Miracle-dz/UniFAR-FTUs huggingface dataset:
Identifying the specific clinical actions of amitriptyline: interrelationships of behaviour, affect and plasma levels in depression

SYNOPSIS Despite increasing knowledge of the neurochemical bases of the action of the tricyclic drugs, little is known about the sequence of psychological effects which precede recovery in drug-responsive patients. This research was aimed at identifying the specific behavioural effects associated with the therapeutic action of amitriptyline in depression. The design involved measurement (post-hoc) of weekly changes in a severely depressed placebo-resistant group who recovered with drug treatment, compared with a group of similar patients treated for the equivalent four weeks, who showed minimal to no clinical response. The research strategy, in accordance with a dose–response paradigm, was to determine which of the early changes in emotion and behaviour found in treatment responders were systematically associated with plasma concentrations of amitriptyline or its major metabolite. Amitriptyline was found to act within seven days on the components of anxiety and on hostility in the responders, and on sleep disorder in all patients. After 12 to 14 days of treatment these effects increased, with improvements in other significant components distinguishing the responders from the non-responders. At the 12th to 14th treatment days when a steady state concentration of drug in plasma was approached, reductions in anxiety and hostility and in certain somatic components correlated significantly with plasma concentrations of amitriptyline. Implications of the findings for clarifying the specificity of clinical actions of the tricyclic drugs, and for understanding the psychobiological dynamics underlying rapid drug-induced recovery in depression, were explored.
Puerarin protects differentiated PC12 cells from H2O2‐induced apoptosis through the PI3K/Akt signalling pathway

Oxidative stress has been implicated as a major mechanism underlying the pathogenesis of neurodegenerative disorders. ROS (reactive oxygen species) can cause cell death via apoptosis. NGF (nerve growth factor) differentiated rat PC12 cells have been extensively used to study the differentiation and apoptosis of neurons. This study has investigated the protective effects of puerarin in H2O2‐induced apoptosis of differentiated PC12 cells, and the possible molecular mechanisms involved. Differentiated PC12 cells were incubated with 700 μM H2O2 in the absence or presence of different doses of puerarin (4, 8 and 16 μM). Apoptosis was assessed by MTS [3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium] assay, TUNEL (terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling) analysis and Annexin V‐PI (propidium iodide) double staining flow cytometry. Protein levels of phospho‐Akt and phospho‐BAD (Bcl‐2/Bcl‐XL‐antagonist, causing cell death) were assayed by Western blotting. After stimulation with H2O2 for 18 h, the viability of differentiated PC12 cells decreased significantly and a large number of cells underwent apoptosis. Differentiated PC12 cells were rescued from H2O2‐induced apoptosis at different concentrations of puerarin in a dose‐dependent manner. This was through increased production of phospho‐Akt and phospho‐BAD, an effect that could be reversed by wortmannin, an inhibitor of PI3K (phosphoinositide 3‐kinase). The results suggest that puerarin may have neuroprotective effect through activation of the PI3K/Akt signalling pathway.
Decoupling Among CSR Policies, Programs, and Impacts: An Empirical Study

There are relatively few empirical studies on the impacts of corporate social responsibility (CSR) policies and programs. This article addresses the research gap by analyzing the incidence of, and the conditions that affect, decoupling (defined as divergence) among CSR policies, implementation of CSR programs, and CSR impacts for various environmental and social issues. Complete decoupling is a condition of full divergence among policies, programs, and impacts amounting to purely ceremonial CSR. Using ratings from a sustainability rating agency on a sample of about 1,000 large companies in 24 countries, the authors find empirical evidence not supporting a conclusion of complete decoupling. The empirical evidence suggests four levels of nondivergence in the sample. First, for most CSR issues examined, CSR policies of high quality (as measured by scope and level of detail) do have relatively strong effects on CSR implementation. Second, CSR programs of high quality (as measured by scope, the use of targets, and the use of strict deadlines) do have relatively strong effects on CSR impacts. Third, for most CSR issues, even low-quality CSR policies enforce the incidence and quality of programs in comparison with having no policy at all. Fourth, weak programs have more impact on the realization of CSR goals than having no program at all. The authors also find that the quality of CSR reporting (as measured by the implementation level of Global Reporting Initiative guidelines) and locating the responsibility for CSR at the board level reduce decoupling by strengthening the quality of CSR programs.
Annexin 1: a paracrine/juxtacrine mediator of glucorticoid action in the neuroendocrine system

