segments and thickness of the RPE layer were measured by unbiased stereology. RESULTS Following doxycycline induction of cre, Sod2(flox/flox) cre mice demonstrated increased signs of oxidative stress in the RPE and accumulation of autofluorescent material by age 2 months. They showed a gradual decline in the ERG response and thinning of the outer nuclear layer (by SD-OCT), which were statistically significant by 6 months. In addition, OCT and electron microscopy revealed increased porosity of the choroid. At the same interval, hypopigmented foci appeared in fundus micrographs, and vascular abnormalities were detected by fluorescein angiography. By 9 months, the RPE layer in Sod2(flox/flox) cre mice was thicker than in nontransgenic littermates, and the rod outer segments were significantly longer over most of the retina, although localized atrophy of photoreceptors was also obvious in some eyes. CONCLUSIONS Conditional tissue-specific reduction in MnSOD induced oxidative stress in mouse RPE, leading to RPE dysfunction, damage to the choroid, and death of photoreceptor cells. The RPE oxidative stress did not cause drusen-like deposits, but the model recapitulated certain key aspects of the pathology of dry AMD and may be useful in testing therapies.
Mosapride citrate, a novel 5‐HT4 agonist and partial 5‐HT3 antagonist, ameliorates constipation in parkinsonian patients

Mosapride citrate is a novel selective 5‐HT4 receptor agonist. It facilitates acetylcholine release from the enteric cholinergic neurons. In contrast to cisapride, mosapride does not block K+ channels or D2 dopaminergic receptors. The objective of this study is to perform an open study of mosapride citrate's effects on constipation, a prominent lower gastrointestinal tract disorder in parkinsonian patients. A total of 14 parkinsonian patients (7 with Parkinson's disease, 7 with multiple system atrophy; 10 men, 4 women; mean age, 67 years) with constipation (10 with bowel movement < 3 times/week; 14 with difficulty in defecation) were treated with 15 mg/day of mosapride citrate for 3 months. Pre‐ and posttreatment objective parameters in colonic transit time (CTT) and rectoanal videomanometry were obtained. Statistical analysis was made by Student's t test. Mosapride was well tolerated by all patients except for 1, who discontinued use of the drug because of epigastric discomfort. None had a worsening of parkinsonism or other adverse events. Thirteen patients reported subjective improvements in bowel frequency (>3 times/week, 13) and difficult defecation (13). Mosapride shortened CTT of the left colon (P < 0.01) and the total colon (P < 0.05). During rectal filling, mosapride lessened the first sensation (P < 0.05) and augmented the amplitude in phasic rectal contraction. During defecation, mosapride augmented the amplitude in rectal contraction (P < 0.05) and lessened the volume of postdefecation residuals. The present study showed for the first time that mosapride citrate augmented lower gastrointestinal tract motility, as shown in CTT and videomanometry, and thereby ameliorated constipation in parkinsonian patients without serious adverse effects. © 2005 Movement Disorder Society
K+ amino acid transporter KAAT1 mutant Y147F has increased transport activity and altered substrate selectivity

SUMMARY KAAT1, a K+-coupled, neutral amino acid transporter from larval insect midgut, differs from other members of the Na+:neurotransmitter transporter family (SNF) in two important ways: (1) it transports nutrient L-, α-amino acids, rather than neurotransmitters such as γ-aminobutyric acid (GABA), and (2) it accepts K+ as well as Na+ as a co-substrate. To determine whether the restoration of KAAT1 residues to their GABA transporter GAT1 cation-binding equivalents might abolish its K+ but not its Na+ recognition site, we constructed a multiple mutant in which nine divergent KAAT1 residues were mutated back to the conserved form of the superfamily. To investigate the amino-acid-binding site, we constructed several single mutants that had been identified in GAT1. Wild-type (WT) or mutant cRNA was injected into Xenopus oocytes and the effects of external amino acids and ions upon labeled leucine uptake and substrate-induced currents were examined. The multiple mutant exhibited no amino-acid-induced currents, indicating that one or more of the mutated residues are crucial for function. W75L and R76E mutations in the first transmembrane helix of KAAT1 led to results equivalent to those observed in the corresponding mutants of GAT1; namely, substrate (leucine) uptake and substrate-evoked net inward current were severely curtailed. The KAAT1 A523S mutant, which corresponds to a serotonin transporter mutant that is thought to render Li+ equivalent to Na+ as a co-transported ion, functioned no differently to WT. The effects of mutation Y147F in the third transmembrane helix of KAAT1 were dramatically different from the equivalent mutation, Y140F, in GAT1. Although kinetic characteristics, expression levels and plasma membrane localization were all similar in Y147F and WT, the Y147F mutant exhibited a sevenfold increase in labeled leucine uptake by Xenopus oocytes in Na+ buffer. This increase is in sharp contrast to the complete loss of uptake activity in the GAT1 Y140F mutant. KAAT1 Y147F also differed from WT in cation selectivity and substrate spectrum, as revealed by amino-acid-induced net inward currents that were measured with a two-electrode voltage clamp. Amino-acid-independent currents induced by Li+ and Na+ chloride salts were observed in both WT and the Y147F mutant. The Li+-induced current was 30% higher in Y147F than in WT, whereas no substrate-independent K+-induced currents above control levels were detected either in WT or Y147F. These results suggest that transport of K+, the physiological co-substrate in insect midgut, is tightly coupled to that of amino acids in KAAT1, in contrast to the independence of cation and amino acid transport in the closely related cation amino acid transporter channel, CAATCH1.
Audit Review Effectiveness in an Analytical Review Task

