Miracle-dz/UniFAR-FTUs huggingface dataset:
Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long‐term follow‐up of a randomized clinical trial

We have previously demonstrated that hydroxyurea (HU) reduces the rate of vascular complications in patients with essential thrombocythaemia (ET) at high risk of thrombosis. However, the relatively short follow‐up (median 27 months) did not enable the evaluation of the risk of developing secondary malignancies. In this study, we report the long‐term outcome of the 114 patients included in the trial: 56 patients randomized to receive HU and 58 patients to receive no cytoreductive therapy. Before randomization, 15 patients had been treated with busulphan. During the observation period, 29 patients (50%) shifted from the control to the HU group mainly because of thrombosis. Median follow‐up was 73 months (range 3–94). Analysis was by intention to treat and, when indicated, by treatment.
An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease.

RATIONALE Although cigarette smoking is the most important cause of chronic obstructive pulmonary disease (COPD), a substantial proportion of COPD cases cannot be explained by smoking alone. OBJECTIVES To evaluate the risk factors for COPD besides personal cigarette smoking. METHODS We constituted an ad hoc subcommittee of the American Thoracic Society Environmental and Occupational Health Assembly. An international group of members was invited, based on their scientific expertise in a specific risk factor for COPD. For each risk factor area, the committee reviewed the literature, summarized the evidence, and developed conclusions about the likelihood of it causing COPD. All conclusions were based on unanimous consensus. MEASUREMENTS AND MAIN RESULTS The population-attributable fraction for smoking as a cause of COPD ranged from 9.7 to 97.9%, but was less than 80% in most studies, indicating a substantial burden of disease attributable to nonsmoking risk factors. On the basis of our review, we concluded that specific genetic syndromes and occupational exposures were causally related to the development of COPD. Traffic and other outdoor pollution, secondhand smoke, biomass smoke, and dietary factors are associated with COPD, but sufficient criteria for causation were not met. Chronic asthma and tuberculosis are associated with irreversible loss of lung function, but there remains uncertainty about whether there are important phenotypic differences compared with COPD as it is typically encountered in clinical settings. CONCLUSIONS In public health terms, a substantive burden of COPD is attributable to risk factors other than smoking. To prevent COPD-related disability and mortality, efforts must focus on prevention and cessation of exposure to smoking and these other, less well-recognized risk factors.
Structural complexity of phonological systems

In the linguistic tradition, including phonology, complexity has often been evoked when looking for explanatory arguments (a given phenomenon is rarer because it is more complex than another) or looking for a balance of complexity within subsystems of a language, or directly comparing and ranking several languages according to a linguistic dimension (for a review, see Chitoran and Cohn, and Pellegrino et al. this volume). In this perspective, the concept of complexity is intrinsically relative and necessarily yields to judging something as more or less complex than something else regarding a particular property or even globally. Thus, anyone involved in the enterprise of evaluating phonological complexity faces the tricky issue of, as a first step, defining a set of (phonological) properties and for each property defining a scale of complexity. Then, and only then, is one able to start comparing the phonological complexity of the chosen phonological elements. In that perspective, “to be complex” or not is a (possibly gradient) quality assigned to a particular set of elements. This task is all but straightforward. If choosing the set of properties can be quite simple, characterising them with a scale of complexity is much trickier. Moreover, as one tries to combine several properties of an element to evaluate its overall complexity, the issue of weighting these different dimensions can easily lead to a dead end. In this regard, Maddieson (this volume), is very insightful and presents an excellent summary of where to find and how to define phonological complexity, as well as the limits of this notion. Interestingly, an alternative conception of complexity has developed for a half-century, stemming from cybernetics, systems theory and systems dynamics (e.g. Abraham, 2001 for an epistemological view). First found in statistical physics, biology and computer science, it has rapidly proven relevant within the field of humanities and social sciences and it is now definitively associated with the notion of “complex system”. In that framework, a system is or is not complex according to whether its structure and behaviour satisfies particular characteristics. The picture is thus substan-
ABCA1 Is Required for Normal Central Nervous System ApoE Levels and for Lipidation of Astrocyte-secreted apoE*