Glucocorticoids (GCs) play an essential role in the maintenance of homeostasis. In normal circumstances their secretion is tightly regulated by a complex servo mechanism through which the steroids suppress the synthesis and release of ACTH and its hypothalamic releasing factors (CRH and AVP) and thereby reduce the positive drive to the adrenal cortex. The feedback actions of GCs on hormone release develop rapidly (within minutes), well before any changes in hormone synthesis are apparent. By using immunoneutralization, gene targeting and pharmacological strategies in in vivo and in vitro models, we have identified annexin 1, a Ca2+‐ and phospholipid‐binding protein, as a key mediator of the early inhibitory actions of GCs on peptide release. This brief review outlines this work and describes molecular and cellular studies which have provided insight into the mechanism of annexin 1‐dependent GC signalling in the neuroendocrine system. Copyright © 2003 John Wiley & Sons, Ltd.
Discussion of The Multiperiod Information Content of Accounting Earnings: Confirmation and Contradictions of Previous Earnings Reports

In their study, Freeman and Tse pursue a topic which has long been a central focus of accounting researchers. They ask why it is that the stock price reaction to a given amount of earnings "surprise" is not an intertemporal constant.1 The earnings persistence literature (Beaver, Lambert, and Morse [1980], Kormendi and Lipe [1987], Collins and Kothari [1989], Beaver, Lambert, and Ryan [1987], and Easton and Zmijewski [1989]) suggests that the answer rests with the degree to which the trading activity of market agents reflects a consensus that any deviations from prior expectations will be permanent. This idea is perhaps most transparently illustrated in Cornell and Landsman [1989]. Using a discounted cash flow model, Cornell and Landsman argue that information provided by an earnings announcement not only gives rise to a market forecast error of current earnings, but also a revision in market forecasts regarding future-period earnings.2 If a given level of positive (negative) "surprise" is believed to be sustainable or permanent, then the (discounted) stream of future-period "expected" earnings can be thought of as being shifted upward (downward) relative to the stream expected before the earnings release. Conversely, if the level of "surprise" is believed to be entirely transitory, then the
Modulation of Psoralen DNA Crosslinking Kinetics Associated with a Triplex‐forming Oligonucleotide

A triplex‐forming oligonucleotide (TFO), HPRT3, conjugated to a psoralen derivative, was designed to target a psoralen reaction site within the HPRT gene. HPRT3 bound with high affinity to a synthetic duplex target sequence. At a uniform UVA radiation dose, the ratio of psoralen monoadducts (MA) to interstrand crosslinks decreased and inverted with increasing TFO concentration. As the TFO concentration increased from 10 nm to 10 μm, the efficiency of psoralen MA formation remained relatively constant but the efficiency of interstrand crosslink formation increased several‐fold. Neither shortening the TFO to reduce its dissociation constant nor altering the DNA sequences flanking the TFO binding site altered the concentration dependence of MA and crosslink yields. The psoralen photokinetics associated with 10 nm HPRT3 converted to those associated with 10 μm HPRT3 with the addition of other unrelated TFOs at 10 μm that do not specifically interact with the HPRT3 target sequence. Glycerol at concentrations of 0.5% (vol/vol) or higher also mimicked high TFO concentrations in enhancing crosslink formation. These results demonstrate that while psoralen may be targeted to react at a particular sequence by TFOs, photoreactivity associated with triplex formation is also modulated by sequence‐independent factors that may affect the local macromolecular environment.
Substitution of a single amino acid residue is sufficient to allow the human amphotropic murine leukemia virus receptor to also function as a gibbon ape leukemia virus receptor