Ismail and Trotman (1995) examined the before and after review performance of auditors in generating hypotheses in an analytical review task. This study extends the earlier study using two additional measures of performance, namely, the inclusion of the correct-seeded error in the hypothesis set and the selection of the correct-seeded error as the most likely hypothesis. The study manipulates the existence of discussion between the reviewer and the reviewee (discussion/no discussion) and measures the rank of the reviewer (manager/senior). The results showed a general trend for the review process to improve performance on both measures used. While no significant discussion effects were found, there was evidence that the improvements from manager-reviewed groups were greater than those for senior-reviewed groups.
MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis

Background GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1, encoding β‐galactosidase. The range of severity is from type I infantile disease, lethal in early childhood, to type III adult onset, resulting in gradually progressive neurological symtpoms in adulthood. The intermediate group of patients has been recently classified as having type II late infantile subtype with onset of symptoms at one to three years of age or type II juvenile subtype with symptom onset at 2–10 years. To characterize disease severity and progression, six Late infantile and nine juvenile patients were evaluated using magnetic resonance imaging (MRI), and MR spectroscopy (MRS). Since difficulties with ambulation (gross motor function) and speech (expressive language) are often the first reported symptoms in type II GM1, patients were also scored in these domains. Deterioration of expressive language and ambulation was more rapid in the late infantile patients. Fourteen MRI scans in six Late infantile patients identified progressive atrophy in the cerebrum and cerebellum. Twenty‐six MRI scans in nine juvenile patients revealed greater variability in extent and progression of atrophy. Quantitative MRS demonstrated a deficit of N‐acetylaspartate in both the late infantile and juvenile patients with greater in the late infantile patients. This correlates with clinical measures of ambulation and expressive language. The two subtypes of type II GM1 gangliosidosis have different clinical trajectories. MRI scoring, quantitative MRS and brain volume correlate with clinical disease progression and may serve as important minimally‐invasive outcome measures for clinical trials. © 2015 Wiley Periodicals, Inc.
Bubbles and Crises: The Role of House Prices and Credit

This paper exploits a quarterly panel data set for 16 OECD countries over the period 1975q1–2013q2 to explore the importance of house prices and credit in affecting the likelihood of a financial crisis. Estimating a set of multivariate logit models, we find that booms in credit to both households and non-financial enterprises are important to account for when evaluating the stability of the financial system. In addition, we find that global housing market developments have predictive power for domestic financial stability. Finally, econometric measures of bubble-like behavior in housing and credit markets enter with positive and highly significant coefficients. Specifically, we find that the probability of a crisis increases markedly when bubble-like behavior coincides with high leverage.
Decentralization as a determinant of health care expenditure: empirical analysis for OECD countries

Territorial decentralization involves the transfer of responsibilities from a central government to lower levels of government. A common trend in different developed countries has been to decentralize some health functions (managerial and/or financial) to local governments. The set-up of the health care system and its degree of decentralization are here utilized in a panel data analysis as a determinant of health care expenditure in a sample of 20 Organization for Economic Co-operation and Development (OECD) countries for the period 1990 to 2000. These findings lend support that demographic, supply-related and socio-economic factors impact on overall health care costs and a decentralized health care setting implies higher health expenditure.
Policy Influences on Unemployment: The European Experience