ABCA1 is an ATP-binding cassette protein that transports cellular cholesterol and phospholipids onto high density lipoproteins (HDL) in plasma. Lack of ABCA1 in humans and mice causes abnormal lipidation and increased catabolism of HDL, resulting in very low plasma apoA-I, apoA-II, and HDL. Herein, we have used Abca1-/- mice to ask whether ABCA1 is involved in lipidation of HDL in the central nervous system (CNS). ApoE is the most abundant CNS apolipoprotein and is present in HDL-like lipoproteins in CSF. We found that Abca1-/- mice have greatly decreased apoE levels in both the cortex (80% reduction) and the CSF (98% reduction). CSF from Abca1-/- mice had significantly reduced cholesterol as well as small apoE-containing lipoproteins, suggesting abnormal lipidation of apoE. Astrocytes, the primary producer of CNS apoE, were cultured from Abca1+/+, +/-, and -/- mice, and nascent lipoprotein particles were collected. Abca1-/- astrocytes secreted lipoprotein particles that had markedly decreased cholesterol and apoE and had smaller apoE-containing particles than particles from Abca1+/+ astrocytes. These findings demonstrate that ABCA1 plays a critical role in CNS apoE metabolism. Since apoE isoforms and levels strongly influence Alzheimer's disease pathology and risk, these data suggest that ABCA1 may be a novel therapeutic target.
An antigen specific to the liver stage of rodent malaria recognized by a monoclonal antibody

Summary Vaccines currently being evaluated against malaria are based on proteins derived from the blood, sporozoite and sexual stages. Antigens from the liver stage, which is now recognized as the major target of protective sporozoite induced immunity, have received comparatively little attention. This paper describes the generation of a monoclonal antibody (MoAb), which recognizes an antigen specific to the liver stage of the rodent malaria Plasmodium berghei. The antigen is expressed throughout liver stage development and appears to be localized to the parasitophorous vacuole membrane. The MoAb did not affect the growth of liver stages cultured in vitro nor could protection be demonstrated in vivo following passive transfer of the antibody.
MMP-2 and MMP-9 Increase the Neurite-Promoting Potential of Schwann Cell Basal Laminae and Are Upregulated in Degenerated Nerve

Compared to degenerated nerves, the ability of normal adult peripheral nerve to support axonal regeneration is poor and may be attributed to the inhibition of endoneurial laminin by chondroitin sulfate proteoglycan (CSPG). In cryoculture assays, neuritic growth of neonatal and adult peripheral neurons was increased on sections of normal nerve by pretreatment with CSPG-degrading enzymes, including the matrix metalloproteinases MMP-2 and MMP-9. Axonal regeneration is known to occur within the Schwann cell basal laminae of degenerated nerve. Similarly, deconvolution microscopy revealed that neuritic growth on nerve tissue sections occurred principally on the lumenal surface of enzymatically modified basal laminae. Compared to normal nerve, there was a marked increase in the neurite-promoting activity of the degenerated nerve, and this activity was not increased significantly by subsequent MMP treatment. Additionally, the expression and activation of MMP-2 and MMP-9 were elevated in degenerated nerve, suggesting that degradation of inhibitory CSPG by the MMPs contributes to the growth-promoting properties of degenerated nerve.
Motivational interviewing and cognitive behaviour therapy for anxiety following traumatic brain injury: A pilot randomised controlled trial

Although cognitive-behavioural therapy (CBT) is the treatment of choice for anxiety, its delivery needs to be adapted for individuals with traumatic brain injury (TBI). It also requires clients' active engagement for maximum benefit. This study was a pilot randomised controlled trial involving an anxiety treatment programme adapted for people with TBI, based on CBT and motivational interviewing (MI). Twenty-seven participants with moderate/severe TBI (aged 21–73 years, 78% males) recruited from a brain injury rehabilitation hospital were randomly allocated to receive MI + CBT (n = 9), non-directive counselling (NDC) + CBT (n = 10) and treatment-as-usual (TAU) (n = 8). CBT and MI were manualised and delivered in 12 weekly individual sessions. Primary outcome was self-reported anxiety symptoms assessed at baseline, at the end of NDC/MI and immediately following CBT. Assessment was conducted by assessors blinded to group assignment. Intention-to-treat analyses showed that the two active treatment groups demonstrated significantly greater anxiety reduction than TAU. Participants receiving MI showed greater response to CBT, in terms of reduction in anxiety, stress and non-productive coping, compared to participants who received NDC. The results provided preliminary support for the adapted CBT programme, and the potential utility of MI as treatment prelude. Longer follow-up data are required to evaluate the maintenance of treatment effects.
The Analgesic Potency of Dexmedetomidine Is Enhanced After Nerve Injury: A Possible Role for Peripheral alpha2-Adrenoceptors