We have previously reported the unique properties of a receptor for amphotropic murine leukemia viruses (A-MuLVs) expressed on Chinese hamster E36 cells (C.A. Wilson, K.B. Farrell, and M.V. Eiden, J. Virol. 68:7697-7703, 1994). This receptor, HaPiT2 (formerly designated EAR), in contrast to the human form of the A-MuLV receptor (PiT2), functions as a receptor not only for A-MuLVs but also for gibbon ape leukemia virus (GALV). Comparison of the deduced amino acid sequences of the HaPiT2 and PiT2 proteins suggested that differences in the amino acid composition of the extracellular region(s) of the hamster and human proteins account for their functional differences. We substituted extracellular regions of HaPiT2 for those of PiT2 to map the region of the HaPiT2 protein required for GALV receptor function. Only those PiT2-HaPiT2 chimeric receptors containing the fourth and fifth extracellular regions of HaPiT2 functioned as GALV receptors. We have now determined that the substitution of a single amino acid residue, glutamic acid, for the lysine residue at position 522 in the fourth extracellular region of the PiT2 protein is sufficient to render PiT2 functional as a GALV receptor.
The role of Frizzled-4 mutations in familial exudative vitreoretinopathy and Coats disease

Aim The aim of this study is to assess the role of Frizzled-4 (FZD4) in familial exudative vitreoretinopathy (FEVR) and Coats disease. Methods Tissue samples were collected for DNA extraction and automated DNA sequencing of the two coding exons of FZD4 in both directions. Cases carrying a FZD4 mutation and demonstrating extreme disease severity were selected for direct automated sequencing of all coding exons of LRP5, NDP and TSPAN12. Clinical data were obtained for the purpose of identifying genotype–phenotype correlations. Results 68 probands were diagnosed as having autosomal dominant or sporadic FEVR. Eleven FZD4 mutations (five missense, three deletions, one insertion, two nonsense) were identified. Six of these mutations are novel, and none were found in 346 control chromosomes. In 16 cases of Coats disease, one polymorphism combination was found in two samples: no mutations were detected. No genotype–phenotype correlation emerged. Three severely affected cases with FZD4 mutations failed to show additional mutations in the three other FEVR genes. Conclusion The authors identified 12 FEVR probands with FZD4 mutations. FZD4 mutation screening can be a useful tool especially in mild or atypical cases of FEVR. Germ-line mutations in FZD4 do not appear to be a common cause of Coats disease.
Patient Preferences and Comparative Ocular Responses to Rigid and Soft Contact Lenses

Patient preferences and ocular responses were compared between rigid and soft contact lenses by randomly fitting 32 neophyte subjects with a rigid lens in 1 eye and a soft lens in the contralateral eye. Twentyseven of 32 subjects completed the 3-month study and 16 subjects were willing to continue for an additional 3-month extension. Subjects preferred the comfort and handling of the soft lens but preferred the vision provided by the rigid lens and initially its ease of maintenance. There was also a marked preference for the soft lens when all aspects of lens wear were compared. Objectively, the rigid lenses were responsible for more ocular changes than the soft lenses. Palpebral aperture sizes of the rigid gas permeable (RGP) wearing eyes decreased significantly (0.5 mm; p<0.05) compared to the soft lens wearing eyes. The incidence of corneal staining was significantly greater in the rigid lens wearing eye (50% RGP vs. 22% soft) but limbal injection was greater in the soft lens wearing eye (18% soft vs. 6% RGP). Refractive sphere, cylinder, and corneal astigmatism decreased in the rigid lens wearing eye after 3 months. This daily wear clinical trial has shown a marked subjective preference for wearing soft lenses with fewer short-term ocular effects.
Accidental overdose among injecting drug users in Dorset, UK.

