Miracle-dz/UniFAR-FTUs huggingface dataset:
Innovation and Performance: The Role of Environmental Dynamism on the Success of Innovation Choices

Innovation has become the cornerstone for achieving competitive advantage and is currently one of the principal topics of debate in the management literature. Innovations can be internally generated or can be adopted from external sources. Innovations also vary in terms of degree of radicalness. In this study, we examine the nature of innovation (in terms of where it is generated and its degree of radicalness) and an external environmental factor (dynamism) to identify the types of innovation that are more likely to succeed in different environments. Organizations expend substantial financial and human resources innovating. While some innovations succeed in enhancing organizational performance, many fail and may affect performance adversely in the short term. A sample of 381 Spanish firms was used to analyze how organizations, in order to be competitive, need to identify the appropriate type of strategies-in terms of innovation generation versus adoption, and extent of radicalness-that are consistent with the environmental conditions that they operate in. First, we find that in dynamic environments, the more radical and internally generated the innovations, the higher the company's perceived and objective performance. Second, we find that in stable environments, the less radical and more internally generated the innovations, higher the company's objective performance. Implications for theory and practice are discussed.
Impact of highly active antiretroviral therapy on hepatitis C virus protease quasispecies diversity in HIV co‐infected patients

Many hepatitis C virus (HCV)‐infected patients are also infected with HIV, and undergo antiretroviral (ARV) treatment for their human immunodeficiency virus (HIV) infection. Due to changes in HIV burden and immunologic status, HIV ARV treatment may have indirect effects on the HCV population, which could impact the effectiveness of subsequent HCV protease inhibitor (PI) treatment. The genetic variability of the protease‐encoding HCV NS3 gene was evaluated in 10 co‐infected patients initiating ARVs (both before and after ARV initiation), and compared to the genetic variability in 10 patients on stable ARV therapy. After RT‐PCR of plasma‐derived HCV RNA, a mean of 20 clones per patient time‐point were sequenced and analyzed for changes in the HCV quasispecies population. No significant differences in sequence diversity or complexity at the nucleic acid or amino acid levels were seen at baseline between groups or between the two time points in either group. HCV protease diversity in the pre‐ and post‐ARV treatment samples was not significantly different than samples from patients on stable ARV therapy. There was no significant development of amino acid substitutions known to confer HCV PI resistance in either group. Initiation of ARV for HIV infection does not significantly alter the genetic diversity or complexity of the HCV NS3 gene or result in increased number of HCV PI‐associated amino acid changes. These results suggest ARV treatment for HIV would not affect the efficacy of HCV PI treatment. J. Med. Virol. 82: 791–798, 2010. © 2010 Wiley‐Liss, Inc.
Plant traits that predict resistance to herbivores

Summary 1. Although secondary metabolites are recognized as fundamental to the defence of plants against insect and mammalian herbivores, their relative importance compared to other potential defensive plant traits (e.g. physical resistance, gross morphology, life-history, primary chemistry and physiology) are not well understood. 2. We conducted a meta-analysis to answer the question: What types of genetically variable plant traits most strongly predict resistance against herbivores? We performed a comprehensive literature search and obtained 499 separate measurements of the strength of covariation (measured as genetic correlations) between plant traits and herbivore susceptibility – these were extracted from 72 studies involving 19 plant families. 3. Surprisingly, we found no overall association between the concentrations of secondary metabolites and herbivore susceptibility – plant traits other than secondary metabolites most strongly predicted herbivore susceptibility. Specifically, genetic variation in life-history traits (e.g. flowering time, growth rate) consistently exhibited the strongest genetic correlations with susceptibility. Genetic variation in gross morphological traits (e.g. no. branches, plant size) and physical resistance traits (e.g. latex, trichomes) were also frequently correlated with variation in herbivore susceptibility, but these relationships depended on attributes of the herbivores (e.g. feeding guild) and plants (e.g. longevity). 4. These results call into question the conventional wisdom that secondary metabolites are the most important anti-herbivore defence of plants. We propose the hypothesis that herbivores select most strongly on genetic variation in life-history, morphological and physical resistance traits, but the greater pleiotropic effects of genes controlling these traits impose strong constraints on their evolution. Meanwhile, secondary metabolites could have evolved to be important defensive mechanisms not because they have the largest effect on herbivores, but because the constraints on their evolution are the weakest.
Baroreflexes and Cardiovascular Regulation in Hypertension

