Miracle-dz/UniFAR-FTUs huggingface dataset:
Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer's Disease Treatment Studies.

OBJECTIVE It is well established that regional cerebral metabolic rates for glucose assessed by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with Alzheimer's disease in the mental resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index of Alzheimer's disease dementia. Few studies, however, have evaluated longitudinal declines in regional cerebral glucose metabolism in patients with dementia caused by Alzheimer's disease. In addition, the available studies have not used recently developed brain mapping algorithms to characterize the progression of Alzheimer's disease throughout the brain, and none considered the statistical power of regional cerebral glucose metabolism in testing the ability of treatments to attenuate the progression of dementia. METHOD The authors used FDG PET and a brain mapping algorithm to investigate cross-sectional reductions in regional cerebral glucose metabolism, longitudinal decline in regional cerebral glucose metabolism after a 1-year follow-up, and the power of this method to evaluate treatments for Alzheimer's disease in patients with mild to moderate dementia. PET scans were initially acquired in 14 patients with Alzheimer's disease and 34 healthy comparison subjects of similar age and sex. Repeat scans were obtained in the patients 1 year later. Power analyses for voxels showing maximal decline over the 1-year period in regional cerebral glucose metabolism (mg/100 g per minute) were computed to estimate the sample sizes needed to detect a significant treatment response in a 1-year, double-blind, placebo-controlled treatment study. RESULTS The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. Using maximal glucose metabolism reductions in the left frontal cortex, we estimated that as few as 36 patients per group would be needed to detect a 33% treatment response with one-tailed significance of p</=0.005 and 80% power in a 1-year, double-blind, placebo-controlled treatment study. CONCLUSIONS These findings indicate that brain metabolism as assessed by FDG PET during mental rest is a sensitive marker of disease progression in Alzheimer's disease over a 1-year period. These findings also support the feasibility of using FDG PET as an outcome measure to test the ability of treatments to attenuate the progression of Alzheimer's disease.
Staff injuries after patient–staff incidences in psychiatric acute wards

The aim of the study was to describe the pattern of injuries to various body parts in patient–staff incidents; 507 patient–staff incidents in a psychiatric acute ward during the period 1990–1997 were included. Staff members registered 193 injuries in the head, 112 in the trunk, 265 in the upper extremities and 69 in the lower extremities. No differences between the two sexes or between different levels of education among the nurses were found in the pattern of injuries. Doctors were more often injured in the head and less often injured in the upper extremity than the nurses. The head was more often injured when there was no understandable provocation before the incident and seldom injured when the patients were denied something. Injuries to the trunk were more frequently followed by use of parenteral medication. Parenteral medication and holding the patient with force were more frequently used in incidents where more than one body part was injured. The knowledge of injures after patient–staff incidences may contribute to the education and protective training of the staff of psychiatric acute wards.
A Formal Approach to Modeling the Cost of Cognitive Control

This paper introduces a formal method to model the level of demand on control when executing cognitive processes. The cost of cognitive control is parsed into an intensity cost which encapsulates how much additional input information is required so as to get the specified response, and an interaction cost which encapsulates the level of interference between individual processes in a network. We develop a formal relationship between the probability of successful execution of desired processes and the control signals (additive control biases). This relationship is also used to specify optimal control policies to achieve a desired probability of activation for processes. We observe that there are boundary cases when finding such control policies which leads us to introduce the interaction cost. We show that the interaction cost is influenced by the relative strengths of individual processes, as well as the directionality of the underlying competition between processes.
Evaluation of Ki-67 index in EUS–FNA specimens for the assessment of malignancy risk in pancreatic neuroendocrine tumors