AIMS To establish the prevalence and frequency of non-fatal accidental overdose among Dorset injecting drug users (IDUs), map their response to it and their beliefs about protective and risk behaviours. DESIGN Survey of a community sample of IDUs. SETTING Ten Dorset towns. PARTICIPANTS Two hundred and twelve IDUs, recruited through multisource sampling, who had injected in the 2 months before interview. MEASUREMENTS Structured interview, SDS and LDQ. FINDINGS In the previous year, 30% of interviewees had overdosed and 58% had witnessed another do so. Most (79%) had had a personal acquaintance die from an accidental overdose. Interviewees commonly attributed their own most recent overdose(s) to excessive consumption of drugs, mixing drugs and low tolerance, believed that these factors generally increased risk and described a repertoire of protective behaviours. Those who had overdosed in the previous year had significantly greater involvement with drug injecting. Virtually all who had witnessed another's overdose described peoples' attempts to help: many were appropriate, some dangerous. Avoiding seeking medical help was common. Half (52%) demonstrated the rudiments of putting people into the recovery position, and a minority (31%) cardio-pulmonary resuscitation. Most interviewees (55%) said that they would "probably" or "definitely" attend a workshop on Overdose Aid. CONCLUSIONS There is potential for preventing overdose by promoting protective behaviours. Since IDUs often witness overdose, training them in first aid may be valuable, and tackling the reasons that delay their seeking help is crucial.
Notch Signaling Influences Neuroprotective and Proliferative Properties of Mature Müller Glia

Notch signaling is known to play important roles during retinal development. Recently, Notch signaling has been shown to be active in proliferating Müller glia in acutely damaged chick retina (Hayes et al., 2007). However, the roles of Notch in mature, undamaged retina remain unknown. Thus, the purpose of this study was to determine the role of the Notch-signaling pathway in the postnatal retina. Here we show that components of the Notch-signaling pathway are expressed in most Müller glia at low levels in undamaged retina. The expression of Notch-related genes varies during early postnatal development and across regions, with higher expression in peripheral versus central retina. Blockade of Notch activity with a small molecule inhibitor before damage was protective to retinal interneurons (amacrine and bipolar cells) and projection neurons (ganglion cells). In the absence of damage, Notch is upregulated in retinas treated with insulin and FGF2; the combination of these factors is known to stimulate the proliferation and dedifferentiation of Müller glia (Fischer et al., 2002b). Inhibition of Notch signaling during FGF2 treatment reduces levels of the downstream effectors of the MAPK-signaling pathway—p38 MAPK and pCREB in Müller glia. Further, inhibition of Notch activity potently inhibits FGF2-induced proliferation of Müller glia. Together, our data indicate that Notch signaling is downstream of, and is required for, FGF2/MAPK signaling to drive the proliferation of Müller glia. In addition, our data suggest that low levels of Notch signaling in Müller glia diminish the neuroprotective activities of these glial cells.
Processivity of the Kinesin-2 KIF3A Results from Rear Head Gating and Not Front Head Gating*