The primary purpose of the arterial baroreflex is to keep blood pressure close to a particular set point over a relatively short period of time. The rapid resetting of arterial baroreceptor afferents toward any sustained new level of blood pressure ensures that the reflex acts as an effective buffer of short-term blood pressure fluctuations that accompany daily life but also ensures that arterial baroreflexes play little role in setting the long-term level of blood pressure. Nevertheless, the minimization of blood pressure variability by baroreflex mechanisms is important as studies suggest that a diminished baroreflex is an independent risk factor for sudden death after myocardial infarction. In hypertensive humans and animals, the baroreflex control of heart rate is diminished. Using the steady-state method for assessment of the cardiac baroreflex in rats, we have shown that the change in baroreflex sensitivity is due to a reduction in the vagal range. Although the cardiac sympathetic component of the baroreflex is normal, the level of cardiac sympathetic activity is enhanced, particularly in young hypertensive rats. We have shown that there is a stronger inverse relationship between vagal heart rate range and levels of cardiac hypertrophy than with other variables, such as blood pressure, hypertension, or indexes of vascular hypertrophy. Treatments that reduce cardiac hypertrophy restore cardiac vagal function. Centrally acting antihypertensive agents increase the sensitivity of vagal baroreceptor heart rate reflexes, mainly through an action on central α2adrenoceptors. They also reduce cardiac sympathetic activity and diminish cardiac sympathetic baroreflexes through a non-α2adrenoceptor, possibly an imidazoline receptor mechanism. Both of these effects are beneficial in hypertension, where cardiac sympathetic function is enhanced and vagal activity is reduced. Thus, these actions would be expected to cause a desirable reduction in blood pressure variability. The effect of hypertension on baroreflex control of sympathetic vasomotor function is less clear. Studies have shown diminished, normal, and enhanced sympathetic vasomotor baroreflex control. Basal renal sympathetic drive, however, appears to be increased in human essential hypertension. Our studies in conscious rabbits have shown that rilmenidine reduces renal sympathetic baroreflex function. Rilmenidine acts principally at the level of the rostral ventrolateral medullary imidazoline receptors to markedly reduce the basal renal sympathetic nerve activity and the maximum response to transient fluctuations in blood pressure. Thus, in addition to their antihypertensive actions, centrally acting agents, such as rilmenidine, reduce cardiac and renal sympathetic baroreflex responses and increase cardiac vagal baroreflex sensitivity. This provides an ideal profile of action for the restoration of baroreflex function in addition to reversal of cardiac and vascular hypertrophy in hypertension.
Use of Bone Turnover Markers in Clinical Osteoporosis Assessment in Women: Current Issues and Future Options

Monitoring bone turnover of the adult and aging skeleton is essential for optimal treatment of bone metabolic diseases, such as postmenopausal osteoporosis. Diagnosis of osteoporosis is based solely on dual-emission x-ray absorptiometry-based measurements of bone mineral density. However, within the last 20 years, biochemical markers of bone turnover have been implemented to a larger degree, and especially within the field of drug development. Numerous clinical studies have underscored that the markers have promise in terms of predicting patients at high risk of losing bone, future fracture events and importantly also the fracture efficacy of drugs in development. Furthermore, while classical methods often require years to monitor the changes, the bone turnover markers do so within a shorter time span. The aims of this article are to provide an update on the different biochemical markers of bone turnover, and to give an overview of their applications in epidemiological and clinical research especially in women. The main emphasis will be on their utility in clinical trials testing the efficacy of drugs for the treatment of osteoporosis, and their ability to supplement bone mass measurements. Finally, recent evidence suggests that biochemical markers may provide information on bone age that may indirectly relate to bone quality, and this is discussed together with future possibilities for measuring bone quality using bone turnover markers. In summary, a more targeted use of biomarkers could assist in the identification of high-risk patients, the process of drug discovery and monitoring of the efficacy of osteoporosis treatment in clinical settings.
A novel ATP1A2 gene mutation in familial hemiplegic migraine and epilepsy