This study investigated the analgesic potency and site of action of systemic dexmedetomidine, a selective alpha2-adrenoceptor (alpha2 AR) agonist, in normal and neuropathic rats. Ligation of the L5-6 spinal nerves produced a chronic mechanical and thermal neuropathic hyperalgesia in rats. von Frey fibers and a thermoelectric Peltier device were used to measure mechanical and heat withdrawal thresholds over the hindpaw. Systemic dexmedetomidine dose-dependently increased the mechanical and thermal thresholds in the control animals (50% effective dose [ED50] 144 and 180 [micro sign]g/kg intraperitoneally [IP], respectively). Neuropathic animals responded to much smaller doses of dexmedetomidine with mechanical and thermal ED50 values of 52 and 29 [micro sign]g/kg IP, respectively. There was no difference between the control and neuropathic animals with respect to dexmedetomidine-evoked sedation, as determined by decreased grid crossings in an open-field activity chamber (ED50 12 and 9 [micro sign]g/kg IP, respectively). Atipamezole, a selective alpha2 AR antagonist, blocked the analgesic and sedative actions of dexmedetomidine in both the neuropathic and control animals. However, L-659,066, a peripherally restricted alpha2 AR antagonist, could only block the analgesic actions of dexmedetomidine in the neuropathic rats, with no effect in control animals. In conclusion, nerve injury enhanced the analgesic but not the sedative potency of systemic dexmedetomidine and may have shifted the site of alpha2 analgesic action to outside the blood-brain barrier. Implications: We tested the analgesic efficacy of the alpha2 agonist dexmedetomidine in normal and nerve-injured rats. The analgesic potency of dexmedetomidine was enhanced after nerve injury with a site of action outside the central nervous system. Peripherally restricted alpha2 agonists may be useful in the management of neuropathic pain. (Anesth Analg 1998;87:941-8)
Treatment of intrahepatic malignancy with radiofrequency ablation

Radiofrequency (RF)‐induced tissue coagulation represents a new approach for the thermal destruction of tumors within the liver. The purpose of the current study was to 1) assess technique safety; 2) determine the extent and evolution of induced cellular damage; and 3) correlate the observed pathologic effects with radiologic studies.
Agomelatine: a new opportunity to reduce neuropathic pain—preclinical evidence

Abstract Antidepressants are first-line treatments of neuropathic pain but not all these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect norepinephrine release. Melatonin, serotonin, and norepinephrine have been involved in the pathophysiology of neuropathic pain. Yet, no study has been conducted to determine agomelatine effects on neuropathic pain in animal models. Using 3 rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, we investigated the antihypersensitivity effect of acute and repeated agomelatine administration. We then determined the influence of melatonergic, 5-HT2C, &agr;-2 and &bgr;-1/2 adrenergic receptor antagonists in the antihypersensitivity effect of agomelatine. The effect of the combination of agomelatine + gabapentin was evaluated using an isobolographic approach. In STZ and CCI models, single doses of agomelatine significantly and dose dependently reduced mechanical hypersensitivity. After daily administrations for 2 weeks, this effect was confirmed in the CCI model and agomelatine also displayed a marked antihypersensitivity effect in the OXA model. The antihypersensitivity effect of agomelatine involved melatonergic, 5-HT2C, and &agr;-2 adrenergic receptors but not beta adrenoceptors. The isobolographic analysis demonstrated that the combination of agomelatine + gabapentin had additive effects. Agomelatine exerts a clear-cut antihypersensitivity effect in 3 different neuropathic pain models. Its effect is mediated by melatonergic and 5-HT2C receptors and, although agomelatine has no affinity, also by &agr;-2 adrenergic receptors. Finally, agomelatine combined with gabapentin produces an additive antihypersensitivity effect.
Developmental and growth factor-induced regulation of nestin in oligodendrocyte lineage cells