Background and study aim: Malignancy in pancreatic neuroendocrine tumors (PNETs) is graded by assessing the resected specimens according to the World Health Organization (WHO) 2010 criteria. The feasibility of such grading using endoscopic ultrasound-guided fine-needle aspiration (EUS–FNA) specimens remains unclear. The aim of this study was to ascertain the optimal method of measuring the Ki-67 index in EUS–FNA specimens, using resected specimens as the criterion standard. Patients and methods: A total of 58 consecutive patients diagnosed with PNETs between March 1998 and May 2011 were included. The study measured intratumoral Ki-67 index heterogeneity, concordance rates of PNET grading by EUS–FNA with grade of the resected tumor, optimal method of measuring the Ki-67 index in EUS–FNA specimens, and survival analysis based on EUS–FNA specimen grading. Results: Intratumoral dispersion of Ki-67 index in resected specimens was 0.033 for Grade 1 and 0.782 for Grade 2 tumors (P < 0.001). Concordance rates for WHO classification between EUS–FNA and resected specimens were 74.0 % using the mean Ki-67 index in EUS–FNA specimens and 77.8 % using the highest Ki-67 index. The concordance rate rose to 90 % when EUS–FNA samples with less than 2000 tumor cells were excluded (26 % of EUS–FNA cases). The Kaplan–Meier survival curves were significantly stratified by the EUS–FNA grading of PNETs with 5-year survival rates of 100 %, 58.3 %, and 0 %, for Grade 1, Grade 2, and neuroendocrine carcinoma (NEC) tumors, respectively. Conclusions: Grading of PNETs by the highest Ki-67 index in EUS–FNA specimens with adequate cellularity has a high concordance with grading of resected specimens, and can predict long term patient survival with high accuracy.
A novel assessment of peripheral tissue microcirculatory vasoreactivity using vascular occlusion testing during cardiopulmonary bypass.

OBJECTIVE Cardiac surgery and cardiopulmonary bypass are associated with release of inflammatory mediators and microcirculatory alterations that result in organ dysfunction. Near-infrared spectroscopic measurement of tissue oxygen saturation (StO2) and the vascular occlusion test (VOT) were utilized in a study of elective cardiac surgical patients as a novel, noninvasive method of assessing microcirculatory vasoreactivity during nonpulsatile cardiopulmonary bypass (CPB). The objective of this pilot study was to determine whether differences in microcirculatory function and vasoreactivity could be measured in cardiac surgery using StO2 and VOT. DESIGN A prospective, observational trial. SETTING Tertiary care teaching hospital. PARTICIPANTS Thirteen patients undergoing elective cardiac surgery using tepid, nonpulsatile cardiopulmonary bypass. INTERVENTIONS Patients had continuous regional oxygen saturation monitoring using near-infrared spectroscopy and vascular occlusion tests performed in the perioperative period before, during, and after cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS Occlusion slope and hyperemic area did not vary significantly. Mean reperfusion slope was significantly lower during cardiopulmonary bypass (2.4%/second) compared to before and after bypass (4.1 and 3.5%/second, respectively). Reperfusion slope decreased as a function of CPB duration. CONCLUSIONS This pilot study demonstrates a significant difference in reperfusion slopes during cardiopulmonary bypass when compared to prebypass and postbypass, suggesting impaired peripheral microvascular reactivity. Reperfusion slopes also exhibited a successive decline with duration of CPB, implying worsening microcirculatory dysfunction that returned to baseline values in all patients within 1 hour of separation from CPB. This noninvasive technique has potential to optimize circulatory parameters during cardiopulmonary bypass.
A two‐dimensional continuum model of biofilm growth incorporating fluid flow and shear stress based detachment

We present a two‐dimensional biofilm growth model in a continuum framework using an Eulerian description. A computational technique based on the eXtended Finite Element Method (XFEM) and the level set method is used to simulate the growth of the biofilm. The model considers fluid flow around the biofilm surface, the advection–diffusion and reaction of substrate, variable biomass volume fraction and erosion due to the interfacial shear stress at the biofilm–fluid interface. The key assumptions of the model and the governing equations of transport, biofilm kinetics and biofilm mechanics are presented. Our 2D biofilm growth results are in good agreement with those obtained by Picioreanu et al. (Biotechnol Bioeng 69(5):504–515, 2000). Detachment due to erosion is modeled using two continuous speed functions based on: (a) interfacial shear stress and (b) biofilm height. A relation between the two detachment models in the case of a 1D biofilm is established and simulated biofilm results with detachment in 2D are presented. The stress in the biofilm due to fluid flow is evaluated and higher stresses are observed close to the substratum where the biofilm is attached. Biotechnol. Bioeng. 2009;103: 92–104. © 2008 Wiley Periodicals, Inc.
A randomized, multicenter, controlled trial using intravenous pulses of methylprednisolone in the initial treatment of simple forms of giant cell arteritis: a one year followup study of 164 patients.