Background: KIF3A/B is less processive than kinesin-1, particularly under load. Results: In an engineered KIF3A dimer, intramolecular strain in the two-head-bound state does not alter nucleotide binding. In ADP, the motor dissociates slowly from microtubules. Conclusion: KIF3A lacks front head gating and maintains processivity through weak microtubule binding. Significance: During bidirectional transport, kinesin-2 is expected to detach more readily than kinesin-1. The kinesin-2 family motor KIF3A/B works together with dynein to bidirectionally transport intraflagellar particles, melanosomes, and neuronal vesicles. Compared with kinesin-1, kinesin-2 is less processive, and its processivity is more sensitive to load, suggesting that processivity may be controlled by different gating mechanisms. We used stopped-flow and steady-state kinetics experiments, along with single-molecule and multimotor assays to characterize the entire kinetic cycle of a KIF3A homodimer that exhibits motility similar to that of full-length KIF3A/B. Upon first encounter with a microtubule, the motor rapidly exchanges both mADP and mATP. When adenosine 5′-[(β,γ)-imido]triphosphate was used to entrap the motor in a two-head-bound state, exchange kinetics were unchanged, indicating that rearward strain in the two-head-bound state does not alter nucleotide binding to the front head. A similar lack of front head gating was found when intramolecular strain was enhanced by shortening the neck linker domain from 17 to 14 residues. In single-molecule assays in ADP, the motor dissociates at 2.1 s−1, 20-fold slower than the stepping rate, demonstrating the presence of rear head gating. In microtubule pelleting assays, the KDMt is similar in ADP and ATP. The data and accompanying simulations suggest that, rather than KIF3A processivity resulting from strain-dependent regulation of nucleotide binding (front head gating), the motor spends a significant fraction of its hydrolysis cycle in a low affinity state but dissociates only slowly from this state. This work provides a mechanism to explain differences in the load-dependent properties of kinesin-1 and kinesin-2.
Revisiting the Twin Deficit Hypothesis for the Economies of Europe

This study presents empirical evidence linking the current account balance to its major determinants such as exchange rate, interest rate and budget balance in 7 of the EU member countries: Bulgaria, Greece, Ireland, Italy, Latvia, Portugal and Spain. Using the panel version of various cointegration tests, we find a long-run relationship between the current account and its determinants. The long-run coefficient of the interest rate is found statistically significant in all estimation techniques. On the other hand, weak evidence is found for the existence of the twin deficit hypothesis.
The relationship between exporting performance and the integrated effect of sustainability management R&D and marketing

The paper presents the findings of an empirical research using a sample of 59 large and important Brazilian firms with the objective to verify if environmental management practices can influence the their competitiveness in the international market. Because the sample used was constituted of Brazilian enterprises, most of them internationalized, it can be considered that the results reflects a reality that extrapolates the country borders. Using structural equations modeling techniques it was possible to conclude that the environmental corporate management when integrated with R&D and marketing promotion provides a significant, relationship with export performance. Besides these important findings some considerations regarding other relevant characteristics that can influence the competitiveness are also discussed like: the lack of support from the high level management, the existence of a very low awareness about the importance of sustainability and also the existence of a weak communication about sustainability with internal and external stakeholders. Some recommendations for future researches and for practitioners are also presented.
Macro Economic Determinants of Family Takaful Demand: Evidence from Pakistan

The family takaful business in Pakistan has experienced encouraging growth despite its infancy of been started in 2006. Annual growth rate is achieving new heights but even then less than 5% of Pakistanis are covered by family takaful since 2006 signifying that the market is still under tapped.The present research aims to identify the driving force of family takaful consumption in Pakistan using time series data for the period 2006-2013. It was found in the study that per capita income is a robust predictor of family takaful demand in Pakistan, while other macro economic factors such as interest rate, and KSE 100 index is having significant and positive relationship with takaful demand. The saving rate and inflation are having negative as well as significant relationship with takaful consumption.
Mott cell tumor of the stomach with Helicobacter pylori infection

A plasma cell tumor of the stomach with unusual histology is reported. Macroscopically, the tumor formed two ulcers in the gastric body, and microscopic examination revealed proliferation of plasma cells producing immunoglobulin G kappa monotypic immunoglobulin, with metastatic infiltration in some perigastric lymph nodes. Most of these plasma cells had various‐sized Russell bodies in the cytoplasm; hence the tumor may be called Mott cell tumor. The Russell bodies showed a strong affinity to concanavalin A by lectin immunohistochemistry, compared with those in reactive Mott cells. In addition, Helicobacter pylori (H. pylori) infection was proved by Gimenez stain and immunohistochemistry. The mixture of some centrocyte‐like cells and presence of reactive lymph follicles with follicular colonization by tumor cells suggest that this lesion may be a variant of mucosa‐associated lymphoid tissue lymphoma in association with H. pylori infection. The patient has shown no evidence of recurrence of the tumor after 11 years of follow up.