The expression and regulation of nestin, an intermediate filament protein associated with neuroepithelium-derived progenitor cells, was studied in developing oligodendrocytes. We analyzed glial cells cultured from late embryonic rat cerebral cortex, tissue prints from neonatal rat brains, and the oligodendrocyte cell line CG-4. Using cortical- or CG-4-derived oligodendrocyte lineage cells, Northern blot analysis demonstrated that nestin mRNA was highly expressed in proliferating O-2A progenitors, but downregulated in differentiated oligodendrocytes. Immunocytochemistry of cultured cells and tissue prints demonstrated that pre-O-2A cells and O-2A progenitors expressed high levels of the nestin protein. In contrast, nestin expression decreased during the pro-oligodendroblast stage, and the majority of oligodendrocytes were not labeled with anti-nestin antibodies. Culture conditions (PDGF+bFGF or B104-conditioned medium) that maintained O-2A progenitor proliferation and prevented differentiation enhanced expression of nestin mRNA transcripts and protein. In comparison, analysis of cortical astrocyte cultures demonstrated that type 1 astrocytes, but not type 2, expressed nestin mRNA and protein. Our findings demonstrate that nestin is expressed in developing glial cells, which is suggestive that this intermediate filament protein may play an important role during gliogenesis.
OSCE checklists do not capture increasing levels of expertise.

PURPOSE To evaluate the effectiveness of binary content checklists in measuring increasing levels of clinical competence. METHOD Fourteen clinical clerks, 14 family practice residents, and 14 family physicians participated in two 15-minute standardized patient interviews. An examiner rated each participant's performance using a binary content checklist and a global process rating. The participants provided a diagnosis two minutes into and at the end of the interview. RESULTS On global scales, the experienced clinicians scored significantly better than did the residents and clerks, but on checklists, the experienced clinicians scored significantly worse than did the residents and clerks. Diagnostic accuracy increased for all groups between the two-minute and 15-minute marks without significant differences between the groups. CONCLUSION These findings are consistent with the hypothesis that binary checklists may not be valid measures of increasing clinical competence.
Alterations in Monocyte Phenotypes and Functions after a Hip Fracture in Elderly Individuals: A 6-Month Longitudinal Study

Background: Healthy elderly individuals are particularly prone to catastrophic events at any moment of their lives. One stressful event for individuals aged 65 and older is a fall that results in a fracture of the hip (HF). HF causes a state of inflammation that may affect immune responses. In this connection, we have reported that HF induced alterations in neutrophil functions. Objective: To assess the impact of HF on classical (cM), intermediate (iM) and non-classical (ncM) monocyte subsets. Methods: Distribution, functions (chemotaxis, phagocytosis, superoxide production and cytokine production), phenotype and activation (NF-κB and PI3K) were evaluated in monocyte subsets before surgery and 6 weeks and 6 months after the event. Results: The distribution of cM and ncM was unchanged, but iM transiently increased before surgery. Sustained increases (iM response to CCL2 and CX3CL1) and decreases (cM and ncM response to CCL2) in chemotaxis were observed. Phagocytosis and superoxide production were impaired in cM but not in iM or ncM. Sustained expression of HLA-DR occurred in cM but not in iM and ncM. Sustained decreased expression of CD11b occurred only in ncM. Sustained decreases (cM and ncM) and increases (iM) in CCR2 expression were observed. An elevated expression of CX3CR1 was found only in iM. cM produced elevated quantities of TNFα. There was a transient oxidative burst of production before surgery in iM and a sustained decrease in ncM. IL-10 production was severely impaired in cM and decreased in iM prior to surgery. Sustained activation (cM), inhibition (ncM) and transient activation (iM) of NF-κB were observed. Activation of PI3K was severely impaired in cM and ncM but was sustained in iM. Conclusion: HF had more impact on cM and ncM functions than on iM. HF triggered a switch in cM functions from phagocytic to inflammatory elevated TNFα-producing cells. These changes may impact clinical outcomes of HF with respect to inflammation, opportunistic infections and physical recovery.
Genetic control of susceptibility to carcinogen-induced colorectal cancer in mice: The Ccs3 and Ccs5 loci regulate different aspects of tumorigenesis