OBJECTIVE (1) To evaluate the corticosteroid sparing effect of an initial intravenous (i.v.) pulse of methylprednisolone (MP) in the treatment of simple forms of giant cell arteritis (GCA). (2) To analyze corticosteroid response, steroid related side effects, and GCA complications. METHODS Patients received a 240 mg i.v. pulse of MP followed by 0.7 mg/kg/day oral prednisone (Group 1) or 0.7 mg/kg/day prednisone without an i.v. pulse (Group 2, controls), or a 240 mg i.v. pulse of MP followed by 0.5 mg/kg/day prednisone (Group 3). Corticosteroid dosage was reduced after normalization of 2 biological inflammatory variables to obtain half-dosage after 4 weeks in Groups 1 and 2 and 20 mg/day after 2 weeks in Group 3. Tapering was systematically attempted from the 6th month of treatment. RESULTS One hundred sixty-four patients were included in the trial (1992-96). Cumulative doses of corticosteroids after one year were identical for all groups (p = 0.39). No significant differences were observed in the time required for normalization of C-reactive protein, corticosteroid resistance (13.5%), and corticosteroid related side effects (39% of patients; p = 0.37). Corticosteroid resistant patients received larger doses and showed a high risk of GCA related complications (p = 0.02). CONCLUSION MP pulses have no significant longterm, corticosteroid sparing effects in the treatment of simple forms of GCA and should be limited to complicated forms. Moreover, corticosteroid resistance is a real risk factor for GCA complications.
Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma

Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. DOI: http://dx.doi. org/10.7554/eLife.10483. 001
Analysis of the binding mode of laulimalide to microtubules: Establishing a laulimalide–tubulin pharmacophore

Laulimalide (LA) is a microtubule-stabilizing agent, currently in preclinical studies. However, studying the binding of this species and successfully synthesizing potent analogues have been challenging. The LA binding site is located between tubulin protofilaments, and therefore LA is in contact with two adjacent -tubulin units. Here, an improved model of the binding mode of LA in microtubules is presented, using the newly available crystal structure pose and an extended tubulin heterodimer complex, as well as molecular dynamics simulations. With this model, a series of LA analogues developed by Mooberry and coworkers are also analyzed in order to establish important pharmacophores in LA binding and cytotoxicity. In the side chain, – interactions are important contributors to LA binding, as are water-mediated hydrogen bonds. An intramolecular hydrogen bond is correlated with high cytotoxicity, and is dependent on macrocycle conformation. Therefore, while the epoxide and olefin groups in the macrocycle do not engage in specific interactions with the protein, they are essential contributions to an active macrocycle conformation, and therefore potency. Calculations reveal that a balance in binding affinity is important for LA activity, where the more potent compounds have larger interactions with the adjacent tubulin unit than the less-active analogs. Several modifications are suggested for the rational design of LA analogues that should not disrupt the active macrocycle conformation.
Food-Related Gastrointestinal Symptoms in the Irritable Bowel Syndrome