Background Familial hemiplegic migraine (FHM) is a rare autosomal dominant migraine subtype, characterized by fully reversible motor weakness as a specific symptom of aura. Mutations in the ion transportation coding genes CACNA1A, ATP1A2 and SCN1A are responsible for the FHM phenotype. Moreover, some mutations in ATP1A2 or SCN1A also may lead to epilepsy. Case Here we report on a three-generation family with five patients having a novel ATP1A2 mutation on exon 19, causing guanine-to-adenine substitution (c.2620G>A, p.Gly874Ser) that co-segregated in the five living relatives with migraine, four of whom had hemiplegic migraine. Moreover, three patients presented with epilepsy, one of whom had generalized epilepsy with febrile seizures plus (GEFS+). Conclusions The present study provides further evidence on the involvement of ATP1A2 mutations in both migraine and epilepsy, underlying the relevance of genetic analysis in families with a comorbidity of both disorders.
Depression and suicidal behaviors in medicare primary care patients under age 65

OBJECTIVE: To examine suicidal behavior and depression prevalence among a group of Medicare patients under age 65 with functional impairment and recent significant health care services use.DESIGN: An observational study of baseline characteristics of participants in a randomized controlled trial.SETTING: A Medicare demonstration (N=1,605) that enrolled primary care patients in 8 counties in New York, 6 counties in West Virginia, and 5 counties in Ohio.PATIENTS/PARTICIPANTS: All demonstration participants under age 65 (n=164). Participants were required to have impairment in at least 2 activities of daily living or 3 instrumental activities of daily living, and to have had recent significant health care use.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: The Paykel questionnaire for suicidal ideation and attempts, the Mini-international Neuropsychiatric Interview Major Depressive Episode module, and the 15-item Geriatric Depression Scale were administered at baseline; 14.8% of the patients indicated suicidal ideation during the past year, 4.9% reported a suicide attempt during that time, 25.9% indicated at least 1 lifetime suicide attempt, 34.6% had a major depressive episode in the last month, and 58.3% had clinically significant depressive symptoms during the previous week.CONCLUSIONS: These levels of suicidal ideation and behaviors and of deprssion are far higher than those found in studies of nonelderly American adults, and may indicate the need for routine screening in this population.
Neuropeptide Y mediates orexin A-mediated suppression of pulsatile gonadotropin-releasing hormone secretion in ovariectomized rats.

OBJECTIVES Reproductive functions are influenced by various feeding regulators. Orexin, which is one of orexinergic peptides, suppresses the pulsatile secretion of luteinizing hormone (LH) in bilaterally ovariectomized (OVX) rats. However, the mechanism of this effect is still not clear. To investigate whether neuropeptide Y (NPY) is involved in the orexin A-mediated suppression of pulsatile LH secretion, we evaluated the effects of NPY antibody on the suppressive effect of orexin A. METHODS Orexin A was administered intracerebroventricularly (icv) and NPY antibody (NPY-Ab) was injected before icv administration of orexin A in OVX rats. Pulsatile LH secretion was analyzed by measuring serum LH concentrations in the next 2 h in blood samples drawn at 6-min intervals by radioimmunoassay. RESULTS Administration of orexin A significantly reduced the mean LH concentration and LH pulse frequency. Co-administration of NPY antibody with orexin A significantly restored the suppressive effect of orexin A on the mean LH concentration and LH pulse frequency. CONCLUSION NPY mediated the suppressive effect of intracerebroventricularly injected orexin A on pulsatile LH secretion, suggesting that hypothalamic orexin suppressed pulsatile gonadotropin-releasing hormone (GnRH) secretion via NPY in the hypothalamus of female rats.
Phospholipid Synthesis in Sindbis Virus-Infected Cells