Colorectal cancer (CRC) is a multistep disease that involves a two-way interaction between a complex genetic pre-disposition component, and a set of poorly understood extrinsic environmental factors. In mice, CRC can be induced by treatment with azoxymethane (AOM). Using a set of AcB/BcA recombinant congenic strains derived from CRC-susceptible A/J and CRC-resistant C57Bl/6J (B6) progenitors, we previously detected the Ccs3 locus (colon cancer susceptibility locus 3) as a major regulator of CRC susceptibility. Phenotyping of additional AcB/BcA strains for susceptibility to AOM-induced CRC has refined the Ccs3 interval to a 6.7 Mb segment on chromosome 3. In addition, the presence of intermediate susceptibility phenotypes in individual AcB/BcA strains suggested additional gene effects regulating CRC susceptibility in A/J and B6 strains. Those were investigated by linkage analysis and whole genome scanning in a set of 208 informative (B6 x A/J)F2 progeny, using tumor multiplicity as a quantitative measure of susceptibility. This analysis validated the important role of Ccs3 in regulating this trait, and additionally detected contribution from a second locus on the distal portion of chromosome 9 (LOD = 3.76), that was given the temporary designation of Ccs5. Ccs5 modulates tumor multiplicity in F2 animals bearing at least one A/J-derived susceptibility allele at Ccs3, with A/J-derived Ccs5 susceptibility alleles being inherited in a recessive manner. There is a strong additive effect of Ccs3 and Ccs5 on tumor multiplicity in F2 mice: mice doubly homozygotes for A/J or B6 alleles at Ccs3 and Ccs5 show tumor numbers similar to those of parental A/J and B6, respectively. Interestingly, the Ccs5 region overlaps several quantitative trait loci previously reported to regulate intestinal homeostasis and susceptibility to intestinal colitis in mice and humans. Our findings identify a novel two-locus system regulating CRC susceptibility in mice, of which the relevance to human CRC can now be tested experimentally.
Motivations and postsecondary aspirations in a technical college dual enrollment program

Students enrolled in a dual enrollment program in a technical college in Georgia were surveyed in an attempt to measure their postsecondary motivations and aspirations and to determine the relationship between the two. The study also sought to examine demographic factors that might be related to changes in postsecondary aspirations for dual enrollment participants. Participants answered an initial and final survey as well as responded to journal questions at the beginning, in the middle, and at the end of the term. Both quantitative and qualitative methods were used to arrive at the conclusion that while there is some evidence that dual enrollment can impact students’ aspirations; the current study design was unable to definitively show a causal relation between dual enrollment and college aspirations. INDEX WORDS: Dual Enrollment, Motivation, Postsecondary Aspirations, Technical College MOTIVATIONS AND POSTSECONDARY ASPIRATIONS IN A TECHNICAL COLLEGE DUAL ENROLLMENT PROGRAM
Cysteine Oxidation of Tau and Microtubule-associated Protein-2 by Peroxynitrite

Alterations in the redox status of proteins have been implicated in the pathology of several neurodegenerative conditions including Alzheimer and Parkinson diseases. We report that peroxynitrite- and hydrogen peroxide-induced disulfides in the neuron-specific microtubule-associated proteins tau and microtubule-associated protein-2 are substrates for the ubiquitous thioredoxin reductase system composed of thioredoxin reductase, human or Escherichia coli thioredoxin, and NADPH. Tau and microtubule-associated protein-2 cysteine oxidation and reduction were quantitated by monitoring the incorporation of 5-iodoacetamidofluorescein, a thiol-specific labeling reagent. Cysteine oxidation of tau and microtubule-associated protein-2 to disulfides altered the ability of the proteins to promote the assembly of microtubules from purified porcine tubulin. Treatment of tau and microtubule-associated protein-2 with either the thioredoxin reductase system or small molecule reductants fully restores the ability of the MAPs to promote microtubule assembly. Thus changes in the redox state of microtubule-associated proteins may regulate microtubule polymerization in vivo.