This paper considers the implications of four kinds of labour market policies for the 1980s rise in European unemployment: unemployment compensation, active labour market policies, employment protection legislation and taxation. It finds evidence that all have played a role in the determination of unemployment and discusses the mechanisms involved, the extent of the influence of each and the lessons learned from this experience. One of the main findings is that there is a trade-off between wage inequality and unemployment. Policy has played a role in determining how a country responded to the negative macroeconomic shocks of the 1980s but policy alone cannot explain the full rise in European unemployment and North American wage inequality. Copyright 1999 by Scottish Economic Society.
Trouble with champions: local public sector–third sector partnerships and the future prospects for collaborative governance in the UK

In Britain, the former Labour government employed a range of collaborative governance initiatives to get public sector officers (PSOs) and third sector champions (TSCs) working together successfully. This article draws upon evidence from a series of policy seminars undertaken in a subregion of North East England to explore the strengths and weaknesses of inter- and intra-sector relationships. The article shows that PSOs' perceptions of the ‘troublesomeness’ of TSCs arise from, firstly, difficulties in communicating effectively with the third sector because of TSCs' inability to represent sector-wide interests effectively. Secondly, because many TSCs are unwilling to conform to public sector protocol, this leads to accusations of unprofessional practice. The article considers whether the perception of TSCs as troublesome can be interpreted as a convenient device when PSOs are reticent about yielding control over the delivery of public sector services to the third sector. In the context of significant reductions in public sector funding by the new coalition government, the article concludes that the landscape of partnership working and prospects for collaborative governance will change significantly – but not necessarily always to the detriment of inter-sector relationships.
Comparison of two anterior fusion methods in two-level cervical spondylosis myelopathy: a meta-analysis

Objective The aim of this study was to evaluate the efficacy and safety of anterior cervical corpectomy and fusion (ACCF) and anterior cervical discectomy and fusion (ACDF) for treating two-adjacent-level cervical spondylosis myelopathy (CSM). Design A meta-analysis of the two anterior fusion methods was conducted. The electronic databases of PubMed, the Cochrane Central Register of Controlled Trials, ScienceDirect, CNKI, WANFANG DATA and CQVIP were searched. Quality assessment of the included studies was evaluated using the Cochrane Risk of Bias Tool and the Methodological Index for Non-Randomised Studies criteria. Pooled risk ratios of dichotomous outcomes and standardised mean differences (SMDs) of continuous outcomes were generated. Using the χ2 and I2 tests, the statistical heterogeneity was assessed. Subgroup and sensitivity analyses were also performed. Participants Nine eligible trials with a total of 631 patients and a male-to-female ratio of 1.38:1 were included in this meta-analysis. Inclusion criteria Randomised controlled trials (RCTs) and non-randomised controlled trials that adopted ACCF and ACDF to treat two-adjacent-level CSM were included. Results No significant differences were identified between the two groups regarding hospital stay, the Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS) scores for neck and arm pain, total cervical range of motion (ROM), fusion ROM, fusion rate, adjacent-level ossification and complications, while ACDF had significantly less bleeding (SMD=1.14, 95% CI (0.74 to 1.53)); a shorter operation time (SMD=1.13, 95% CI (0.82 to 1.45)); greater cervical lordosis, total cervical (SMD=−2.95, 95% CI (−4.79 to −1.12)) and fused segment (SMD=−2.24, 95% CI (−3.31 to −1.17)); higher segmental height (SMD=−0.68, 95% CI (−1.03 to −0.34)) and less graft subsidence (SMD=0.40, 95% CI (0.06 to 0.75)) compared to ACCF. Conclusions The results suggested that ACDF has more advantages compared to ACCF. However, additional high-quality RCTs and a longer follow-up duration are needed.
What Works? Countermeasures to Terrorism: A Case Study of PKK

What works? This can be the ultimate question in the war on terrorism. How can we reduce and hopefully eliminate this type of human suffering? A good many ideas or suggestions are available; however, we are still uncertain what counter terrorism measures or tactics do indeed work. By using the case study method, this paper attempts to answer this question. The Turkish government has long struggled against PKK terrorism and has adopted several different policy measures to put an end to this persistent problem. This paper will examine the efforts of the Turkish government to uncover what measures indeed work and what other measures have not proven to be effective against its goal to counter terrorism. Several existing theoretical perspectives or counter terrorism suggestions will be introduced and examined in order to identify the best plausible suggestion to reduce or eliminate terrorism inherent in the Turkish case. Five different Turkish counter terrorism measures were selected and will be examined whether they indeed impacted the reduction or elimination of PKK terrorism.
Engaged Versus Disengaged Ownership: The Case of Pension Funds in the UK