Background/Aims: Postprandial symptoms are common in patients with irritable bowel syndrome (IBS). However, existing studies have come to different conclusions about the role of food in the pathophysiology of IBS. We explored the prevalence of subjective food-related gastrointestinal (GI) symptoms and its relationship to clinical characteristics and psychological factors in IBS. Methods: 330 patients with IBS and 80 healthy volunteers completed a food questionnaire developed for this study. The subjects graded their subjective symptoms after 35 different foods and a food score was obtained by adding the item scores. The relationship between subjective food-related GI symptoms and referral status, IBS subgroup (predominant bowel pattern), sex, anxiety, depression and body mass index (BMI) was estimated. Results: In 209 (63%) of the patients the GI symptoms were related to meals. Gas problems and abdominal pain were the most frequently reported symptoms. Foods rich in carbohydrates, as well as fatty food, coffee, alcohol and hot spices were most frequently reported to cause symptoms. The food score was higher in patients than in controls (p < 0.0001). In the IBS group higher scores were observed in patients with anxiety (p = 0.005), and females (p < 0.001), but the results were unrelated to IBS subgroup, referral status or BMI. The BMI did not differ between groups. Conclusion: A majority of IBS patients consider their symptoms to be related to meals. Especially foods rich in carbohydrates and fat cause problems. Nevertheless, the majority of IBS patients are normal or overweight. Female sex and anxiety predict a high degree of food-related symptoms in IBS.
Favorable prognosis of renal cell carcinoma with increased expression of chemokines associated with a Th1‐type immune response

The potential role of chemokines in clinical tumors remains poorly understood. Recent investigations have shown the differential expression of chemokine receptors on lymphocytes mediating Th1‐ and Th2‐type immune responses. We examined Th1‐ and Th2‐associated cytokines and chemokines, as well as the expression of their receptors in tumor‐infiltrating lymphocytes in renal cell carcinoma (RCC). Sixty‐seven patients with sporadic RCC were analyzed for the expression of Th1‐ and Th2‐associated genes using real‐time polymerase chain reaction. Tumor infiltration by CXC chemokine receptor 3 (CXCR3)‐positive and CC chemokine receptor 5 (CCR5)‐positive cells was detected by immunohistochemistry and by flow cytometry. The expression of Th1‐associated genes was significantly increased in tumors compared to normal kidney tissues. The expression of interferon‐γ correlated positively with that of Th1 chemokines. Tumors expressing higher Th1 chemokines did not recur after curative surgery. Multivariate analysis showed that increased monokine induced by interferon (IFN)‐γ (MIG) expression was an independent favorable prognostic factor. Immunohistochemistry showed that the degree of CXCR3‐positive cell infiltration significantly correlated with IFN‐γ inducible protein 10, MIG and IFN‐γ‐inducible T cell a chemoattractant expression (I‐TAC). Flow cytometric analysis showed increased expression of CXCR3 and CCR5 in tumor‐infiltrating T lymphocytes compared to that in peripheral blood T cells. These results suggest that upregulation of the Th1‐type immune response in RCC tumors with a favorable prognosis may be mediated by Th1‐associated chemokines. Integrity of the Th1‐type immune response seems to be required for tumor regression, suggesting that detection and correction of a defect in the Th1‐type response cascade would thus be one of the main targets for tailor‐made immunotherapy and gene therapy in RCC. (Cancer Sci 2006; 97: 780–786)
Contribution of bradykinin and nitric oxide to AT2 receptor‐mediated differentiation in PC12 W cells

We investigated the effect of angiotensin II on intracellular cyclic GMP content and neurite outgrowth as an indicator of cell differentiation in PC12 W cells. Neurite outgrowth was examined by phase‐contrast microscopy. Outgrown neurites were classified as small, medium and large, and were expressed as neurites per 100 cells. Angiotensin II (10−7 m) increased the outgrowth of medium and large neurites by mean ± SEM 20.2 ± 2.3 and 6.6 ± 1.4 compared with 1.66 ± 0.5 and 0.1 ± 0.06 neurites per 100 cells in control. Cellular cyclic GMP content increased by 50–250% with angiotensin II at concentrations of 10−6–10−4 m. Both blockade of AT2 receptors and of nitric oxide synthase markedly reduced angiotensin II‐induced neurite outgrowth and cyclic GMP production. In contrast, B2 receptor blockade had no effect or even increased these angiotensin II effects. Sodium nitroprusside and 8‐bromo‐cyclic GMP both mimicked the effects of angiotensin II on cell differentiation. The protein kinase G inhibitor KT‐5823 inhibited the neurite outgrowth induced by both angiotensin II and 8‐bromo‐cyclic GMP. Our results demonstrate that angiotensin II can stimulate cell differentiation in PC12 W cells by nitric oxide‐related and cyclic GMP‐dependent mechanisms. The effects of angiotensin II on cell differentiation and cyclic GMP production were mediated via the AT2 receptor and further enhanced by bradykinin B2 receptor blockade.
Identification and Initial Characterization of Four Novel Members of the Interleukin-1 Family*