We investigated the metabolic requirements for the decrease in phospholipid synthesis previously observed by Pfefferkorn and Hunter in primary cultures of chick embryo fibroblasts infected with Sindbis virus. The incorporation of 32PO4 into all classes of phospholipids was found to decline at the same rate and to the same extent; thus, incorporation of 14C-choline into acid-precipitable form provided a convenient measure of phospholipid synthesis that was used in subsequent experiments. Experiments with temperature-sensitive mutants suggested that some viral ribonucleic acid (RNA) synthesis was essential for the inhibition of choline incorporation, but that functional viral structural proteins were not required. The reduction in phospholipid synthesis was probably a secondary effect of infection resulting from viral inhibition of the cellular RNA and protein synthesis. All three inhibitory effects required about the same amount of viral RNA synthesis; the inhibition of host RNA and protein synthesis began sooner than the decline in phospholipid synthesis; and both actinomycin D and cycloheximide inhibited 14C-choline incorporation in uninfected cells. In contrast, incorporation of 14C-choline into BHK-21 cells was not decreased by 10 hr of exposure to actinomycin D and declined only slowly after cycloheximide treatment. Growth of Sindbis virus in BHK cells did not cause the marked stimulation of phospholipid synthesis seen in picornavirus infections of other mammalian cells; however, inhibition was seen only late in infection.
Highly Potent Antidiuretic Antagonists: Conformational Studies of Vasopressin Analogues Modified with 1‐Naphthylalanine Enantiomers at Position 2

In this paper, we investigated the structure–activity relationship of two vasopressin analogues, [Cpa1,(L‐1‐Nal)2]AVP (I) and [Cpa1,(D‐Nal)2]AVP (II) by NMR spectroscopy and molecular modeling. Both peptides exhibit antioxytocic and antipressor potency. Inversion of configuration of the residue at position 2 converted a weak antidiuretic agonist (peptide I) into a highly potent antidiuretic antagonist (peptide II). For this reason, the purpose of our study was to explain the causes of different interactions of the analogues with V2 receptors. The results have shown that both analogues display the tendency to adopt β‐turns in the 1–4 and 2–5 fragments, which is characteristic of OT and V1a receptors antagonists. In addition, the [Cpa1,(L‐1‐Nal)2]AVP (I) shows the propensity to assume β‐turn at position 7,8, which is believed to enhance antidiuretic activity, although not being crucial for its appearance. Moreover, the C‐terminal amide group seems to be crucial for signal transduction. Its high accessibility in [Cpa1,(L‐1‐Nal)2]AVP (I) in contrast to [Cpa1,(D‐1‐Nal)2]AVP (II), probably results in V2 receptor activation.
Cortical excitability in hereditary motor neuronopathy with pyramidal signs: comparison with ALS

Background: Distal hereditary motor neuronopathy with pyramidal features (dHMNP) is a hereditary neurodegenerative disorder characterised by the presence of upper and lower motor neuron signs. The pathophysiological mechanisms underlying these clinical findings remain elusive. Given that cortical hyperexcitability appears to underlie neurodegeneration in amyotrophic lateral sclerosis (ALS), a disorder that may clinically resemble dHMNP, the present study applied novel cortical excitability studies to further investigate the pathophysiological mechanisms in dHMNP. Methods: Threshold tracking transcranial magnetic stimulation (TMS) studies were undertaken using a 90 mm circular coil. Peripheral nerve excitability was performed by stimulating the median nerve at the wrist, with recording made over the abductor pollicis brevis muscle. Studies were undertaken in six dHMNP and 52 ALS patients, and compared with 55 normal controls. Results: Central motor conduction time (CMCT) was significantly prolonged in dHMNP (dHMNP 7.7 (SEM 0.7) ms; ALS 4.9 (0.3) ms; controls 5.1 (0.2) ms, p<0.01). Short interval intacortical inhibition (SICI) was significantly reduced in ALS patients (0.8 (0.8)%) when compared with dHMNP (6.4 (0.7)%, p<0.0001) and controls (8.6 (1.1)%, p<0.0001). Reduction in SICI was accompanied by significant increases in the magnetic stimulus–response curve gradient and intracortical facilitation, and reduction in cortical silent period duration in ALS, while all these parameters of cortical excitability were normal in dHMNP. Conclusions: The present study has established a prolonged CMCT and normal cortical excitability in dHMNP, thereby providing further support for the hypothesis that cortical hyperexcitability underlies neurodegeneration in ALS.
Typical Electronic Health Record Use in Primary Care Practices and the Quality of Diabetes Care