Manuscript Type. Empirical. Research Question/Issue. This study examines how the practice of pension fund investment management informs the ownership behavior of pension funds vis‐a‐vis investee corporations. Research Findings/Insights. Using data from: 35 in‐depth semi‐structured interviews with pension fund trustees, executives, investment officers and financial intermediaries; documentary analysis; and observations of four fund investment meetings, we find a variation in pension fund behavior, where a very small number of well‐resourced and internally managed pension funds exhibit engaged ownership behavior. By contrast, the vast majority of pension funds operate at a considerable distance from their investee corporations having delegated pension fund investment management to a chain of external relationships involving actuaries, investment consultants, and fund managers. These relationships are laced with divergent interests and influence dynamics, which explain why these pension funds give primary emphasis to fund investment performance and display little concern for matters of ownership and corporate governance. Theoretical/Academic Implications. The “New Financial Capitalism” is characterized by ownership concentration, yet at the same time liquidity and a lack of institutional investor engagement with corporations. Findings suggest that the principal‐agent view of the relationship between institutional investors and corporate managers is more assumed than demonstrated. This widely assumed theory of investor ownership and control is shown to be contingent upon the meanings and practices that underpin investment fund management by institutions. Practitioner/Policy Implications. Shareowner engagement is proposed as a solution to problems of corporate governance. Findings about the relationships within the investment chain undermine the notions of pension funds behaving as owners and upholding corporate governance and accountability. This raises skepticism about realizing aspirations for engaged ownership and shareowner stewardship contained in institutional investors' engagement codes such as the Stewardship Code (2010) and contemporary policy debate in the UK and beyond.
Efficiency in the provision of university teaching and research: An empirical analysis of UK universities

A flexible three-output, two-input cost function model is used to examine the cost efficiency of UK universities as producers of teaching and research 'outputs'. Unlike previous studies, a comprehensive peer review of research quality is incorporated. Overall, product-specific and input-specific economies of scale, global and product-specific economies of scope, marginal costs and cost complementarities are estimated. Overall and product-specific scale results indicate considerable increasing returns, while the scope results generally suggest neither economies nor diseconomies. Sensitivity analysis is used to simulate the impact of current government policy, regarding the expansion of undergraduate teaching output, on these results. Copyright 1995 by John Wiley & Sons, Ltd.
Association of a G994 →T Missense Mutation in the Plasma Platelet-Activating Factor Acetylhydrolase Gene With Risk of Abdominal Aortic Aneurysm in Japanese

ObjectiveTo investigate a possible association with plasma platelet activating factor acetylhydrolase (PAF-AH) gene mutation with the risk of abdominal aortic aneurysm (AAA). Summary Background DataPlasma platelet activating factor acetylhydrolase is known to catalyze platelet activating factor (PAF), thereby inactivating its inflammatory function. Deficiency of this enzyme is caused by a missense mutation (G994 →T) in exon 9 of the plasma PAF-AH gene. MethodsWe did a case-control study including 131 patients (median age 73.4 [range 50–84] years) and 106 controls matched for age and sex. Genomic DNA was analyzed for the mutant allele by a specific polymerase-chain reaction. Plasma PAF-AH activity was measured in both groups. ResultsThe frequency of the mutant allele (T allele) in the plasma PAF-AH gene in AAA patients was significantly higher than in control subjects. The association of the missense mutation with AAA was statistically significant and independent of other risk factors. Among AAA patients with normal genomic type, plasma PAF-AH activity was strongly correlated to the plasma concentration of low density lipoprotein cholesterol (LDL-C), while the correlation was not observed among AAA patients with heterozygotes genotype. Patients having AAA with both T allele and hyperlipidemia were more likely to have other atherosclerotic diseases such as ischemic heart disease, stroke and peripheral arterial occlusive diseases than patients with the normal genomic type and normal lipid level. ConclusionsThe genetic mutation of plasma PAF-AH gene appear to be an independent risk factor for AAA. Our findings need to be confirmed in a larger, prospective study including patients from different populations.