Interleukin-1 (IL-1), fibroblast growth factors (FGFs), and their homologues are secreted factors that share a common β-barrel structure and act on target cells by binding to cell surface receptors with immunoglobulin-like folds in their extracellular domain. While numerous members of the FGF family have been discovered, the IL-1 family has remained small and outnumbered by IL-1 receptor homologues. From expressed sequence tag data base searches, we have now identified four additional IL-1 homologues, IL-1H1, IL-1H2, IL-1H3, and IL-1H4. Like most other IL-1/FGFs, these proteins do not contain a hydrophobic leader sequence. IL-1H4 has a propeptide sequence, while IL-1H1, IL-1H2, and IL-1H3 encode only the mature protein. Circular dichroism spectra and thermal stability analysis suggest that IL-1H1 folds similarly to IL-1ra. The novel homologues are not widely expressed in mammals. IL-1H1 is constitutively expressed only in placenta and the squamous epithelium of the esophagus. However, IL-1H1 could be inducedin vitro in keratinocytes by interferon-γ and tumor necrosis factor-α and in vivo via a contact hypersensitivity reaction or herpes simplex virus infection. This suggests that IL-1H1 may be involved in pathogenesis of immune mediated disease processes. The addition of four novel IL-1 homologues suggests that the IL-1 family is significantly larger than previously thought.
Cultural Proximity: A Source of Trade Flow Resilience?

While the significant influence of cultural proximity on bilateral trade flows has been extensively documented in the literature, its possible role in times of crisis has not yet been raised. Relying on a panel estimation of a gravity model incorporating cultural proximity parameters, we evidence the existence of a significant surge in the impact of the different components of cultural proximity during economic recession. The trade resilience among countries sharing a cultural bond is not a pure composition effect as it also appears within product categories. To understand this unexpected effect, we discuss different mechanisms that emphasize the potential mitigating influence of cultural proximity on some determinants of the trade collapse, namely the uncertainty shock, the increased moral hazard and the emergence of ethnocentric preferences.
Including smoking status as a new vital sign: it works!

BACKGROUND Despite the adverse health consequences of smoking, many physicians still neglect to counsel smokers to quit. This study evaluated the effect of including smoking status as a vital sign on the frequency of physician discussions with patients about smoking and physician advice to quit smoking. METHODS A consecutive sample of adult ambulatory patients in our metropolitan family practice residency program completed exit surveys on physician and nurse counseling about smoking. Control group data were collected for 1 month before the change was made to include smoking status as a vital sign on patient charts. Charts were then marked with a stamp as a chart prompt in the vital signs section. Data were collected for 2 months after smoking status was added to the stamp. RESULTS There were 637 individuals surveyed, of whom 179 were current smokers; 95 in the "prestamp" group and 84 in the "poststamp" group. The percentage of patient-physician encounters during which smoking was discussed increased from 47% to 86% (P < .001). Physician advice to quit increased from 50% to 80% (P < .001). Physician discussion of smoking with patients increased across all of the five stages of change but most dramatically (53% to 95%) in the "preparation" stage. Physicians were much less likely to counsel patients in the "precontemplation" stage to quit smoking. CONCLUSIONS Including smoking as a new vital sign significantly increased the likelihood of smoking-related discussions between patients and their physicians. The stamp is inexpensive and easy to use, and because it is a one-time office system change, it is more likely to be implemented and maintained in busy practices.