PURPOSE Recent efforts to encourage meaningful use of electronic health records (EHRs) assume that widespread adoption will improve the quality of ambulatory care, especially for complex clinical conditions such as diabetes. Cross-sectional studies of typical uses of commercially available ambulatory EHRs provide conflicting evidence for an association between EHR use and improved care, and effects of longer-term EHR use in community-based primary care settings on the quality of care are not well understood. METHODS We analyzed data from 16 EHR-using and 26 non–EHR-using practices in 2 northeastern states participating in a group-randomized quality improvement trial. Measures of care were assessed for 798 patients with diabetes. We used hierarchical linear models to examine the relationship between EHR use and adherence to evidence-based diabetes care guidelines, and hierarchical logistic models to compare rates of improvement over 3 years. RESULTS EHR use was not associated with better adherence to care guidelines or a more rapid improvement in adherence. In fact, patients in practices that did not use an EHR were more likely than those in practices that used an EHR to meet all of 3 intermediate outcomes targets for hemoglobin A1c, low-density lipoprotein cholesterol, and blood pressure at the 2-year follow-up (odds ratio = 1.67; 95% CI, 1.12–2.51). Although the quality of care improved across all practices, rates of improvement did not differ between the 2 groups. CONCLUSIONS Consistent use of an EHR over 3 years does not ensure successful use for improving the quality of diabetes care. Ongoing efforts to encourage adoption and meaningful use of EHRs in primary care should focus on ensuring that use succeeds in improving care. These efforts will need to include provision of assistance to longer-term EHR users.
Long‐term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis

Summary Background Therapy with fumaric acid esters (FAE) has been shown to be safe and effective in patients with severe psoriasis in several clinical studies with limited follow‐up periods. In view of the chronic character of psoriasis, long‐term safety aspects are of major importance in determining the suitability of a drug during prolonged periods of treatment.
MDA-7 regulates cell growth and radiosensitivity in vitro of primary (Non-Established) human glioma cells

We examined the impact of purified bacterially synthesized GST-MDA-7 (IL-24) and ionizing radiation on the proliferation and survival of non-established human glioblastoma multiforme (GBM) cells. Glioma cell types expressing mutated PTEN and p53 molecules, activated ERBB1VIII, over-expressing wild type ERBB1 or without receptor over-expression were selected. In MTT assays, GST-MDA-7 caused a dose-dependent reduction in the proliferation of non-established glioma cells; however only at higher concentrations did GST-MDA-7 reduce cell viability. The anti-proliferative and cytotoxic effects of GST-MDA-7 were enhanced by radiation in a greater than additive fashion that correlated with JNK1/2/3 activation. The reduction in cell growth and enhancement in cell killing by the combination of GST-MDA-7 and radiation were blocked by an ROS scavenger, N-acetyl cysteine (NAC), a JNK1/2/3 inhibitor SP600125, a pan-caspase inhibitor (zVAD) and by an inhibitor of caspase 9 (LEHD), but not by an inhibitor of caspase 8 (IETD). Low concentrations of either GST-MDA-7 or radiation reduced clonogenic survival, however colony formation ability was significantly further decreased when the two treatments were combined, which was also blocked by inhibition of caspase 9 function. In general agreement with activation of the intrinsic caspase pathway, cell death correlated with reduced BCL-XL expression and with increased levels of the pro-apoptotic proteins BAD and BAX. Inhibition of caspase 9 after combination treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD and BAX, but did block caspase 3 cleavage, reduced expression of BCL-XL and inhibition of ERK1/2 activity. In contrast, incubation with NAC blocked JNK1/2/3 activation and cell killing, but not the increases in BAD and BAX expression. These findings argue that after combination treatment JNK1/2/3 activation is a primary pro-apoptotic event and loss of BCL-XL expression and ERK1/2 activity are secondary caspase-dependent processes. This data also argues that GST-MDA-7 induces two parallel pro-apoptotic pathways via ROS-dependent and -independent mechanisms. Infection of primary human astrocytes with a recombinant adenovirus to express MDA-7, Ad.mda-7, but not infection with either Ad.cmv or Ad.mda-7SP- lacking MDA-7 secretion, resulted in the suppression of GBM cell colony formation in soft agar overlay assays, an effect that was enhanced in a greater than additive fashion by radiation. Collectively, our findings demonstrate that MDA-7 reduces proliferation and enhances the radiosensitivity of non-established human GBM cells in vitro, and when grown in 3 dimensions, and that sensitization occurs independently of basal EGFR / ERK1/2 / AKT activity or the functions of PTEN and p53.